WO2009114729A2

WO2009114729A2 - Compounds, compositions and methods for treating lysosomal storage diseases and disorders

Info

Publication number: WO2009114729A2
Application number: PCT/US2009/037020
Authority: WO
Inventors: Peter G. Schultz; Sassan Azarian
Original assignee: IRM LLC
Current assignee: IRM LLC
Priority date: 2008-03-14
Filing date: 2009-03-12
Publication date: 2009-09-17
Anticipated expiration: 2010-09-14
Also published as: WO2009114729A3

Abstract

Provided herein are lysosomotropic agents, composition and methods used to treat lysosomal-storage diseases, including ophthalmic conditions associated with the overproduction of waste products that accumulate during the course of phototransduction.

Description

COMPOUNDS, COMPOSITIONS AND METHODS FOR TREATING LYSOSOMAL STORAGE DISEASES AND DISORDERS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority under 35 U. S. C. §119(e) to U.S. Provisional Patent Application No. 61/036,603, filed March 14, 2008 , the disclosure of which is incorporated herein by reference in its entirety and for all purposes.

FIELD OF THE INVENTION

[0002] The invention relates to compounds, compositions and methods for the treatment of lysosomal-storage diseases and disorders.

BACKGROUND OF THE INVENTION

[0003] Lysosomal-storage diseases (LSDs) are a group of genetically inherited disorders that result in defective lysosomal function. The characteristics associated with LSDs are often neurological, but can also be multisystemic, with skeletal, central nervous system (CNS), cardiovascular and ocular system involvement. Macular degeneration is a group of eye diseases that can cause blindness. In particular, age-related macular degeneration or dystrophy, a particularly debilitating disease, leads to gradual loss of vision and eventually severe damage to the central vision.

SUMMARY OF THE INVENTION

[0004] Provided herein are compounds, compositions and methods for treating lysosomal- storage diseases.

[0005] One aspect provided herein is pharmaceutical compositions for treating a lysosomal-storage disease, wheein the pharmaceutical composition comprises a therapeutically effective amount of a lysosomotropic agent and optionally a pharmaceutically acceptable excipient. Another aspect provided herein is pharmaceutical compositions for reducing the concentration of a toxic metabolite in a lysosome, wherein the toxic metabolite is associated with a lysosomal-storage disease and the pharmaceutical compositions comprises an effective amount of a lysosomotropic agent and optionally a pharmaceutically acceptable carrier.

[0006] In certain embodiments of such pharmaceutical compositions, the lysosomal- storage disease is selected from Tay-Sachs disease, Batten Disease, Krabbe Disease, Pompe disease, Gaucher Disease, Mucopolysacchiradosis I (MPS I/Hurler/Hurler- Scheie/Scheie), Mucopolysacchiradosis II (MPS II/Hunter Disease), Fabry Disease, leukodystrophies, Niemann-Pick Disease, Stargardt's Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration. In certain embodiments of such pharmaceutical compositions, the the lysosomal-storage disease is a macular degeneration disease. In other embodiments, the macular degeneration disease is selected from Stargardt's Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration.

[0007] A further aspect provided herein is pharmaceutical compositions for reducing the concentration of N-retinylidene-N-retinylethanolamine (A2E) in an eye of a mammal, wherein the pharmaceutical compositions comprises an effective amount of a lysosomotropic agent and optionally a pharmaceutically acceptable carrier. Another aspect provided herein is pharmaceutical compositions for reducing the concentration of lipofusion in an eye of a mammal comprising an effective amount of a lysosomotropic agent and optionally a pharmaceuticall acceptable carrier. Another aspect provided herein is pharmaceutical compositions for treating dry form age-related macular degeneration in an eye of a mammal comprising an effective amount of a lysosomotropic agent and optionally a pharmaceutically acceptable carrier.

[0008] In certain embodiments of the pharmaceutical compositions provided herein, the lysosomotropic agent is selected from chlorpromazine, LysoTracker® green (7-(3-(2- (dimethylamino)ethylamino)- 3 -oxopropyl) -5,5 -difluoro- 1 , 3 -dimethyl-2 , 5 -dihydro- 1 H- dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5-uide), LysoTracker® red (7-(3-(2- (dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-3-(lH-pyrrol-2-yl)-2,5-dihydro-lH- dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5-uide), amantadine, 4-aminoquinoline, amiodarone, amodiaquine, azithromycin, chloroquine, clindamycin, N-(3-[(2,4- dinitrophenyl)-amino]-propyl)-N-(3-aminopropyl-methylamine)dihydrochloride (DAMP), imipramine, methylamine, monensin, monodansylcadaverine, NH₄Cl, perhexilene, phenylalanine methyl ester, primaquine, quinacrine, suramin, thioridazine, tilorone, tributylamine, and ketotifen fumarate.

[0009] In other embodiments of the pharmaceutical compositions provided herein, the pharmaceutical compositions further comprises a compound selected from the group consisting of fenretinide, an inducer of nitric oxide production, an antioxidant, an antiinflammatory agent, a mineral, an anti-oxidant, a carotenoid, a negatively charged phospholipid and a statin. In other embodiments of the pharmaceutical compositions provided herein, the pharmaceutical compositions further comprise fenretinide.

[00010] Another apect provided herein is medicaments for treating a lysosomal-storage disease, wherein the medicament comprises a therapeutically effective amount of a lysosomotropic agent. A further aspect provided herein is the use of a lysosomotropic agent in the manufacture of a medicament for treating a lysosomal-storage disease.

[00011] In certain embodimenst of the medicaments provided herein, the lysosomal- storage disease is selected from Tay-Sachs disease, Batten Disease, Krabbe Disease, Pompe disease, Gaucher Disease, Mucopolysacchiradosis I (MPS I/Hurler/Hurler- Scheie/Scheie), Mucopolysacchiradosis II (MPS II/Hunter Disease), Fabry Disease, leukodystrophies, Niemann-Pick Disease, Stargardt's Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration. In other embodiments of such medicaments, the lysosomal-storage disease is a macular degeneration disease. In certain embodiments the macular degeneration disease is selected from Stargardt's Disease, Cone- Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration.

[00012] In certain embodiments of the medicaments provided herein, the lysosomotropic agent is selected from chlorpromazine, LysoTracker® green (7-(3-(2- (dimethylamino)ethylamino)- 3 -oxopropyl) -5,5 -difluoro- 1 , 3 -dimethyl-2 , 5 -dihydro- 1 H- dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5-uide), LysoTracker® red (7-(3-(2- (dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-3-(lH-pyrrol-2-yl)-2,5-dihydro-lH- dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5-uide), amantadine, 4-aminoquinoline, amiodarone, amodiaquine, azithromycin, chloroquine, clindamycin, N-(3-[(2,4- dinitrophenyl)-amino]-propyl)-N-(3-aminopropyl-methylamine)dihydrochloride (DAMP), imipramine, methylamine, monensin, monodansylcadaverine, NH₄Cl, perhexilene, phenylalanine methyl ester, primaquine, quinacrine, suramin, thioridazine, tilorone, tributylamine, and ketotifen fumarate. In certain embodiments of the medicaments provided herein, the medicament further comprises a compound selected from the group consisting of fenretinide, an inducer of nitric oxide production, an antioxidant, an anti-inflammatory agent, a mineral, an anti-oxidant, a carotenoid, a negatively charged phospholipid and a statin. In othern embodiments of the medicaments provided herein, the medicaments further comprise fenretinide.

[00013] Another aspect provided herein are methods for treating a lysosomal-storage disease comprising administering to a subject in need thereof, a therapeutically effective amount of a lysosomotropic agent, thereby treating the lysosomal-storage disease.

[00014] In certain embodiments of such methods the lysosomal-storage disease is selected from Tay-Sachs disease, Batten Disease, Krabbe Disease, Pompe disease, Gaucher Disease, Mucopolysacchiradosis I (MPS I/Hurler/Hurler-Scheie/Scheie), Mucopolysacchiradosis II (MPS II/Hunter Disease), Fabry Disease, leukodystrophies, Niemann-Pick Disease, Stargardt's Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration. [00015] In certain embodiments of such methods, the lysosomotropic agent is selected from:

Acridine orange: N,N,N',N'-tetramethylacridine-3,6-diamine; CAS Registry No. 494-38-2

1 - adamantanamine : N,N-dimethyladamantan-l -amine; CAS Registry No. 768-94-5

Amantadine: adamantan-1 -amine; CAS Registry No. 665-66-7

4- aminoquinoline : quinolin-4-amine; CAS Registry No. 578-68-7

Amiodarone: (2-butylbenzofuran-3-yl)-[4-(2-diethylaminoethoxy)-3,5-diiodo- phenyljmethanone; CAS Registry No. 1951-25-3

Amodiaquine: 4 -[(7-chloroquinolin-4-yl)amino]-2-(diethylaminomethyl)phenol; CAS Registry No. 86-42-0 Azithromycin: (2R,3R,4R,5R,8R,10R,l lR,13S,14R)-ll-[(2S,3R,4S,6R)-4-dimethylamino-3- hydroxy-6-methyl-oxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13- [(2S,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-oxan-2-yl]oxy- 3,5,6,8,10,12,14-heptamethyl-l-oxa-6-azacyclopentadecan-15-one dehydrate; CAS Registry No. 117772-70-0; 4-benzoyl-oxi-2-azetidinove: (4-oxoazetidin-2-yl) benzoate; CAS Registry No. 28562-58-5

Chloroquine: N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-l,4-diamine; CAS Registry No. 54-05-7 Chlorpromazine : 3-(2-chloro- 10H-phenothiazin- 10-yl)-N,N-dimethyl-propan- 1-amine; CAS Registry No. 50-53-3 Citalopram: l-(3-dimethylaminopropyl)-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-5- carbonitrile; CAS Registry No. 59729-33-8 Clindamycin: (2S,4R)-N-[2-chloro-l-[(2R,3S,4S,5R,6R)-3,4,5-trihydroxy-6-methylsulfanyl- oxan-2-yl]propyl]-l-methyl-4-propyl-pyrrolidine-2-carboxamide; CAS Registry No. 24696-19-3

Clomipramine: 3-(3-chloro-10,ll-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan- 1-amine; CAS Registry No. 303-49-1

DAMP: N-(3-[(2,4-dinitrophenyl)-amino]-propyl)-N-(3-aminopropyl- methylamine)dihydrochloride,

Fluoxetine: N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-propan- 1-amine; CAS Registry No. 54910-89-3 Flupentixol: 2-[4-[3-[2-(trifluoromethyl)thioxanthen-9-ylidene] propyl]piperazin-l- yljethanol; CAS Registry No. 2709-56-0 Fluphenazine: 2-[4-[3-[2-(trifluoromethyl)-10H-phenothiazin-10-yl]propyl]-piperazin-l- yljethanol; CAS Registry No. 69-23-8 Haloperidol: 4- [4-(4-chlorophenyl)-4-hydroxy- 1 -piperidyl] - 1 -(4-fluorophenyl)-butan- 1 - one; CAS Registry No. 52-86-8 Hydroxizine: 2-[2-[4-[(4-chlorophenyl)-phenyl-methyl]piperazin-l-yl]ethoxy]ethanol; CAS

Registry No. 68-88-2 Hydroxychloriquine sulfate: 2-[ { 4- [(7-chloroquinolin-4-yl)amino]pentyl } (ethyl)amino]ethanol;

CAS Registry No. 118-42-3 Imipramine: 3-(5,6-dihydrobenzo[b][l]benzazepin-l l-yl)-N,N-dimethylpropan-l-amine;

CAS Registry No. 50-49-7; ketotifen fumarate: 4-(l-methylpiperidin-4-ylidene)-4,9-dihydro-10H-benzo[4,5]cyclohepta[l,2- b]thiophen-10-one; CAS Registry No. 34580-14-8 Levomepromazine: (2R)-3-(2-Methoxyphenothiazine-10-yl-)-N,N,2-trimethylpropanamine; CAS

Registry No. 60-99-1 LysoTracker® green: 7-(3-(2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-l,3-dimethyl-

2,5-dihydro-lH-dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5-uide; CAS

Registry No. 220524-71-0, LysoTracker® red: 7-(3-(2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-3-(lH-pyrrol-

2-yl)-2,5-dihydro-lH-dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5-uide;

CAS- No. 231946-72-8 Meclofenoxate: 2-dimethylaminoethyl 2-(4-chlorophenoxy)acetate; CAS Registry No. 51-68-

3 Mesoridazine: 10-{2-[(RS)l-Methylpiperidin-2-yl]ethyl}- 2-methylsulfinyl- 10H- phenothiazine; CAS Registry No. 5588-33-0 Methylamine: methanamine; CAS Registry No. [74-89-5]

Monensin: 4-[2-[5-ethyl-5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyl-oxan-2-yl]-3- methyl-oxolan-2-yl]oxolan-2-yl]-9-hydroxy-2,8-dimethyl-l,6- dioxaspiro[4.5]dec-7-yl]-3-methoxy-2-methyl-pentanoic acid; CAS Registry

No. 22373-78-0 Monodansylcadaverine: N-(5-aminopentyl)-5-(dimethylamino)naphthalene-l-sulfonamide;

CAS Registry No. 10121-91-2

NH₄Cl, azanium chloride; CAS Registry No. 12125-02-9

Nile Blue A: [9-(diethylamino)benzo[a]phenoxazin-5-ylidene]azanium sulfate;

Perhexilene: 2-(2,2-dicyclohexylethyl)piperidine; CAS Registry No. 6621-47-2

Perphenazine: 2-[4-[3-(2-chloro-10H-phenothiazin-10-yl) propyl]piperazin-l-yl]ethanol;

CAS Registry No. 58-39-9 phenylalanine methyl ester: methyl (2S)-2-amino-3-phenyl-propanoate hydrochloride; CAS

Registry No. 2577-90-4

Piperazine: Piperazine; CAS Registry No. 110-85-0 primaquine: N-(6-methoxyquinolin-8-yl)pentane-l,4-diamine; CAS Registry No. 491-92-9

Prochlorperazine : 2-chloro- 10- [3-(4-methyl- 1 -piperazinyl)propyl] - 1 OH-phenothiazine; CAS

Registry No. 58-38-8 Promazine: N,N-dimethyl-3-(10H-phenothiazin-10-yl) propan-1- amine; CAS Registry No.

58-40-2 Propranolol: l-(isopropylamino)-3-(naphthalen-l-yloxy)propan-2-ol; CAS Registry No.

525-66-6 Suramin: 8-[[4-methyl-3-[[3-[[3-[[2-methyl-5-[(4,6,8-trisulfonaphthalen-l- y^carbamoyllphenyllcarbamoyllphenyllcarbamoylaminolbenzoyllaminolbenz oyl]amino]naphthalene-l,3,5-trisulfonic acid; CAS Registry No. 145-63-1;

Thioridazine: 10-{2-[(RS)-l-Methylpiperidin-2-yl]ethyl}-2-methylsulfanyl-phenothiazine;

CAS Registry No. 50-52-2

Tributylamine: N,N-dibutylbutan-l -amine; CAS Registry No. 6309-30-4

Trifluoperazine: 10-[3-(4-methylpiperazin-l-yl)propyl]-2-(trifluoromethyl)-10H-phenothiazine;

CAS Registry No. 117-89-5

Triflupromazine: N,N-dimethyl-3-[2-(trifluoromethyl)- 10H-phenothiazin-10-yl]-propan-l- amine; CAS Registry No. 146-54-3

[00016] In certain embodiments of such methods, the method further comprises the administration a second compound selected from the group consisting of fenretinide, an inducer of nitric oxide production, an antioxidant, an anti-inflammatory agent, a mineral, an anti-oxidant, a carotenoid, a negatively charged phospholipid and a statin.

[00017] In certain embodiments of such methods, the lysosomal-storage disease is a macular degeneration disease. In certain embodiments of such methods, the macular degeneration disease is selected from Stargardt's Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy,

Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration.

[00018] In certain embodiments of such methods, the subject is a human subject, while in other embodiments the subject is an animal subject.

[00019] Another aspect provided herein are methods for reducing the concentration of a toxic metabolite in a lysosome comprising administering of an effective amount of a lysosomotropic agent thereby reducing the concentration of the toxic metabolite in the lysosome, and wherein the toxic metabolite is associated with a lysosomal-storage disease.

[00020] In certain embodiments of such methods, the lysosomal-storage disease is selected from Tay-Sachs disease, Batten Disease, Krabbe Disease, Pompe disease, Gaucher Disease,

Mucopolysacchiradosis I (MPS I/Hurler/Hurler-Scheie/Scheie), Mucopolysacchiradosis II (MPS

II/Hunter Disease), Fabry Disease, leukodystrophies, Niemann-Pick Disease, Stargardt's Disease,

Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best

Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration.

[00021] In certain embodiments of such methods, the lysosomotropic agent is selected from

1-adamantanamine: N,N-dimethyladamantan-l -amine; CAS Registry No. 768-94-5 Amantadine: adamantan-1 -amine; CAS Registry No. 665-66-7 4- aminoquinoline : quinolin-4-amine; CAS Registry No. 578-68-7 Amiodarone: (2-butylbenzofuran-3-yl)-[4-(2-diethylaminoethoxy)-3,5-diiodo- phenyljmethanone; CAS Registry No. 1951-25-3

Amodiaquine: 4 -[(7-chloroquinolin-4-yl)amino]-2-(diethylaminomethyl)phenol; CAS

Registry No. 86-42-0 Azithromycin: (2R,3R,4R,5R,8R,10R,l lR,13S,14R)-ll-[(2S,3R,4S,6R)-4-dimethylamino-3- hydroxy-6-methyl-oxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-

[(2S,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-oxan-2-yl]oxy-

3,5,6,8,10,12,14-heptamethyl-l-oxa-6-azacyclopentadecan-15-one dehydrate;

CAS Registry No. 117772-70-0;

4-benzoyl-oxi-2-azetidinove: (4-oxoazetidin-2-yl) benzoate; CAS Registry No. 28562-58-5 Chloroquine: N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-l,4-diamine;

CAS Registry No. 54-05-7 Chlorpromazine: 3-(2-chloro- 10H-phenothiazin- 10-yl)-N,N-dimethyl-propan- 1-amine; CAS

Registry No. 50-53-3 Citalopram: l-(3-dimethylaminopropyl)-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-5- carbonitrile; CAS Registry No. 59729-33-8 Clindamycin: (2S,4R)-N-[2-chloro-l-[(2R,3S,4S,5R,6R)-3,4,5-trihydroxy-6-methylsulfanyl- oxan-2-yl]propyl]-l-methyl-4-propyl-pyrrolidine-2-carboxamide; CAS

Registry No. 24696-19-3 Clomipramine: S-CS-chloro-lOJl-dihydro-SH-dibenzo^fJazepin-S-yO-N^-dimethylpropan-

1-amine; CAS Registry No. 303-49-1 DAMP: N-(3-[(2,4-dinitrophenyl)-amino]-propyl)-N-(3-aminopropyl- methylamine)dihydrochloride, Fluoxetine: N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-propan- 1-amine; CAS

Registry No. 54910-89-3 Flupentixol: 2-[4-[3-[2-(trifluoromethyl)thioxanthen-9-ylidene] propyl]piperazin-l- yljethanol; CAS Registry No. 2709-56-0 Fluphenazine: 2-[4-[3-[2-(trifluoromethyl)-10H-phenothiazin-10-yl]propyl]-piperazin-l- yljethanol; CAS Registry No. 69-23-8 Haloperidol: 4- [4-(4-chlorophenyl)-4-hydroxy- 1 -piperidyl] - 1 -(4-fluorophenyl)-butan- 1 - one; CAS Registry No. 52-86-8 Hydroxizine: 2-[2-[4-[(4-chlorophenyl)-phenyl-methyl]piperazin-l-yl]ethoxy]ethanol; CAS

2,5-dihydro-lH-dipyrrolo[l,2-c:r,2'-f][l,3,2]diazaborinin-4-ium-5-uide; CAS

2-yl)-2,5-dihydro-lH-dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5-uide;

CAS Registry No. 10121-91-2

NH₄Cl, azanium chloride; CAS Registry No. 12125-02-9

Nile Blue A: [9-(diethylamino)benzo[a]phenoxazin-5-ylidene]azanium sulfate;

Perhexilene: 2-(2,2-dicyclohexylethyl)piperidine; CAS Registry No. 6621-47-2

Registry No. 2577-90-4

Registry No. 58-38-8 Promazine: N,N-dimethyl-3-(10H-phenothiazin-10-yl) propan-1 -amine; CAS Registry

No. 58-40-2 Propranolol: l-(isopropylamino)-3-(naphthalen-l-yloxy)propan-2-ol; CAS Registry No.

525-66-6 Suramin: 8-[[4-methyl-3-[[3-[[3-[[2-methyl-5-[(4,6,8-trisulfonaphthalen-l- y^carbamoyljphenyljcarbamoyljphenyljcarbamoylaminojbenzoyljaminojbenz oyl]amino]naphthalene-l,3,5-trisulfonic acid; CAS Registry No. 145-63-1; Thioridazine: 10-{2-[(RS)-l-Methylpiperidin-2-yl]ethyl}-2-methylsulfanyl-phenothiazine;

CAS Registry No. 50-52-2 Thioridazine: 10-{2-[(RS)-l-Methylpiperidin-2-yl]ethyl}-2-methylsulfanyl-phenothiazine;

CAS Registry No. 50-52-2

Tributylamine: N,N-dibutylbutan-l -amine; CAS Registry No. 6309-30-4

CAS Registry No. 117-89-5 Triflupromazine: N,N-dimethyl-3-[2-(trifluoromethyl)- 10H-phenothiazin-10-yl]-propan-l- amine; CAS Registry No. 146-54-3. [00022] Another aspect provided herein are methods for reducing the concentration of N- retinylidene-N-retinylethanolamine (A2E) in an eye of a mammal, wherein the method comprises administering to the mammal at least once an effective amount of a lysosomotropic agent. [00023] Another aspect provided herein are methods for reducing the concentration of lipofusion in an eye of a mammal comprising administering to the mammal an effective amount of a lysosomotropic agent. [00024] Another aspect provided herein are methods for treating dry form age-related macular degeneration in an eye of a mammal comprising administering to the mammal an effective amount of a lysosomotropic agent.

[00025] In certain embodiments of such methods, wherein the method comprises multiple administrations of the effective amount of the lysosomotropic agent, and the time between multiple administrations is at least one day.

[00026] In certain embodiments of such methods, the method further comprising a drug holiday, wherein the administration of the lysosomotropic agent is temporarily suspended or the dose of the lysosomotropic agent administered is temporarily reduced. In certain embodiments, the drug holiday lasts at least seven days.

[00027] In certain embodiments of such methods, the effective amount of the lysosomotropic agent is administered orally to the mammal. In certain embodiments of such methods, the effective amount of the lysosomotropic agent is administered ophthalmically to the mammal.

[00028] In certain embodiments of such methods, the mammal is a human having a macular degeneration disease. In certain embodiments of such methods, the macular degeneration disease is selected from Stargardt's Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy,

In certain embodiments of such methods, the lysosomotropic agent is selected from Acridine orange: N,N,N',N'-tetramethylacridine-3,6-diamine; CAS Registry No. 494-38-2 1-adamantanamine: N,N-dimethyladamantan-l -amine; CAS Registry No. 768-94-5 Amantadine: adamantan-1 -amine; CAS Registry No. 665-66-7

4-aminoquinoline: quinolin-4-amine; CAS Registry No. 578-68-7 Amiodarone: (2-butylbenzofuran-3-yl)-[4-(2-diethylaminoethoxy)-3,5-diiodo- phenyljmethanone; CAS Registry No. 1951-25-3 Amodiaquine: 4 -[(7-chloroquinolin-4-yl)amino]-2-(diethylaminomethyl)phenol; CAS

[(2S,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-oxan-2-yl]oxy-

3,5,6,8,10,12,14-heptamethyl-l-oxa-6-azacyclopentadecan-15-one dehydrate;

CAS Registry No. 117772-70-0;

Registry No. 50-53-3 Citalopram: l-(3-dimethylaminopropyl)-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-5- carbonitrile; CAS Registry No. 59729-33-8 Clindamycin: (2S,4R)-N-[2-chloro-l-[(2R,3S,4S,5R,6R)-3,4,5-trihydroxy-6-methylsulfanyl- oxan-2-yl]propyl]-l-methyl-4-propyl-pyrrolidine-2-carboxamide; CAS Registry No. 24696-19-3

Clomipramine: S-CS-chloro-lOJl-dihydro-SH-dibenzofb^azepin-S-yO-N^-dimethylpropan- 1-amine; CAS Registry No. 303-49-1

Fluoxetine: N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-propan-l-amine; CAS Registry No. 54910-89-3

Flupentixol: 2-[4-[3-[2-(trifluoromethyl)thioxanthen-9-ylidene] propyl]piperazin-l- yljethanol; CAS Registry No. 2709-56-0 Fluphenazine: 2-[4-[3-[2-(trifluoromethyl)-10H-phenothiazin-10-yl]propyl]-piperazin-l- yljethanol; CAS Registry No. 69-23-8 Haloperidol: 4-[4-(4-chlorophenyl)-4-hydroxy-l-piperidyl]-l-(4-fluorophenyl)-butan-l- one; CAS Registry No. 52-86-8 Hydroxizine: 2-[2-[4-[(4-chlorophenyl)-phenyl-methyl]piperazin-l-yl]ethoxy]ethanol; CAS Registry No. 68-88-2 Hydroxychloriquine sulfate: 2-[ { 4- [(7-chloroquinolin-4-yl)amino]pentyl } (ethyl)amino]ethanol;

CAS Registry No. 118-42-3

Imipramine: 3-(5,6-dihydrobenzo[b][l]benzazepin-l l-yl)-N,N-dimethylpropan-l-amine; CAS Registry No. 50-49-7; ketotifen fumarate: 4-(l-methylpiperidin-4-ylidene)-4,9-dihydro-10H-benzo[4,5]cyclohepta[l,2- b]thiophen-10-one; CAS Registry No. 34580-14-8

Le vomepromazine : (2R)-3-(2-Methoxyphenothiazine-10-yl-)-N,N,2-trimethylpropanamine; CAS Registry No. 60-99-1

LysoTracker® green: 7-(3-(2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-l,3-dimethyl- 2,5-dihydro-lH-dipyrrolo[l,2-c:r,2'-f][l,3,2]diazaborinin-4-ium-5-uide; CAS Registry No. 220524-71-0,

LysoTracker® red: 7-(3-(2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-3-(lH-pyrrol- 2-yl)-2,5-dihydro-lH-dipyrrolo[l,2-c:r,2'-f][l,3,2]diazaborinin-4-ium-5-uide; CAS- No. 231946-72-8

Meclofenoxate: 2-dimethylaminoethyl 2-(4-chlorophenoxy)acetate; CAS Registry No. 51-68- 3 Mesoridazine: 10-{2-[(RS)l-Methylpiperidin-2-yl]ethyl}- 2-methylsulfinyl- 10H- phenothiazine; CAS Registry No. 5588-33-0

Methylamine: methanamine; CAS Registry No. [74-89-5] Monensin: 4-[2-[5-ethyl-5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyl-oxan-2-yl]-3- methyl-oxolan-2-yl]oxolan-2-yl]-9-hydroxy-2,8-dimethyl-l,6- dioxaspiro[4.5]dec-7-yl]-3-methoxy-2-methyl-pentanoic acid; CAS Registry No. 22373-78-0 Monodansylcadaverine: N-(5-aminopentyl)-5-(dimethylamino)naphthalene-l-sulfonamide;

CAS Registry No. 10121-91-2

NH₄Cl, azanium chloride; CAS Registry No. 12125-02-9

Nile Blue A: [9-(diethylamino)benzo[a]phenoxazin-5-ylidene]azanium sulfate;

Perhexilene: 2-(2,2-dicyclohexylethyl)piperidine; CAS Registry No. 6621-47-2

Registry No. 2577-90-4

525-66-6 Suramin: 8-[[4-methyl-3-[[3-[[3-[[2-methyl-5-[(4,6,8-trisulfonaphthalen-l- y^carbamoyllphenyljcarbamoyllphenyllcarbamoylaminolbenzoyllaminolbenz oyl]amino]naphthalene-l,3,5-trisulfonic acid; CAS Registry No. 145-63-1; Thioridazine: 10-{2-[(RS)-l-Methylpiperidin-2-yl]ethyl}-2-methylsulfanyl-phenothiazine;

CAS Registry No. 50-52-2

Tributylamine: N,N-dibutylbutan-l -amine; CAS Registry No. 6309-30-4

CAS Registry No. 117-89-5 Triflupromazine: N,N-dimethyl-3-[2-(trifluoromethyl)- 10H-phenothiazin-10-yl]-propan-l- amine; CAS Registry No. 146-54-3. [00029] In certain embodiments of such methods, the method further comprises measuring the autofluorescence of N-retinylidene-phosphatidylethanolamine, dihydro-N-retinylidene-N-retinyl- phosphatidylethanolamine, N-retinylidene-N-retinyl-phosphatidylethanolamine, dihydro-N- retinylidene-N-retinyl-ethanolamine, and/or N-retinylidene-phosphatidylethanolamine in the eye of the mammal.

[00030] In certain embodiments of such methods, the method further comprises administration of a second compound selected from the group consisting of fenretinide, an inducer of nitric oxide production, an antioxidant, an anti-inflammatory agent, a mineral, an anti-oxidant, a carotenoid, a negatively charged phospholipid, a complement inhibitor, a fish oil, and a statin.

[00031] Another aspect provided herein are methods for identifying a lysosomotropic agent for the treatment of lysosomal-storage disease, wherein such methods comprise incubating a cell sample containing a fluorescent compound with at least one candidate lysosomotropic agent and measuring the emission spectra of the fluorescent compound, wherein the candidate lysosomotropic agent decreases the emission spectra of the fluorescent compound in the cell sample after incubation.

[00032] In certain embodiments of such identification methods, the lysosomotropic agent is selected from:

Acridine orange: N,N,N',N'-tetramethylacridine-3,6-diamine; CAS Registry No. 494-38-2 1 - adamantanamine N,N-dimethyladamantan-l -amine; CAS Registry No. 768-94-5

Amantadine: adamantan-1 -amine; CAS Registry No. 665-66-7

4- aminoquinoline : quinolin-4-amine; CAS Registry No. 578-68-7

[(2S,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-oxan-2-yl]oxy-

3,5,6,8,10,12,14-heptamethyl-l-oxa-6-azacyclopentadecan-15-one dehydrate;

CAS Registry No. 117772-70-0;

2,5-dihydro-lH-dipyrrolo[l,2-c:r,2'-f][l,3,2]diazaborinin-4-ium-5-uide; CAS

Registry No. 220524-71-0, LysoTracker® red: 7-(3-(2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-3-(lH-pyrrol- 2-yl)-2,5-dihydro-lH-dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5-uide; CAS- No. 231946-72-8

CAS Registry No. 10121-91-2

NH₄Cl, azanium chloride; CAS Registry No. 12125-02-9 Nile Blue A: [9-(diethylamino)benzo[a]phenoxazin-5-ylidene]azanium sulfate; Perhexilene: 2-(2,2-dicyclohexylethyl)piperidine; CAS Registry No. 6621-47-2 Perphenazine: 2-[4-[3-(2-chloro-10H-phenothiazin-10-yl) propyl]piperazin-l-yl]ethanol; CAS Registry No. 58-39-9 phenylalanine methyl ester: methyl (2S)-2-amino-3-phenyl-propanoate hydrochloride; CAS

Registry No. 2577-90-4

Piperazine: Piperazine; CAS Registry No. 110-85-0 primaquine: N-(6-methoxyquinolin-8-yl)pentane-l,4-diamine; CAS Registry No. 491-92-9 Prochlorperazine : 2-chloro-10-[3-(4-methyl-l-piperazinyl)propyl]-10H-phenothiazine; CAS Registry No. 58-38-8

Promazine: N,N-dimethyl-3-(10H-phenothiazin-10-yl) propan-1- amine; CAS Registry No. 58-40-2

Propranolol: l-(isopropylamino)-3-(naphthalen-l-yloxy)propan-2-ol; CAS Registry No. 525-66-6

Suramin: 8-[[4-methyl-3-[[3-[[3-[[2-methyl-5-[(4,6,8-trisulfonaphthalen-l- y^carbamoyljphenyljcarbamoyljphenyljcarbamoylaminojbenzoyljaminojbenz oyl]amino]naphthalene-l,3,5-trisulfonic acid; CAS Registry No. 145-63-1;

Thioridazine: 10-{2-[(RS)-l-Methylpiperidin-2-yl]ethyl}-2-methylsulfanyl-phenothiazine; CAS Registry No. 50-52-2 Thioridazine: 10-{2-[(RS)-l-Methylpiperidin-2-yl]ethyl}-2-methylsulfanyl-phenothiazine; CAS Registry No. 50-52-2

Tributylamine: N,N-dibutylbutan-l -amine; CAS Registry No. 6309-30-4 Trifluoperazine: 10-[3-(4-methylpiperazin-l-yl)propyl]-2-(trifluoromethyl)-10H-phenothiazine; CAS Registry No. 117-89-5

Triflupromazine : N,N-dimethyl-3-[2-(trifluoromethyl)- 10H-phenothiazin-10-yl]-propan-l- amine; CAS Registry No. 146-54-3.

[00033] In certain embodiments of such identification methods, the fluorescent compound absorbs at between 300 nm and 550 nm and emits at between 520 nm and 700 nm.

[00034] In certain embodiments of such identification methods, the fluorescent compound is N- retinylidene-N-retinyl-phosphatidylethanolamine ( A2E) .

[00035] In certain embodiments of such identification methods, the cell sample comprises a RPE cell.

[00036] Another aspect provided herein is compounds for use in a method of medical treatment, wherein the method of medical treatment is for treating a lysosomal-storage disease, wherein the lysosomal-storage disease is sleeted from Tay-Sachs disease, Batten Disease, Krabbe Disease, Pompe disease, Gaucher Disease, Mucopolysacchiradosis I (MPS I/Hurler/Hurler-Scheie/Scheie), Mucopolysacchiradosis II (MPS II/Hunter Disease), Fabry Disease, leukodystrophies, Niemann-Pick Disease, Stargardt's Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration, and wherein th compound is a lysosomotropic agent. In certain embodiments of this aspect, the lysosomotropic agent is selected from:

1 - adamantanamine : N,N-dimethyladamantan-l -amine; CAS Registry No. 768-94-5

Amantadine: adamantan-1 -amine; CAS Registry No. 665-66-7

4- aminoquinoline : quinolin-4-amine; CAS Registry No. 578-68-7

Chloroquine: N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-l,4-diamine; CAS Registry No. 54-05-7 Chlorpromazine: 3-(2-chloro- 10H-phenothiazin- 10-yl)-N,N-dimethyl-propan- 1-amine; CAS Registry No. 50-53-3 Citalopram: l-(3-dimethylaminopropyl)-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-5- carbonitrile; CAS Registry No. 59729-33-8 Clindamycin: (2S,4R)-N-[2-chloro-l-[(2R,3S,4S,5R,6R)-3,4,5-trihydroxy-6-methylsulfanyl- oxan-2-yl]propyl]-l-methyl-4-propyl-pyrrolidine-2-carboxamide; CAS Registry No. 24696-19-3

Fluoxetine: N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-propan- 1-amine; CAS Registry No. 54910-89-3

Flupentixol: 2-[4-[3-[2-(trifluoromethyl)thioxanthen-9-ylidene] propyl]piperazin-l- yljethanol; CAS Registry No. 2709-56-0 Fluphenazine: 2-[4-[3-[2-(trifluoromethyl)-10H-phenothiazin-10-yl]propyl]-piperazin-l- yljethanol; CAS Registry No. 69-23-8 Haloperidol: 4- [4-(4-chlorophenyl)-4-hydroxy- 1 -piperidyl] - 1 -(4-fluorophenyl)-butan- 1 - one; CAS Registry No. 52-86-8 Hydroxizine: 2-[2-[4-[(4-chlorophenyl)-phenyl-methyl]piperazin-l-yl]ethoxy]ethanol; CAS

2,5-dihydro-lH-dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5-uide; CAS

2-yl)-2,5-dihydro-lH-dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5-uide;

CAS Registry No. 10121-91-2

NH₄Cl, azanium chloride; CAS Registry No. 12125-02-9

Nile Blue A: [9-(diethylamino)benzo[a]phenoxazin-5-ylidene]azanium sulfate;

Perhexilene: 2-(2,2-dicyclohexylethyl)piperidine; CAS Registry No. 6621-47-2

Registry No. 2577-90-4

Tributylamine: N,N-dibutylbutan-l -amine; CAS Registry No. 6309-30-4 Trifluoperazine : 10-[3-(4-methylpiperazin-l-yl)propyl]-2-(trifluoromethyl)-10H-phenothiazine; CAS Registry No. 117-89-5

Triflupromazine : N,N-dimethyl-3-[2-(trifluoromethyl)- 10H-phenothiazin-10-yl]-propan-l- amine; CAS Registry No. 146-54-3. [00037] In other embodiments of this aspect, the method of medical treatment further comprises the use a second compound selected from the group consisting of fenretinide, an inducer of nitric oxide production, an antioxidant, an anti-inflammatory agent, a mineral, an anti-oxidant, a carotenoid, a negatively charged phospholipid and a statin.

BRIEF DESCRIPTION OF THE DRAWINGS

[00038] The novel features of the methods and compositions disclosed herein are set forth with particularity in the appended claims. A better understanding of the features and advantages will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles disclosed herein are utilized, and the accompanying drawings. [00039] FIG. 1 shows the clearance of A2E from RPE cells by chlorpromazine (CPZ).

FIG. 1 (A) is an image taken with Opera™ confocal microplate imager (Perkin Elmer).

FIG. 1 (B) (left) is an image taken with the ViewLux™ microplate imager (Perkin

Elmer).

FIG. 1 (B) (right) is a plot quantifying the ViewLux™ microplate imager (Perkin Elmer).

[00040] FIG. 2 shows the clearance of LysoTracker® Green from RPE cells by chlorpromazine

(CPZ).

[00041] FIG. 3 shows the fluorescence intensity of different concentration of A2E with 100 μM

CPZ added.

[00042] FIG. 4 shows that CPZ treatment reduces A2E in cells and increased A2E content in the media.

[00043] FIG. 5 shows the dose response of A2E clearance by CPZ.

[00044] FIG. 6 shows the effect of various lysosomotropes on A2E clearance in ARPE- 19 cells. DETAILED DESCRIPTION OF THE INVENTION

Definitions [00045] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[00046] The term "administration" or "administering" of the subject compound means providing a lysosomotropic agent, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or prodrug thereof to a subject in need of treatment.

[00047] The term "carrier," as used herein, refers to chemical compounds or agents that facilitate the incorporation of a compound described herein into cells or tissues.

[00048] The terms "co- administration" or "combined administration" or the like as used herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

[00049] The term "diluent," as used herein, refers to chemical compounds that are used to dilute a compound described herein prior to delivery. Diluents can also be used to stabilize compounds described herein.

[00050] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient amount of a compound described herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study. [00051] The terms "enhance" or "enhancing," as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[00052] The term "iatrogenic," as used herein, means a condition, disorder, or disease created or worsened by medical or surgical therapy. [00053] The term "mammal", as used herein, means all mammals including humans. Mammals include, by way of example only, humans, non-human primates, cows, dogs, cats, goats, sheep, pigs, rats, mice and rabbits.

[00054] The term "ophthalmically acceptable", as used herein, means having no persistent detrimental effect on the treated eye or the functioning thereof, or on the general health of the subject being treated. Transient effects such as minor irritation or a "stinging" sensation are common with topical ophthalmic administration of agents and consistent with the formulation, composition or ingredient in question being "ophthalmically acceptable."

[00055] The term "pharmaceutically acceptable," as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein. Such materials are administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[00056] The term "pharmaceutically acceptable salt," as used herein, refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compounds described herein. [00057] The terms "combination" or "pharmaceutical combination," as used herein mean a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non- fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, by way of example, a lysosomotropic agent and an additional therapeutic agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, by way of example, a lysosomotropic agent and an additional therapeutic agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of 3 or more active ingredients.

[00058] The terms "composition" or "pharmaceutical composition," as used herein, refers to a mixture of at least one lysosomotropic agent described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or other excipients.

[00059] The term "subject" or "patient," as used herein, encompasses mammals and non- mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes monkeys, cattle, horses, sheep, goats, swine; rabbits, dogs, cats, rats, mice, guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. [00060] The term "therapeutically effective amount," as used herein, refers to any amount of a compound which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. [00061] The terms "treat," "treating" or "treatment," as used herein, refers to methods of alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.

[00062] The compound names provided herein are either common names, standard IUPAC names or were obtained using ChemDraw Ultra 10.0 (CambridgeSoft®) or JChem version 5.0.3 (ChemAxon).

[00063] Other objects, features and advantages of the methods, compositions and combinations described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only.

[00064] Provided herein are methods, compounds and pharmaceutical compositions thereof for the treatment of lysosomal-storage diseases and/or disorders. Such lysosomal-storage diseases include but are not limited to Tay-Sachs disease, Batten Disease, Krabbe Disease, Pompe disease, Gaucher Disease, Mucopolysacchiradosis I (MPS I/Hurler/Hurler- Scheie/Scheie), Mucopolysacchiradosis II (MPS II/Hunter Disease), Fabry Disease, leukodystrophies, Niemann- Pick Disease, Stargardt's Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration. Such methods of treatment include administration of a lysosomotropic agent, or a pharmaceutical composition containing at least one lysosomotropic agent, to a patient in need thereof. Such lysosomotropic agents include, but are not limited to Acridine orange (N,N,N',N'-tetramethylacridine-3,6-diamine; CAS Registry No. 494-38-2); 1- adamantanamine (N,N-dimethyladamantan-l-amine; CAS Registry No. 768-94-5); Amantadine (adamantan-1-amine; CAS Registry No. 665-66-7 ); 4-aminoquinoline (quinolin-4-amine; CAS Registry No. 578-68-7); Amiodarone ((2-butylbenzofuran-3-yl)-[4-(2-diethylaminoethoxy)-3,5- diiodo-phenyl]methanone; CAS Registry No. 1951-25-3); Amodiaquine (4 -[(7-chloroquinolin-4- yl)amino]-2-(diethylaminomethyl)phenol; CAS Registry No. 86-42-0); Azithromycin ((2R,3R,4R,5R,8R,10R,llR,13S,14R)-ll-[(2S,3R,4S,6R)-4-dimethylamino-3-hydroxy-6-methyl- oxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2S,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl- oxan-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-l-oxa-6-azacyclopentadecan-15-one dehydrate; CAS Registry No. 117772-70-0); 4-benzoyl-oxi-2-azetidinove ((4-oxoazetidin-2-yl) benzoate; CAS Registry No. 28562-58-5); Chloroquine (N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-l,4- diamine; ); CAS Registry No. 54-05-7); Chlorpromazine (3-(2-chloro-10H-phenothiazin-10-yl)- N,N-dimethyl-propan-l -amine; CAS Registry No. 50-53-3); Citalopram (l-(3- dimethylaminopropyl)-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-5-carbonitrile; CAS Registry No. 59729-33-8); Clindamycin ((2S,4R)-N-[2-chloro-l-[(2R,3S,4S,5R,6R)-3,4,5-trihydroxy-6- methylsulfanyl-oxan-2-yl]propyl]- l-methyl-4-propyl-pyrrolidine-2-carboxamide; CAS Registry No. 24696-19-3); Clomipramine (3-(3-chloro-10J l-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N- dimethylpropan-1 -amine; CAS Registry No. 303-49-1); DAMP (N-(3-[(2,4-dinitrophenyl)- amino]-propyl)-N-(3-aminopropyl-methylamine)dihydrochloride,); Fluoxetine (N-methyl-3- phenyl-3-[4-(trifluoromethyl)phenoxy]-propan-l-amine; CAS Registry No. 54910-89-3); Flupentixol (2-[4-[3-[2-(trifluoromethyl)thioxanthen-9-ylidene] propyl]piperazin-l-yl]ethanol; CAS Registry No. 2709-56-0); Fluphenazine (2-[4-[3-[2-(trifluoromethyl)-10H-phenothiazin-10- yl]propyl]-piperazin-l-yl]ethanol; CAS Registry No. 69-23-8); Haloperidol (4-[4-(4- chlorophenyl)-4-hydroxy-l-piperidyl]-l-(4-fluorophenyl)-butan-l-one; CAS Registry No. 52-86- 8); Hydroxizine (2-[2-[4-[(4-chlorophenyl)-phenyl-methyl]piperazin-l-yl]ethoxy]ethanol; CAS Registry No. 68-88-2); Hydroxychloriquine sulfate (2-[{4-[(7-chloroquinolin-4- yl)amino]pentyl}(ethyl)amino]ethanol; CAS Registry No. 118-42-3); Imipramine (3-(5,6- dihydrobenzo[b][l]benzazepin-ll-yl)-N,N-dimethylpropan-l-amine; CAS Registry No. 50-49-7); ketotifen fumarate (4-(l-methylpiperidin-4-ylidene)-4,9-dihydro-10H-benzo[4,5]cyclohepta[l,2- b]thiophen-10-one; CAS Registry No. 34580-14-8); Levomepromazine ((2R)-3-(2- Methoxyphenothiazine-10-yl-)-N,N,2-trimethylpropanamine; CAS Registry No. 60-99-1); LysoTracker® green (7-(3-(2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-l,3- dimethyl-2,5-dihydro-lH-dipyrrolo[l,2-c:r,2'-f][l,3,2]diazaborinin-4-ium-5-uide; CAS Registry No. 220524-71-0, ); LysoTracker® red (7-(3-(2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5- difluoro-3-(lH-pyrrol-2-yl)-2,5-dihydro-lH-dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5- uide; CAS- No. 231946-72-8); Meclofenoxate (2-dimethylaminoethyl 2-(4-chlorophenoxy)acetate; CAS Registry No. 51-68-3); Mesoridazine (10-{2-[(RS)l-Methylpiperidin-2-yl]ethyl}- 2- methylsulfinyl- 10H-phenothiazine; CAS Registry No. 5588-33-0); Methylamine (methanamine; CAS Registry No. [74-89-5] ); Monensin (4-[2-[5-ethyl-5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5- dimethyl-oxan-2-yl]-3-methyl-oxolan-2-yl]oxolan-2-yl]-9-hydroxy-2,8-dimethyl-l,6- dioxaspiro[4.5]dec-7-yl]-3-methoxy-2-methyl-pentanoic acid; CAS Registry No. 22373-78-0); Monodansylcadaverine (N-(5-aminopentyl)-5-(dimethylamino)naphthalene-l-sulfonamide; CAS Registry No. 10121-91-2); NH₄Cl (azanium chloride; CAS Registry No. 12125-02-9); Nile Blue A ([9-(diethylamino)benzo[a]phenoxazin-5-ylidene]azanium sulfate; ); Perhexilene (2-(2,2- dicyclohexylethyl)piperidine; CAS Registry No. 6621-47-2); Perphenazine (2-[4-[3-(2-chloro- lOH-phenothiazin-10-yl) propyl]piperazin-l-yl]ethanol; CAS Registry No. 58-39-9); phenylalanine methyl ester (methyl (2S)-2-amino-3-phenyl-propanoate hydrochloride; CAS Registry No. 2577-90-4); Piperazine (Piperazine; CAS Registry No. 110-85-0); primaquine (N-(6- methoxyquinolin-8-yl)pentane-l,4-diamine; CAS Registry No. 491-92-9); Prochlorperazine (2- chloro-10-[3-(4-methyl-l-piperazinyl)propyl]-10H-phenothiazine; CAS Registry No. 58-38-8); Promazine (N,N-dimethyl-3-(10H-phenothiazin-10-yl) propan-1 -amine; CAS Registry No. 58-40- 2); Propranolol (l-(isopropylamino)-3-(naphthalen-l-yloxy)propan-2-ol; CAS Registry No. 525- 66-6); Suramin (8-[[4-methyl-3-[[3-[[3-[[2-methyl-5-[(4,6,8-trisulfonaphthalen-l- y^carbamoyljphenyljcarbamoyljphenyljcarbamoylaminojbenzoyljaminojbenzoyljaminojnaphthal ene-l,3,5-trisulfonic acid; CAS Registry No. 145-63-1); Thioridazine (10-(2-[(RS)-I- Methylpiperidin-2-yl]ethyl}-2-methylsulfanyl-phenothiazine; CAS Registry No. 50-52-2); Thioridazine ( 10- { 2-[(RS)-I -Methylpiperidin-2-yl]ethyl } -2-methylsulfanyl-phenothiazine; CAS Registry No. 50-52-2 ); Tributylamine (N,N-dibutylbutan-l -amine; CAS Registry No. 6309-30-4); Trifluoperazine (10-[3-(4-methylpiperazin-l-yl)propyl]-2-(trifluoromethyl)-10H-phenothiazine; CAS Registry No. 117-89-5); Triflupromazine (N,N-dimethyl-3-[2-(trifluoromethyl)- 10H- phenothiazin-10-yl]-propan-l-amine; CAS Registry No. 146-54-3).

[00065] Also provided herein are methods for clearing/removing toxic metabolites from a lysosome, wherein the methods include contacting the lysosome with a lysosomotropic agent or a pharmaceutical composition containing at least one lysosomotropic agent. Such lysosomotropic agents include, but are not limited to Acridine orange (N,N,N',N'-tetramethylacridine-3,6-diamine; CAS Registry No. 494-38-2); 1-adamantanamine (N,N-dimethyladamantan-l -amine; CAS Registry No. 768-94-5); Amantadine (adamantan-1- amine; CAS Registry No. 665-66-7 ); 4- aminoquinoline (quinolin-4-amine; CAS Registry No. 578-68-7); Amiodarone ((2- butylbenzofuran-3-yl)-[4-(2-diethylaminoethoxy)-3,5-diiodo-phenyl]methanone; CAS Registry No. 1951-25-3); Amodiaquine (4 -[(7-chloroquinolin-4-yl)amino]-2-(diethylaminomethyl)phenol; CAS Registry No. 86-42-0); Azithromycin ((2R,3R,4R,5R,8R,1OR,11R,13S,14R)-11- [(2S,3R,4S,6R)-4-dimethylamino-3-hydroxy-6-methyl-oxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy- 13-[(2S,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-oxan-2-yl]oxy-3,5,6,8,10,12,14- heptamethyl-l-oxa-ό-azacyclopentadecan-lS-one dehydrate; CAS Registry No. 117772-70-0); 4- benzoyl-oxi-2-azetidinove ((4-oxoazetidin-2-yl) benzoate; CAS Registry No. 28562-58-5); Chloroquine (N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-l,4-diamine; ); CAS Registry No. 54-05-7); Chlorpromazine (3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethyl-propan-l-amine; CAS Registry No. 50-53-3); Citalopram (l-(3-dimethylaminopropyl)-l-(4-fluorophenyl)-l,3- dihydroisobenzofuran-5-carbonitrile; CAS Registry No. 59729-33-8); Clindamycin ((2S,4R)-N-[2- chloro-l-[(2R,3S,4S,5R,6R)-3,4,5-trihydroxy-6-methylsulfanyl-oxan-2-yl]propyl]-l-methyl-4- propyl-pyrrolidine-2-carboxamide; CAS Registry No. 24696-19-3); Clomipramine (3-(3-chloro- 10,l l-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-l-amine; CAS Registry No. 303- 49-1); DAMP (N-(3-[(2,4-dinitrophenyl)-amino]-propyl)-N-(3-aminopropyl- methylamine)dihydrochloride,); Fluoxetine (N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]- propan-1-amine; CAS Registry No. 54910-89-3); Flupentixol (2-[4-[3-[2- (trifluoromethyl)thioxanthen-9-ylidene] propyl]piperazin-l-yl]ethanol; CAS Registry No. 2709- 56-0); Fluphenazine (2-[4-[3-[2-(trifluoromethyl)-10H-phenothiazin-10-yl]propyl]-piperazin-l- yljethanol; CAS Registry No. 69-23-8); Haloperidol (4-[4-(4-chlorophenyl)-4-hydroxy-l- piperidyl]-l-(4-fluorophenyl)-butan-l-one; CAS Registry No. 52-86-8); Hydroxizine (2-[2-[4-[(4- chlorophenyl)-phenyl-methyl]piperazin-l-yl]ethoxy]ethanol; CAS Registry No. 68-88-2); Hydroxychloriquine sulfate (2-[{4-[(7-chloroquinolin-4-yl)amino]pentyl}(ethyl)amino]ethanol; CAS Registry No. 118-42-3); Imipramine (3-(5,6-dihydrobenzo[b][l]benzazepin-ll-yl)-N,N- dimethylpropan-1- amine; CAS Registry No. 50-49-7); ketotifen fumarate (4-(l-methylpiperidin-4- ylidene)-4,9-dihydro-10H-benzo[4,5]cyclohepta[l,2-b]thiophen-10-one; CAS Registry No. 34580- 14-8); Levomepromazine ((2R)-3-(2-Methoxyphenothiazine- 10-yl-)-N,N,2-trimethylpropanamine; CAS Registry No. 60-99-1); LysoTracker® green (7-(3-(2-(dimethylamino)ethylamino)-3- oxopropyl)-5,5-difluoro-l,3-dimethyl-2,5-dihydro-lH-dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin- 4-ium-5-uide; CAS Registry No. 220524-71-0, ); LysoTracker® red (7-(3-(2- (dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-3-(lH-pyrrol-2-yl)-2,5-dihydro-lH- dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5-uide; CAS- No. 231946-72-8); Meclofenoxate (2-dimethylaminoethyl 2-(4-chlorophenoxy)acetate; CAS Registry No. 51-68-3); Mesoridazine (10-{2-[(RS)l-Methylpiperidin-2-yl]ethyl}- 2-methylsulfinyl- 10H-phenothiazine; CAS Registry No. 5588-33-0); Methylamine (methanamine; CAS Registry No. [74-89-5] ); Monensin (4-[2-[5- ethyl-5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyl-oxan-2-yl]-3-methyl-oxolan-2-yl]oxolan- 2-yl]-9-hydroxy-2,8-dimethyl-l,6-dioxaspiro[4.5]dec-7-yl]-3-methoxy-2-methyl-pentanoic acid; CAS Registry No. 22373-78-0); Monodansylcadaverine (N-(5-aminopentyl)-5- (dimethylamino)naphthalene-l -sulfonamide; CAS Registry No. 10121-91-2); NH₄Cl (azanium chloride; CAS Registry No. 12125-02-9); Nile Blue A ([9-(diethylamino)benzo[a]phenoxazin-5- ylidene] azanium sulfate; ); Perhexilene (2-(2,2-dicyclohexylethyl)piperidine; CAS Registry No. 6621-47-2); Perphenazine (2-[4-[3-(2-chloro-10H-phenothiazin-10-yl) propyl]piperazin-l- yl]ethanol; CAS Registry No. 58-39-9); phenylalanine methyl ester (methyl (2S)-2-amino-3- phenyl-propanoate hydrochloride; CAS Registry No. 2577-90-4); Piperazine (Piperazine; CAS Registry No. 110-85-0); primaquine (N-(6-methoxyquinolin-8-yl)pentane-l,4-diamine; CAS Registry No. 491-92-9); Prochlorperazine (2-chloro-10-[3-(4-methyl-l-piperazinyl)propyl]-10H- phenothiazine; CAS Registry No. 58-38-8); Promazine (N,N-dimethyl-3-(10H-phenothiazin-10-yl) propan-1-amine; CAS Registry No. 58-40-2); Propranolol (l-(isopropylamino)-3-(naphthalen-l- yloxy)propan-2-ol; CAS Registry No. 525-66-6); Suramin (8-[[4-methyl-3-[[3-[[3-[[2-methyl-5- [(4,6,8-trisulfonaphthalen-l- y^carbamoyljphenyljcarbamoyljphenyljcarbamoylaminojbenzoyljaminojbenzoyljaminojnaphthal ene-l,3,5-trisulfonic acid; CAS Registry No. 145-63-1); Thioridazine (10-(2-[(RS)-I- Methylpiperidin-2-yl]ethyl}-2-methylsulfanyl-phenothiazine; CAS Registry No. 50-52-2); Thioridazine ( 10- { 2-[(RS)-I -Methylpiperidin-2-yl]ethyl } -2-methylsulfanyl-phenothiazine; CAS Registry No. 50-52-2 ); Tributylamine (N,N-dibutylbutan-l -amine; CAS Registry No. 6309-30-4); Trifluoperazine (10-[3-(4-methylpiperazin-l-yl)propyl]-2-(trifluoromethyl)-10H-phenothiazine; CAS Registry No. 117-89-5); Triflupromazine (N,N-dimethyl-3-[2-(trifluoromethyl)- 10H- phenothiazin-10-yl]-propan-l-amine; CAS Registry No. 146-54-3).

[00066] Also provided herein are methods for reducing the concentration of N-retinylidene-N- retinylethanolamine (A2E) or reducing the concentration of lipofusion in an eye of a mammal, wherein such methods comprises administering to the mammal at least once an effective amount of a lysosomotropic agent. Further provided are methods for treating macular degeneration in an eye of a mammal comprising administering to the mammal an effective amount of a lysosomotropic agent. The macular degeneration disease treated using such methods includes, but is not limited to, Stargardt's Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration. The lysosomotropic agent used in such treatment methods includes, but is not limited to, Acridine orange (N,N,N',N'-tetramethylacridine-3,6-diamine; CAS Registry No. 494-38-2); 1-adamantanamine (N,N-dimethyladamantan-l-amine; CAS Registry No. 768-94- 5); Amantadine (adamantan-1-amine; CAS Registry No. 665-66-7 ); 4-aminoquinoline (quinolin- 4-amine; CAS Registry No. 578-68-7); Amiodarone ((2-butylbenzofuran-3-yl)-[4-(2- diethylaminoethoxy)-3,5-diiodo-phenyl]methanone; CAS Registry No. 1951-25-3); Amodiaquine (4 -[(7-chloroquinolin-4-yl)amino]-2-(diethylaminomethyl)phenol; CAS Registry No. 86-42-0); Azithromycin ((2R,3R,4R,5R,8R,10R,l lR,13S,14R)-ll-[(2S,3R,4S,6R)-4-dimethylamino-3- hydroxy-6-methyl-oxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2S,4R,5S,6S)-5-hydroxy-4- methoxy-4,6-dimethyl-oxan-2-yl]oxy-3,5,6,8, 10,12, M-heptamethyl-l-oxa-ό-azacyclopentadecan- 15-one dehydrate; CAS Registry No. 117772-70-0); 4-benzoyl-oxi-2-azetidinove ((4-oxoazetidin- 2-yl) benzoate; CAS Registry No. 28562-58-5); Chloroquine (N'-(7-chloroquinolin-4-yl)-N,N- diethyl-pentane-l,4-diamine; ); CAS Registry No. 54-05-7); Chlorpromazine (3-(2-chloro-10H- phenothiazin-10-yl)-N,N-dimethyl-propan-l-amine; CAS Registry No. 50-53-3); Citalopram (1- (3-dimethylaminopropyl)- l-(4-fluorophenyl)- 1 ,3-dihydroisobenzofuran-5-carbonitrile; CAS Registry No. 59729-33-8); Clindamycin ((2S,4R)-N-[2-chloro-l-[(2R,3S,4S,5R,6R)-3,4,5- trihydroxy-6-methylsulfanyl-oxan-2-yl]propyl]-l-methyl-4-propyl-pyrrolidine-2-carboxamide; CAS Registry No. 24696-19-3); Clomipramine (3-(3-chloro-10,ll-dihydro-5H- dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-l-amine; CAS Registry No. 303-49-1); DAMP (N- (3-[(2,4-dinitrophenyl)-amino]-propyl)-N-(3-aminopropyl-methylamine)dihydrochloride,); Fluoxetine (N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-propan-l-amine; CAS Registry No. 54910-89-3); Flupentixol (2-[4-[3-[2-(trifluoromethyl)thioxanthen-9-ylidene] propyl]piperazin-l-yl]ethanol; CAS Registry No. 2709-56-0); Fluphenazine (2-[4-[3-[2- (trifluoromethyl)-10H-phenothiazin-10-yl]propyl]-piperazin-l-yl]ethanol; CAS Registry No. 69- 23 -8) ; Haloperidol (4- [4-(4-chlorophenyl)-4-hydroxy- 1 -piperidyl] - 1 -(4-fluorophenyl)-butan- 1 - one; CAS Registry No. 52-86-8); Hydroxizine (2-[2-[4-[(4-chlorophenyl)-phenyl- methyl]piperazin-l-yl]ethoxy]ethanol; CAS Registry No. 68-88-2); Hydroxychloriquine sulfate (2- [{4-[(7-chloroquinolin-4-yl)amino]pentyl}(ethyl)amino]ethanol; CAS Registry No. 118-42-3); Imipramine (3-(5,6-dihydrobenzo[b][l]benzazepin-l l-yl)-N,N-dimethylpropan-l-amine; CAS Registry No. 50-49-7); ketotifen fumarate (4-(l-methylpiperidin-4-ylidene)-4,9-dihydro-10H- benzo[4,5]cyclohepta[l,2-b]thiophen-10-one; CAS Registry No. 34580-14-8); Levomepromazine ((2R)-3-(2-Methoxyphenothiazine-10-yl-)-N,N,2-trimethylpropanamine; CAS Registry No. 60-99- 1); LysoTracker® green (7-(3-(2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-l,3- dimethyl-2,5-dihydro-lH-dipyrrolo[l,2-c:r,2'-f][l,3,2]diazaborinin-4-ium-5-uide; CAS Registry No. 220524-71-0, ); LysoTracker® red (7-(3-(2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5- difluoro-3-(lH-pyrrol-2-yl)-2,5-dihydro-lH-dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5- uide; CAS- No. 231946-72-8); Meclofenoxate (2-dimethylaminoethyl 2-(4-chlorophenoxy)acetate; CAS Registry No. 51-68-3); Mesoridazine (10-{2-[(RS)l-Methylpiperidin-2-yl]ethyl}- 2- methylsulfinyl- 10H-phenothiazine; CAS Registry No. 5588-33-0); Methylamine (methanamine; CAS Registry No. [74-89-5] ); Monensin (4-[2-[5-ethyl-5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5- dimethyl-oxan-2-yl]-3-methyl-oxolan-2-yl]oxolan-2-yl]-9-hydroxy-2,8-dimethyl-l,6- dioxaspiro[4.5]dec-7-yl]-3-methoxy-2-methyl-pentanoic acid; CAS Registry No. 22373-78-0); Monodansylcadaverine (N-(5-aminopentyl)-5-(dimethylamino)naphthalene-l-sulfonamide; CAS Registry No. 10121-91-2); NH₄Cl (azanium chloride; CAS Registry No. 12125-02-9); Nile Blue A ([9-(diethylamino)benzo[a]phenoxazin-5-ylidene]azanium sulfate; ); Perhexilene (2-(2,2- dicyclohexylethyl)piperidine; CAS Registry No. 6621-47-2); Perphenazine (2-[4-[3-(2-chloro- lOH-phenothiazin-10-yl) propyl]piperazin-l-yl]ethanol; CAS Registry No. 58-39-9); phenylalanine methyl ester (methyl (2S)-2-amino-3-phenyl-propanoate hydrochloride; CAS Registry No. 2577-90-4); Piperazine (Piperazine; CAS Registry No. 110-85-0); primaquine (N-(6- methoxyquinolin-8-yl)pentane-l,4-diamine; CAS Registry No. 491-92-9); Prochlorperazine (2- chloro-10-[3-(4-methyl-l-piperazinyl)propyl]-10H-phenothiazine; CAS Registry No. 58-38-8); Promazine (N,N-dimethyl-3-(10H-phenothiazin-10-yl) propan-1 -amine; CAS Registry No. 58-40- 2); Propranolol (l-(isopropylamino)-3-(naphthalen-l-yloxy)propan-2-ol; CAS Registry No. 525- 66-6); Suramin (8-[[4-methyl-3-[[3-[[3-[[2-methyl-5-[(4,6,8-trisulfonaphthalen-l- y^carbamoyllphenyljcarbamoyllphenyllcarbamoylaminolbenzoyllaminolbenzoyllaminolnaphthal ene-l,3,5-trisulfonic acid; CAS Registry No. 145-63-1); Thioridazine (10-(2-[(RS)-I- Methylpiperidin-2-yl]ethyl}-2-methylsulfanyl-phenothiazine; CAS Registry No. 50-52-2); Thioridazine ( 10- { 2-[(RS)-I -Methylpiperidin-2-yl]ethyl } -2-methylsulfanyl-phenothiazine; CAS Registry No. 50-52-2 ); Tributylamine (N,N-dibutylbutan-l -amine; CAS Registry No. 6309-30-4); Trifluoperazine (10-[3-(4-methylpiperazin-l-yl)propyl]-2-(trifluoromethyl)-10H-phenothiazine; CAS Registry No. 117-89-5); Triflupromazine (N,N-dimethyl-3-[2-(trifluoromethyl)- 10H- phenothiazin-10-yl]-propan-l-amine; CAS Registry No. 146-54-3).

[00067] In certain embodiments of such treatment methods, the method further comprises measuring the autofluorescence of N-retinylidene-phosphatidylethanolamine, dihydro-N- retinylidene-N-retinyl-phosphatidylethanolamine, N-retinylidene-N-retinyl- phosphatidylethanolamine, dihydro-N-retinylidene-N-retinyl-ethanolamine, and/or N-retinylidene- phosphatidylethanolamine in the eye of the mammal. In other embodiments, of such treatment methods, the method further comprises administration of a second compound selected from the group consisting of fenretinide, an inducer of nitric oxide production, an antioxidant, an antiinflammatory agent, a mineral, an anti-oxidant, a carotenoid, a negatively charged phospholipid, a complement inhibitor, a fish oil, and a statin. Pharmacolθ2V and Utility

Lysosomal Storage Diseases

[00068] Lysosomal storage diseases (LSDs) are a group of 49 genetically inherited disorders that result in defective lysosomal function. In lysosomal storage diseases, the cell is unable to produce one or more enzymes responsible for the breakdown of large molecules which leads to cell death. The characteristics associated with LSDs are often neurological, but can also be multisystemic, with skeletal, central nervous system (CNS), cardiovascular and ocular system involvement.

[00069] In normal cells, most lysosomal enzymes are synthesized, directed by an amino terminal signal-recognition sequence, in the rough endoplasmic reticulum (RER). After co- translational insertion of the nascent peptide into the RER lumen, the signal-recognition sequence is cleaved and high mannose oligosaccharides are added. These oligosaccharides are trimmed and the glycoprotein moves to the Golgi apparatus where a mannose 6-phosphate (M6Pr) moiety is added. The M6Pr moiety is recognized by mannose 6-phosphate receptors on the lysosome surface, allowing these phosphorylated enzymes to enter and become internalized within the lysosome. Once in the lysosome, the enzyme dissociates from the receptor, which then recycles to the trans-Golgi network. Of the 49 lysosomal storage diseases, 48 utilize this M6P receptor system [00070] The majority of lysosomal storage diseases (LSDs) result from a deficiency of, or loss of normal function of, one or more specific lysosomal enzymes, such as lysosomal acid hydrolases, and the resulting accumulation of partially degraded compounds within the lysosome. Lysosomal enzyme's break down complex cellular compounds, such as such as glycolipids and glycogen, and foreign materials contained within lysosomes after edocytosis or autophagy, into simple products, such as peptides, amino acids, monosaccharides, nucleic acids and fatty acids, which are either utilized or excreted by the cell. Degradation of most substrates occurs by a stepwise pathway of a series of lysosomal enzymes, with each subsequent step of the pathway dependent upon the action of the previous enzyme. If one step in the process fails, further degradation ceases and the partially degraded substrate accumulates. This lysosomal accumulation of partially degraded compounds affects the architecture and function of cells, tissues and organs. Specifically, the accumulation causes lysosomes to enlarge leading eventually to cell degeneration and accumulation of partially degraded macromolecules in various tissues and organs of the body causing these organs to function less efficiently, resulting in progressive deterioration in physical and/or mental state, and eventually death. Furthermore, the accumulated substrate may be cytotoxic, as seen in galactocerebrosidosis.

[00071] Most LSDs have an autosomal recessive inheritance pattern, which means that in order for a person to develop the disease (that is, the person must inherit two copies of the abnormal gene, one from each parent). The cause of the enzyme deficiency in the lysosome is usually a mutation in a structural gene that codes, for the particular lysosomal enzyme. Gaucher disease, MPS I, Pompe disease, and Niemann-Pick disease are all autosomal recessive. Individual LSD's are classified as rare genetic disorders. However, when taken as a group, LSD's are far more common, with a prevalence rate of approximately 1 in 7000-8000 births in some countries. There are no cures for these diseases and treatment is mostly symptomatic, although bone marrow transplantation and enzyme replacement therapy have been tried with some success. [00072] Lysosomal storage diseases are classified by the nature of the primary stored material involved, and can be broadly broken into the following: lipid storage disorders (including Gaucher's and Niemann-Pick diseases); gangliosidosis (including Tay-Sachs disease); leukodystrophies; mucopolysaccharidoses (including Hunter syndrome and Hurler disease); glycoprotein storage disorders and mucolipidoses. Examples of lysosomal storage diseases include: Batten Disease, Fabry Disease, Gaucher Disease, Krabbe Disease, Mucopolysacchiradosis I (MPS I/Hurler/Hurler-Scheie/Scheie), Mucopolysacchiradosis II (MPS II/Hunter Disease), Niemann-Pick B Disease, Pompe Disease and Tay-Sachs Disease - a lysosomal storage disease that occurs more commonly in people of Eastern European Ashkenazi descent and causes degeneration of the brain in infants [00073] Also known as glucosylceramide lipidosis, Gaucher's disease is caused by inactivation of the enzyme glucocerebrosidase and accumulation of glucocerebroside. Glucocerebrosidase normally catalyzes the hydrolysis of glucocerebroside to glucose and ceramide. In Gaucher's disease, glucocerebroside accumulates in tissue macrophages which become engorged and are typically found in liver, spleen and bone marrow and occasionally in lung, kidney and intestine. Secondary hematologic sequelae include severe anemia and thrombocytopenia in addition to the characteristic progressive hepatosplenomegaly and skeletal complications, including osteonecrosis and osteopenia with secondary pathological fractures. Gaucher's disease, first described by Phillipe C. E. Gaucher in 1882, is the oldest and most common lysosomal storage disease known. Type I is the most common among three recognized clinical types and follows a chronic course which does not involve the nervous system. Types 2 and 3 both have a CNS component, the former being an acute infantile form with death by age two and the latter a subacute juvenile form. [00074] Fabry disease is an X-linked recessive LSD characterized by a deficiency of α- galactosidase A (α-Gal A), also known as ceramide trihexosidase, which leads to vascular and other disease manifestations via accumulation of glycosphingolipids with terminal α-galactosyl residues, such as globotriaosylceramide (GL-3). Symptoms may include anhidrosis (absence of sweating), painful fingers, left ventricular hypertrophy, renal manifestations, and ischemic strokes. [00075] Niemann-Pick disease, also known as sphingomyelin lipidosis, comprises a group of disorders characterized by foam cell infiltration of the reticuloendothelial system. Foam cells in Niemann-Pick become engorged with sphingomyelin and, to a lesser extent, other membrane lipids including cholesterol. Niemann-Pick is caused by inactivation of the enzyme sphingomyelinase in Types A and B disease, with 27-fold more residual enzyme activity in Type B. The pathophysiology of major organ systems in Niemann-Pick can be briefly summarized as follows. The spleen is the most extensively involved organ of Type A and B patients. The lungs are involved to a variable extent, and lung pathology in Type B patients is the major cause of mortality due to chronic bronchopneumonia. Liver involvement is variable, but severely affected patients may have life-threatening cirrhosis, portal hypertension, and ascites. The involvement of the lymph nodes is variable depending on the severity of disease. Central nervous system (CNS) involvement differentiates the major types of Niemann-Pick. While most Type B patients do not experience CNS involvement, it is characteristic in Type A patients. The kidneys are only moderately involved in Niemann Pick disease.

[00076] The mucopolysaccharidoses (MPS) comprise a group of LSDs caused by deficiency of enzymes which catalyze the degradation of specific glycosaminoglycans (mucopolysaccharides or GAGs) known as dermatan sulfate and heparan sulfate. GAGs contain long unbranched polysaccharides characterized by a repeating disaccharide unit and are found in the body linked to core proteins to form proteoglycans. Proteoglycans are located primarily in the extracellular matrix and on the surface of cells where they lubricate joints and contribute to structural integrity. [00077] The several mucopolysaccharidoses are distinguished by the particular enzyme affected in GAG degradation. For example, MPS I (Hurler-Scheie) is caused by a deficiency of α-L- iduronidase which hydrolyzes the terminal α-L-iduronic acid residues of dermatan sulfate. Symptoms in MPS I vary along a clinical continuum from mild (MPS IS or Scheie disease) to intermediate (MPS IHS or Hurler-Scheie disease) to severe (MPS IH or Hurler disease), and the clinical presentation correlates with the degree of residual enzyme activity. The mean age at diagnosis for Hurler syndrome is about nine months, and the first presenting symptoms are often among the following: coarse facial features, skeletal abnormalities, clumsiness, stiffness, infections and hernias. Other examples of mucopolysaccharidoses include Hunter (MPS II or iduronate sulfatase deficiency), Morquio (MPS IV; deficiency of galactosamine-6-sulfatase and .beta.-galactosidase in types A and B, respectively) and Maroteaux-Lamy (MPS VI or arylsulfatase B deficiency).

[00078] Pompe disease (also known as glycogen storage disease type II, acid maltase deficiency and glycogenosis type II) is an autosomal recessive LSD characterized by a deficiency of α- glucosidase (also known as acid α-glucosidase and acid maltase). The enzyme α-glucosidase normally participates in the degradation of glycogen to glucose in lysosomes; it can also degrade maltose). The three recognized clinical forms of Pompe disease (infantile, juvenile and adult) are correlated with the level of residual α-glucosidase activity. Infantile Pompe disease (type I or A) is most common and most severe, characterized by failure to thrive, generalized hypotonia, cardiac hypertrophy, and cardiorespiratory failure within the second year of life. Juvenile Pompe disease (type II or B) is intermediate in severity and is characterized by a predominance of muscular symptoms without cardiomegaly. Juvenile Pompe individuals usually die before reaching 20 years of age due to respiratory failure. Adult Pompe disease (type III or C) often presents as a slowly progressive myopathy in the teenage years or as late as the sixth decade. In Pompe, it has been shown that α-glucosidase is extensively modified post-translationally by glycosylation, phosphorylation, and proteolytic processing. Conversion of the 110 kilodalton (kDa) precursor to 76 and 70 kDa mature forms by proteolysis in the lysosome is required for optimum glycogen catalysis. [00079] Tay-Sachs disease, also known as GM2 gangliosidosis, hexosaminidase A deficiency or sphingolipidosis, is a genetic disorder, fatal in its most common variant known as Infantile Tay- Sachs disease. TSD is inherited in an autosomal recessive pattern. Hexosaminidase A is a vital hydrolytic enzyme, found in the lysosomes, that catalyzes the biodegradation of fatty acid derivatives known as gangliosides. The disease results from accumulation of the fatty acid derivative ganglioside in the nerve cells of the brain. Gangliosides are cellular membranes lipids, with the ganglioside GM2 especially common in the nervous tissue of the brain. [00080] Tay-Sachs disease is caused by a genetic mutation on the HEXA gene on chromosome 15. Tay-Sachs disease is classified in variant forms, based on the time of onset of neurological symptoms, however all patients with Tay-Sachs disease have a "cherry-red" spot, on the retina due to accumulation of gangliosides in the surrounding retinal ganglion cells. The variant forms of Tay-Sachs disease reflect diversity in the mutation base. With Infantile Tay-Sachs disease, infants with Tay-Sachs disease appear to develop normally for the first six months of life. However, as nerve cells become distended with ganglioside accumulation, mental and physical abilities deteriorate and the child becomes blind, deaf, and unable to swallow. Muscles begin to atrophy and paralysis sets in. Death usually occurs before the age of 4 or 5. Although rare, Juvenile Tay- Sachs disease presents itself in children between 2 and 10 years of age which develop cognitive, motor, speech difficulties (dysarthria), swallowing difficulties (dysphagia), unsteadiness of gait (ataxia), and spasticity. Patients with Juvenile TSD usually die between 5-15 years. Also rare, Adult/Late Onset Tay-Sachs disease occurs in patients in their 20s and early 30s and is usually non- fatal. It is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms include speech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness, particularly schizophrenic-like psychosis. [00081] Krabbe Disease, also known as globoid cell leukodystrophy or galactosylceramide lipidosis, is a rare, often fatal degenerative disorder that affects the myelin sheath of the nervous system. This condition is inherited in an autosomal recessive pattern. Krabbe disease is caused by mutations in the GALC gene, which causes a deficiency of the enzyme galactosylceramidase. The accumulation of unmetabolized lipids affects the growth of the nerve's protective myelin sheath and causes severe degeneration of mental and motor skills. As part of a group of disorders known as leukodystrophies, Krabbe disease results from the imperfect growth and development of myelin. Infants with Krabbe disease are normal at birth, however symptoms begin between the ages of 3 and 6 months with irritability, fevers, limb stiffness, seizures, feeding difficulties, vomiting, and slowing of mental and motor development. Other symptoms include muscle weakness, spasticity, deafness, optic atrophy and blindness, paralysis, and difficulty when swallowing. Prolonged weight loss may also occur. There are also juvenile- and adult-onset cases of Krabbe disease, which have similar symptoms but slower progression.

[00082] Batten Disease, also known as Spielmeyer-Vogt-Sjogren-Batten disease, is a rare, fatal, neurodegenerative disorder that begins in childhood. It is the most common form of a group of disorders called neuronal ceroid lipofuscinosis (or NCLs). Batten disease is inherited in an autosomal recessive manner, with the mutation causing accumulation of lipofuscins in the body's tissues. Early symptoms appear around ages 4-10, with gradual onset of vision problems, or seizures. Early signs may be subtle personality and behavior changes, slow learning or regression, repetitive speech or echolalia, clumsiness, or stumbling. There may be slowing head growth in the infantile form, poor circulation in lower extremities (legs and feet), decreased body fat and muscle mass, curvature of the spine, hyperventilation and/or breath-holding spells, teeth grinding, and constipation. Over time, affected children suffer mental impairment, worsening seizures, and progressive loss of sight, speech and motor skills. Eventually, children with Batten disease become blind, bedridden, and demented. Batten Disease is a life limiting disease; life expectancy varies depending on the type or variation.

Phototransduction

[00083] Phototransduction is the biological conversion of a photon into an electrochemical signal in the retina. The vertebrate retina contains two types of photoreceptor cells: rods and cones. Rods are specialized for vision under low light conditions, whereas cones are less sensitive, provide vision at high temporal and spatial resolutions, and provide color perception. During daylight the rod response is saturated and vision is mediated entirely by cones. Both rods and cones contain a structure called the outer segment which comprises a stack of membranous discs. The reactions of phototransduction take place on the surfaces of these discs. Part of the cycle occurs within the outer segment of the rods and part of the cycle occurs in the retinal pigment epithelium (RPE).

[00084] The first step in the phototransduction cascade is mediated by light sensitive G-protein coupled receptors (GPCRs) called opsins located in the photoreceptor cells of the retina. Rhodopsin is found in the rod cells of the eye and is the active visual chromophore of the phototransduction pathway. Specifically, rhodopsin is a retinylidene protein that consists of 11-cis retinal covalently linked via a Schiff base to the opsin receptor (GPCR). Rhodopsin, G protein- coupled receptor, has two physiological pathways: phototransduction and/or recovery from bleaching (return of activated components to the dark state) and the retinoid cycle (production of 11-cis -retinal). Absorption of a photon by an opsin-pigment molecule causes the 11-cis retinal to undergo photoisomerization to all-trans retinal, which subsequently changes the conformation of the opsin GPCR. This leads to signal a transduction cascade which causes closure of a cyclic GMP-gated cation channel, and hyperpolarization of the photoreceptor cell.

The Retinoid Cycle

[00085] In vertebrates, restoration of a photosensitive receptor conformation (return to the dark state) requires the formation of 11-cis-retinal from all-trans-retinal via the retinoid cycle. The entire cycle of isomerization and pigment regeneration in humans occurs on a time scale of minutes for rhodopsin, and significantly faster for cone pigments. Thus, before light sensitivity can be regained, the all-trans-retinylidene Schiff base hydrolyzes and all-trans-retinal dissociates from the binding pocket of the opsin apoprotein. This all-trans-retinal is then reduced to all-trans retinol by NADPH-dependent all-trans-retinol dehydrogenase, a membrane-associated enzyme that belongs to large gene family of short-chain alcohol dehydrogenases (SCAD), before returning to the retinal pigment epithelium to regenerate 11-cis retinal. The process by which all-trans-retinol translocates to the RPE is poorly defined but it may involve components like IRBP (a protein that transports Vitamin A within the retina) and retinol binding protein (RBP) present in the interphotoreceptor matrix (IPM), or passive diffusion driven by trapping retinoids (e.g., insoluble fatty acid retinyl esters) in RPE.

[00086] The regeneration of 11-cis retinal involves esterification of all-trans retinol and conversion of the resulting product to 11-cis retinol by the isomerohydrolase RPE65. Esterification occurs in the retinal pigment epithelial cell (RPE) and involves the catalyzed transfer of an acyl group from lecithin to retinol by lecithin:retinol acyltransferase (LRAT). The 11-cis retinol is then oxidized to 11-cis-retinal in a reaction catalyzed by NAD- and NADP-dependent 11-cis-retinol dehydrogenases, which are other short chain dehydrogenase family members. Finally 11-cis-retinal moves back to the rod photoreceptors, either in IRBP-dependent or -independent fashion, where it joins with opsin to regenerate a new, functional visual pigment (rhodopsin). Reduction of all trans- retinal to all-trans-retinol takes place in photoreceptor outer segments whereas all other reactions, including isomerization, occur within the RPE.

[00087] Retinal photoreceptors and associated RPE cells also regenerate photochemically altered chromophores. However, photochemically activated chromophores can also chemically react with other molecules in the retina, especially lipids, to form toxic by-products. The most common by-products of phototransduction comprise the lipofuscins, which are very stable toxic substances, and not readily eliminated from the eye. Lipofuscin is the name given to finely granular yellow brown pigment granules composed of lipid-containing residues of lysosomal digestion. Lipofuscin is primarily responsible for the intrinsic fluorescence of the human ocular fundus, and by the ninth decade of life, lipofuscin granules occupy approximately 19% of the area of a macular RPE cell. One important constituent of lipofuscin is derived from the inability of the retinal pigment epithelium (RPE) to convert all all-Zrαns-retinol into 11-ds-retinal. This component is the compound 2-[2,6-dimethyl-8-(2,6,6-trimethyl-l-cyclohexen-l-yl)-lE,3E,5E,7E- octatetraenyl]-l-(2-hydroxyethyl)-4-[4-methyl-6-(2,6,6-trimethyl-l-cyclohexen-l-yl)-lE,3E,5E- hexatrienylj-pyridinium, also referred to as N-retinyl-N-retinylidene ethanolamine or A2E. A2E is a major fluorophore of lipofuscin that increases the sensitivity of the RPE to blue light and has several toxic effects on RPE cells.

[00088] A2E formation begins in photoreceptor outer segments from condensation reactions between phosphatidylethanolamine (PE) and all-trans-retina\ (atRAL) (1:2 stoichiometry) that generate A2-PE, the immediate precursor of A2E. Photoreceptor outer segments are shed from the photoreceptors in a circadian regulated process and are phagocytosed by the RPE. Thus, A2-PE is deposited in RPE cells during the normal process of outer- segment phagocytosis. Subsequent phosphate cleavage of A2-PE generates A2E. Since the eye is exposed to light, photoisomers of A2E are also generated, including iso-A2E.

[00089] Other products of reactions of αll-trαns-reύn&\ are αll-trαns-τeύna\ dimer- phosphatidylethanolamine (atRAL d-PE) and its cleavage product atRAL dimer-ethanolamine. Besides having structures that are distinct from A2E, atRAL d-PE and atRAL dimer-ethanolamine have UV- visible absorbance spectra that are red-shifted relative to A2E (atRAL d-PE: λ_mαx 265, 510; A2E: λ_mαx, 335, 439).

Macular Degeneration

[00090] Macular degeneration (also referred to as retinal degeneration) is a disease of the eye that involves deterioration of the central portion of the retina, known as the macula, which is a portion of the retina that is responsible for sharp central vision. Such deterioration involves thinning, atrophy, and in some cases, bleeding and/or scarring. Macular degeneration results in loss of central vision, which entails inability to see fine details, to read, or to recognize faces. According to the American Academy of Ophthalmology, it is the leading cause of central vision loss (blindness) in the United States today for those over the age of fifty years. Macular degeneration is used to refer to macular dystrophies affecting younger individuals, however macular degeneration is predominantly found in elderly adults and the term generally refers to age- related macular degeneration (AMD or ARMD).

[00091] There are two general categories of age-related macular degeneration: "dry" (also known as atrophic, nonexudative, drusenoid or non-neovascular) macular degeneration and "wet" (also known as choroidal neovascularization, subretinal neovascularization, exudative, or disciform degeneration) macular degeneration. Approximately 85% to 90% of the cases of macular degeneration are "dry" macular degeneration, while about 10% to 15% of the cases of macular degeneration are "wet" macular degeneration. However, "wet" macular degeneration cases account for approximately 90% of macular degeneration-related blindness.

[00092] In "dry" macular degeneration, the deterioration of the retina is associated with the formation of small yellow deposits, known as drusen, under the macula, and with the accumulation of lipofuscin in the RPE. Drusen are extracellular deposits that accumulate below the RPE. This phenomena leads to a thinning and drying out of the macula, and the location and amount of thinning in the retina caused by the drusen directly correlates to the amount of central vision loss. Degeneration of the pigmented layer of the retina and photoreceptors overlying drusen become atrophic and can cause a slow loss of central vision.

[00093] In "wet" macular degeneration new blood vessels form to improve the blood supply to retinal tissue, specifically beneath the macula. The new vessels are leaky and sometimes rupture, causing leakage of blood and fluid into the macula resulting in damage to photoreceptor cells and the surrounding tissue. Studies have shown that the dry form of macular degeneration can lead to the wet form of macular degeneration, wherein the presence of drusen under the macula can cause damage to such blood vessels. Neovascularization can lead to rapid loss of vision and eventual scarring of the retinal tissues and bleeding in the eye. This scar tissue and blood produces a dark, distorted area in the vision, often rendering the eye legally blind.

[00094] Stargardt's Disease, also known as Stargardt's Macular Dystrophy or Fundus Flavimaculatus, is a macular dystrophy that manifests as a recessive form of macular degeneration with an onset typically during childhood, and is characterized clinically by progressive loss of central vision and progressive atrophy of the RPE overlying the macula. Mutations in the human ABCA4 gene (also known as the ABCR gene) for Rim Protein (RmP) are responsible for Stargardt's Disease. Early in the disease course, patients show delayed dark adaptation but otherwise normal rod function. Histologically, Stargardt's Disease is associated with deposition of lipofuscin pigment granules in RPE cells. In the case of Stargardt's disease, the RPE is confronted with photoreceptor outer segments that contain abnormally high levels of all-Zrαns-retinal and N- retinylidine-PE. As a consequence, during enzymatic digestion within phagosomes N-retinylidine- N-retinylethanolamine (A2E) is generated. A2E is a major fluorophore of lipofuscin and has several toxic effects on the RPE. Removal of N-retinylidine-PE from the disks may be facilitated by an ATP-binding cassette transporter (AB C A4). Mutations in ABCA4 have been implicated in recessive retinitis pigmentosa, recessive cone -rod dystrophy, and non-exudative age-related macular degeneration, although the prevalence of ABCA4 mutations in AMD is still uncertain. However, with reduced function of ABCR, the RPE is poisoned by A2E. The resulting loss of function of the RPE and the possible loss of RPE cells is thought to result in photoreceptor degeneration and subsequent loss of vision.

[00095] In addition, there are several types of macular degenerations that affect children, teenagers or adults that are commonly known as early onset or juvenile macular degeneration. Many of these types are hereditary and are looked upon as macular dystrophies instead of degeneration. Some examples of macular dystrophies include: Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, as well as Stargardt's Disease.

[00096] A2E accumulation in lysosomes within the RPE during aging, or because of an inherited retinal disorder, can be regarded as another type of lysosomal-storage disease. One of the hallmarks of aging and of some inherited retinal disorders is the progressive accumulation of autofluorescent membrane-bound lipofuscin in the retinal pigmented epithelium (RPE). A2E, a major fluorophore of lipofuscin, accumulates abnormally in some types of macular or retinal degeneration or dystrophy, including Stargardt's Disease and probably age-related macular degeneration, presumably due to excess production of the phototransduction retinoid, all-trans- retinaldehyde; a precursor of A2E. As described above, lipofuscin is amassed by the RPE cells by phagocytosis of the large number of outer segment disc membranes that are shed daily by the photoreceptor cells. The greatest accumulation of lipofuscin by RPE cells occurs in the macula, due to the high concentration of photoreceptors in this area. Similar to Stargardt's Disease, lipofuscin deposition in RPE cells is also seen prominently in AMD, and some cases of retinitis pigmentosa.

[00097] The production of lipofuscin, and potentially drusen (extracellular deposits that accumulate below the RPE) under the macula are risk factors for developing age-related macular degeneration. The presence of excessive lipofuscin is detected by fundus autofluorescence, wherein the fluorescence is associated with A2E, an orange-emitting fluorophore, and A2E-related compounds. As presented above, lipofuscin accumulates progressively in a number or retinal diseases, such as recessive and dominant Stargardt's disease, age-related macular degeneration (AMD), ABCA4-mediated autosomal recessive cone-rod dystrophy, and a form of autosomal recessive retinitis pigmentosa (RP19). In addition, strong fundus autofluorescence, indicating the presence of excessive lipofuscin, is also seen in patients with Best vitelliform macular dystrophy and a subset of patients with cone -rod dystrophy.

[00098] Lipofuscin accumulation has been reported in several animal models of inherited retinal and macular degeneration. The Abca4-/- mouse (also called Abcr-/-), a model for recessive Stargardt's disease, exhibits an accumulation of lipofuscin granules and A2E in the RPE cells. Also, mice with deficiency in all-trans-RDH in photoreceptors, contain several-fold higher levels of A2E compared with WT eyes. Transgenic mice with a mutation in the elovl4 gene, the gene involved in dominant Stargardt' s macular degeneration, contain elevated levels of A2E in the RPE. Transgenic mice that express a mutant form of cathepsin D (mcd) in RPE cells manifest many features of AMD including autofluorescent lipofuscin pigments in the RPE. Mice with knockout mutations in the genes for monocyte chemoattractant protein- 1 (Ccl-2), or its cognate chemokine receptor-2 (Ccr-2), show clinical features of AMD and A2E accumulation in RPE cells. In addition, Sodl-/-, reported to be a good animal model for AMD, also have elevated A2E levels compared to WT controls.

[00099] Non-diseased eyes contain low concentrations A2E, indicating that certain levels of A2E are tolerated by the photoreceptors and the RPE. However, diseased eyes have elevated concentrations of A2E, and at high concentrations A2E sensitizes the RPE to light-induced damage, including lysosomal rupture which leads to cell death. In addition, high concentrations of A2E are cytotoxic to the RPE, which leads to retinal damage and destruction. Furthermore, A2E has many toxic properties in vitro, such as inhibition of lysosomal function. For example, in Stargardt's Disease A2E levels can be over 10x higher than that in normal eyes. [000100] Currently, treatment options for the macular degenerations and macular dystrophies are limited and unsatisfactory. Some patients with dry form AMD have responded to high doses of vitamins and minerals. In addition, a few studies have indicated that laser photocoagulation of drusen prevents or delays the development of drusen that can lead to the more severe symptoms of dry form AMD. Finally, certain studies have shown that extracorporeal rheopheresis benefits patients with dry form AMD. However, successes have been limited and there continues to be a strong desire for new methods and treatments to manage and limit vision loss associated with the macular degenerations and dystrophies.

[000101] Thus, because the over-accumulation of toxic products is responsible for the symptoms associated with the macular degenerations and retinal dystrophies, the removal and disposal of toxic products that arise from side reactions in the phototransduction cycle are important. Specifically, the reduction of the amount of A2E in the RPE would be beneficial in reducing lipofuscin build-up, and afford a treatment of Stargardt's and age-related macular degeneration. Furthermore, since A2E excess typically takes decades to build up, removing/clearing out even a small fraction of A2E has therapeutic benefit in prolonging the patient's visual longevity and is applicable in treating all the human retinal diseases listed above, as well as those represented by the animal models.

[000102] Current therapeutic approaches to treating A2E-mediated diseases involve the slowing down or arrest of A2E biosynthesis, and are not designed to affect the existing pool of A2E in the eye. For example, fenretinide is reported to reduce vitamin A delivery to the eye, there by reducing the flow of retinoids in the retinoid cycle. The latter reduces the rate of phototransduction and therefore, the rate of A2E biosynthesis. This approach does not lower the existing pool of A2E below the initial level of A2E at the beginning of the treatment. In contrast, the A2E removal/clearance approach provided herein is used to remove some or all of the existing A2E pool, and to prevent further accumulation of A2E in the RPE as long as the clearing drug is applied.

Lysosomotropic agents

[000103] Lysosomotropic agents are a class of compounds that preferentially accumulate within lysosomes by ionic trapping. Provided herein are lysosomotropic agents, pharmaceutical compositions containing lysomotrpic agents, and methods for the treatment of lysosomal storage diseases, wherein such compositions and methods affect lysosomal clearance/removal of toxic products from within the lysosome. The lysosomotropic agents used in the compositions, methods and combination therapies provided herein include, but are not limited to, Acridine orange (N,N,N',N'-tetramethylacridine-3,6-diamine; CAS Registry No. 494-38-2); 1-adamantanamine (N,N-dimethyladamantan-l-amine; CAS Registry No. 768-94-5); Amantadine (adamantan-1- amine; CAS Registry No. 665-66-7 ); 4-aminoquinoline (quinolin-4-amine; CAS Registry No. 578-68-7); Amiodarone ((2-butylbenzofuran-3-yl)-[4-(2-diethylaminoethoxy)-3,5-diiodo- phenyljmethanone; CAS Registry No. 1951-25-3); Amodiaquine (4 -[(7-chloroquinolin-4- yl)amino]-2-(diethylaminomethyl)phenol; CAS Registry No. 86-42-0); Azithromycin ((2R,3R,4R,5R,8R,10R,llR,13S,14R)-ll-[(2S,3R,4S,6R)-4-dimethylamino-3-hydroxy-6-methyl- oxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2S,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl- oxan-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-l-oxa-6-azacyclopentadecan-15-one dehydrate; CAS Registry No. 117772-70-0); 4-benzoyl-oxi-2-azetidinove ((4-oxoazetidin-2-yl) benzoate; CAS Registry No. 28562-58-5); Chloroquine (N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-l,4- diamine; ); CAS Registry No. 54-05-7); Chlorpromazine (3-(2-chloro-10H-phenothiazin-10-yl)- N,N-dimethyl-propan-l -amine; CAS Registry No. 50-53-3); Citalopram (l-(3- dimethylaminopropyl)-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-5-carbonitrile; CAS Registry No. 59729-33-8); Clindamycin ((2S,4R)-N-[2-chloro-l-[(2R,3S,4S,5R,6R)-3,4,5-trihydroxy-6- methylsulfanyl-oxan-2-yl]propyl]- l-methyl-4-propyl-pyrrolidine-2-carboxamide; CAS Registry No. 24696-19-3); Clomipramine (3-(3-chloro-10,π-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N- dimethylpropan-1 -amine; CAS Registry No. 303-49-1); DAMP (N-(3-[(2,4-dinitrophenyl)-amino]- propyl)-N-(3-aminopropyl-methylamine)dihydrochloride,); Fluoxetine (N-methyl-3-phenyl-3-[4- (trifluoromethyl)phenoxy]-propan-l- amine; CAS Registry No. 54910-89-3); Flupentixol (2-[4-[3- [2-(trifluoromethyl)thioxanthen-9-ylidene] propyl]piperazin-l-yl]ethanol; CAS Registry No. 2709- 56-0); Fluphenazine (2- [4- [3 - [2-(trifluoromethyl)- 10H-phenothiazin- 10-yl]propyl] -piperazin- 1 - yljethanol; CAS Registry No. 69-23-8); Haloperidol (4-[4-(4-chlorophenyl)-4-hydroxy-l- piperidyl]-l-(4-fluorophenyl)-butan-l-one; CAS Registry No. 52-86-8); Hydroxizine (2-[2-[4-[(4- chlorophenyl)-phenyl-methyl]piperazin-l-yl]ethoxy]ethanol; CAS Registry No. 68-88-2); Hydroxychloriquine sulfate (2-[{4-[(7-chloroquinolin-4-yl)amino]pentyl}(ethyl)amino]ethanol; CAS Registry No. 118-42-3); Imipramine (3-(5,6-dihydrobenzo[b][l]benzazepin-ll-yl)-N,N- dimethylpropan-1- amine; CAS Registry No. 50-49-7); ketotifen fumarate (4-(l-methylpiperidin-4- ylidene)-4,9-dihydro-10H-benzo[4,5]cyclohepta[l,2-b]thiophen-10-one; CAS Registry No. 34580- 14-8); Levomepromazine ((2R)-3-(2-Methoxyphenothiazine- 10-yl-)-N,N,2-trimethylpropanamine; CAS Registry No. 60-99-1); LysoTracker® green (7-(3-(2-(dimethylamino)ethylamino)-3- oxopropyl)-5,5-difluoro-l,3-dimethyl-2,5-dihydro-lH-dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin- 4-ium-5-uide; CAS Registry No. 220524-71-0, ); LysoTracker® red (7-(3-(2- (dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-3-(lH-pyrrol-2-yl)-2,5-dihydro-lH- dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5-uide; CAS- No. 231946-72-8); Meclofenoxate (2-dimethylaminoethyl 2-(4-chlorophenoxy)acetate; CAS Registry No. 51-68-3); Mesoridazine (10-{2-[(RS)l-Methylpiperidin-2-yl]ethyl}- 2-methylsulfinyl- 10H-phenothiazine; CAS Registry No. 5588-33-0); Methylamine (methanamine; CAS Registry No. [74-89-5] ); Monensin (4-[2-[5- ethyl-S-fS-fό-hydroxy-ό-Chydroxymethy^-S^-dimethyl-oxan^-yll-S-methyl-oxolan^-ylloxolan- 2-yl]-9-hydroxy-2,8-dimethyl-l,6-dioxaspiro[4.5]dec-7-yl]-3-methoxy-2-methyl-pentanoic acid; CAS Registry No. 22373-78-0); Monodansylcadaverine (N-(5-aminopentyl)-5- (dimethylamino)naphthalene-l -sulfonamide; CAS Registry No. 10121-91-2); NH₄Cl (azanium chloride; CAS Registry No. 12125-02-9); Nile Blue A ([9-(diethylamino)benzo[a]phenoxazin-5- ylidene] azanium sulfate; ); Perhexilene (2-(2,2-dicyclohexylethyl)piperidine; CAS Registry No. 6621-47-2); Perphenazine (2-[4-[3-(2-chloro-10H-phenothiazin-10-yl) propyl]piperazin-l- yljethanol; CAS Registry No. 58-39-9); phenylalanine methyl ester (methyl (2S)-2-amino-3- phenyl-propanoate hydrochloride; CAS Registry No. 2577-90-4); Piperazine (Piperazine; CAS Registry No. 110-85-0); primaquine (N-(6-methoxyquinolin-8-yl)pentane-l,4-diamine; CAS Registry No. 491-92-9); Prochlorperazine (2-chloro-10-[3-(4-methyl-l-piperazinyl)propyl]-10H- phenothiazine; CAS Registry No. 58-38-8); Promazine (N,N-dimethyl-3-(10H-phenothiazin-10-yl) propan-1-amine; CAS Registry No. 58-40-2); Propranolol (l-(isopropylamino)-3-(naphthalen-l- yloxy)propan-2-ol; CAS Registry No. 525-66-6); Suramin (8-[[4-methyl-3-[[3-[[3-[[2-methyl-5- [(4,6,8-trisulfonaphthalen-l- y^carbamoyllphenyljcarbamoyllphenyllcarbamoylaminolbenzoyllaminolbenzoyllaminolnaphthal ene-l,3,5-trisulfonic acid; CAS Registry No. 145-63-1); Thioridazine (10-(2-[(RS)-I- Methylpiperidin-2-yl]ethyl}-2-methylsulfanyl-phenothiazine; CAS Registry No. 50-52-2); Thioridazine ( 10- { 2-[(RS)-I -Methylpiperidin-2-yl]ethyl } -2-methylsulfanyl-phenothiazine; CAS Registry No. 50-52-2 ); Tributylamine (N,N-dibutylbutan-l -amine; CAS Registry No. 6309-30-4); Trifluoperazine (10-[3-(4-methylpiperazin-l-yl)propyl]-2-(trifluoromethyl)-10H-phenothiazine; CAS Registry No. 117-89-5); Triflupromazine (N,N-dimethyl-3-[2-(trifluoromethyl)- 10H- phenothiazin-10-yl]-propan-l-amine; CAS Registry No. 146-54-3)..

[000104] In certain embodiments, the lysosomotropic agents are weakly-basic amines that, in the lower pH environment within the lysosome, are protonated and become positively charged and are thereby less likely to cross the lysosomal membrane.

[000105] In certain embodiments, the lysosomotropic agent used in the compositions, methods and combination therapies provided herein is chlorpromazine. Chlorpromazine (CPZ) is a strongly lysosomotropic agent, with a log Poet of 5.19 and a pKa of 9.3. Lysosomal Clearance

[000106] Provided herein are lysosomotropic agents, pharmaceutical compositions containing lysomotrpic agents, and methods for the treatment of lysosomal storage diseases, wherein such compositions and methods affect lysosomal clearance/removal of toxic products from within the lysosome. Such methods of lysosomal clearance are achieved using lysosomotropic agents, either alone, included in a pharmaceutical composition, or as part of a combination therapy. [000107] In certain embodiments of the lysosomal clearance/removal methods provided herein, a first lysosomotropic agent is administered either alone, included in a pharmaceutical composition, or as part of a combination therapy, followed by administration of a second lysosomotropic agent either alone, included in a pharmaceutical composition, or as part of a combination therapy. In certain embodiments, the first lysosomotropic agent clears the lysosome of toxic agents and subsequently the first lysosomotropic agent is cleared from the lysosome by the second lysosomotropic agent.

[000108] In certain embodiments of the lysosomal clearance/removal methods provided herein, that is the application of lysosomotrope-mediated clearance of lysososomal toxic contents, are therapeutic for all retinal diseases that exhibit above-normal accumulation of lipofuscin, A2E, A2E-related metabolites (such as, by way of example only, A2E isomers like iso-A2E), and other toxic vitamin A-related byproducts phototransduction or the retinoid cycle (such as, by way of example only, all-trans retinal dimer). In other embodiments, such retinal disease are retinal diseases that involve genetic variations in the ABCA4 gene including, but not limited to, recessive Stargardt's macular degeneration, age-related macular degeneration, recessive retinitis pigmentosa, and cone-rod dystrophy. In other embodiments, such retinal disease are retinal diseases where ABCR deficiency is not necessarily involved, such as, by way of example only, age-related macular degeneration associated with mutations in complement factors or other genes, Best vitelliform macular dystrophy (BMD), and dominant Stargardt's macular degeneration. [000109] In certain embodiments, the lysosomal clearance/removal methods provided herein, that is the application of lysosomotrope-mediated clearance of lysososomal toxic contents, are therapeutic for other lysosomal-storage diseases wherein the toxic accumulation of metabolites and undegraded material occurs. This accumulation leads to enlargement of cells, cellular dysfunction, and cell death. In certain embodiments, such lysosomal-storage diseases include, but are not limited to, Tay-Sachs disease, Batten Disease, Krabbe Disease, Pompe disease, Gaucher Disease, Mucopolysacchiradosis I (MPS I/Hurler/Hurler-Scheie/Scheie), Mucopolysacchiradosis II (MPS II/Hunter Disease), Fabry Disease, leukodystrophies and Niemann-Pick Disease. In other embodiments, the lysosomal clearance/removal methods provided herein are therapeutic for treatment of atherosclerosis wherein the accumulation of cholesterol and cholesterol esters in the lysosomes of macrophages, referred to as foam cells, occurs.

[000110] In certain embodiments, the lysosomal clearance/removal is dependent on the concentration of the lysosomotropic agent used. In certain embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of the lysosomotropic agent in the range of 0.5 μM to 200 μM. In other embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of the lysosomotropic agent in the range of 0.5 μM to 150 μM. In other embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of the lysosomotropic agent in the range of 0.5 μM to 100 μM. In other embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of the lysosomotropic agent in the range of 0.5 μM to 80 μM. In other embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of the lysosomotropic agent in the range of 0.5 μM to 60 μM. In other embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of the lysosomotropic agent in the range of 0.5 μM to 50 μM. In other embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of the lysosomotropic agent in the range of 0.5 μM to 40 μM. In other embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of the lysosomotropic agent in the range of 0.5 μM to 30 μM. In other embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of the lysosomotropic agent in the range of 0.5 μM to 25 μM. In other embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of the lysosomotropic agent in the range of 0.5 μM to 20 μM. In other embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of the lysosomotropic agent in the range of 0.5 μM to 10 μM.

[000111] In certain embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of the lysosomotropic agent in the range of 0.5 mg/kg to 50 mg/kg. In other embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of the lysosomotropic agent in the range of 0.5 mg/kg to 40 mg/kg. In certain embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of the lysosomotropic agent in the range of 0.5 mg/kg to 30 mg/kg. In certain embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of the lysosomotropic agent in the range of 0.5 mg/kg to 25 mg/kg. In certain embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of the lysosomotropic agent in the range of 0.5 mg/kg to 20 mg/kg. In certain embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of the lysosomotropic agent in the range of 0.5 mg/kg to 10 mg/kg. In certain embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of the lysosomotropic agent in the range of 0.5 mg/kg to 5 mg/kg. [000112] In certain embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of Chlorpromazine in the range of 0.5 mg/kg to 50 mg/kg. In other embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of Chlorpromazine in the range of 0.5 mg/kg to 40 mg/kg. In certain embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of Chlorpromazine in the range of 0.5 mg/kg to 30 mg/kg. In certain embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of Chlorpromazine in the range of 0.5 mg/kg to 25 mg/kg. In certain embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of Chlorpromazine in the range of 0.5 mg/kg to 20 mg/kg. In certain embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of Chlorpromazine in the range of 0.5 mg/kg to 10 mg/kg. In certain embodiments effective clearance/removal of lysosomal toxic contents is achieved with the concentration of Chlorpromazine in the range of 0.5 mg/kg to 5 mg/kg.

High-Throughput Assays

[000113] High throughput assay for rapidly screening of lysosomotropic agents is described herein, wherein such lysosomotropic agents are for use in the methods, compositions and combination therapies disclosed herein.

[000114] In certain embodiments, the assay detects and/or quantitates potential lysosomotropic agents, wherein the potential lysosomotropic agents or therapeutic candidates are added prior to, during or after incorporation of a Lysotracker® dye into RPE cells. Clearance of the Lysotracker® dye from the RPE cells by the lysosomotropic agents, which includes the lysosomotropic agents provided herein, causes a change in the amount of an optically detectable Lysotracker® within the

RPE cells. The degree of clearance is determined by measuring the amounts of Lysotracker® in solution to that measured within the RPE cells. Alternatively, the degree of clearance is determined by measuring the amounts of Lysotracker® within the RPE cells before and after treatment with a lysosomotropic agent. In certain embodiments, measurements are performed using a high throughput optical device, including microtiter plate fluorescent readers. In certain embodiments, the efficacy of potential lysosomotropic agents is evaluated by comparison of their respective log Poet plots.

[000115] In certain embodiments, the assay detects and/or quantitates potential lysosomotropic agents, wherein the potential lysosomotropic agents or therapeutic candidates are added prior to, during or after A2E incorporation into RPE cells. Clearance of the A2E from the RPE cells by the lysosomotropic agents, which includes the lysosomotropic agents provided herein, causes a change in the amount of an optically detectable A2E within the RPE cells. The degree of clearance is determined by measuring the amounts of A2E in solution to that measured within the RPE cells. Alternatively, the degree of clearance is determined by measuring the amounts of A2E within the RPE cells before and after treatment with a lysosomotropic agent. In certain embodiments, measurements are performed using a high throughput optical device, including microtiter plate fluorescent readers. In certain embodiments, the efficacy of potential lysosomotropic agents is evaluated by comparison of their respective log Poet plots.

[000116] In certain embodiments, the assay detects and/or quantitates potential lysosomotropic agents, wherein the potential lysosomotropic agents or therapeutic candidates are added prior to, during or after incorporation of other metabolites of the retinoid cycle and lipofuscin into RPE cells. Such metabolites include, but are not limited to, A2E precursors (e.g. N-retinylidene- phosphatidylethanolamine, dihydro-A2PE , A2PE, etc.); oxidation products of A2E precursors (e.g. oxidation products of A2PE, etc.); A2E and its photoisomers (e.g. iso-A2E), A2E oxidation products (e.g. peroxy-A2E, furan-A2E, etc.); all-trans-retinal dimer series (e.g. free all-trans retinal, all-trans-retinal dimer-phosphatidylethanolamine, all-trans-retinal dimer-ethanolamine, etc.); as well as other identified and unidentified components of lipofuscin that accumulate in lysosomes. Clearance of such metabolites from the RPE cells by the lysosomotropic agents, which includes the lysosomotropic agents provided herein, causes a change in the amount of a detectable metabolites within the RPE cells. In certain embodiments, such metabolites are detected optically, while in other embodiments are detected by HPLC, LC/MS, or immunocytochemical analyses. The degree of clearance is determined by measuring the amounts of metabolites in solution to that measured within the RPE cells. Alternatively, the degree of clearance is determined by measuring the amounts of metabolites within the RPE cells before and after treatment with a lysosomotropic agent. In certain embodiments, measurements are performed using a high throughput optical device, including microtiter plate fluorescent readers. In certain embodiments, the efficacy of potential lysosomotropic agents is evaluated by comparison of their respective log Poet plots.

Routes of Administration and Pharmaceutical Compositions

[000117] For the therapeutic uses of the lysosomotropic agents described herein, such agents are administered in therapeutically effective amounts either alone or as part of a pharmaceutical composition. Accordingly, provided herein are pharmaceutical compositions, which comprise at least one lysosomotropic agent described herein and one or more pharmaceutically acceptable carriers, diluents, or excipients. In addition, such lysosomotropic agents and pharmaceutical compositions containing at least one lysosomotropic agent are administered singly or in combination with one or more additional therapeutic agents. The routes of administration of such lysosomotropic agents and pharmaceutical compositions include, but are not limited to, oral administration, intravitreal administration, rectal administration, parenteral, intravenous administration, intraperitoneal administration, intramuscular administration, inhalation, transmucosal administration, pulmonary administration, intestinal administration, subcutaneous administration, intramedullary administration, intrathecal administration, direct intraventricular, intranasal administration, topical administration, ophthalmic administration or otic administration. [000118] In certain embodiments, lysosomotropic agents or pharmaceutical compositions described herein are administered locally, while in other embodiments lysosomotropic agents or pharmaceutical composite described herein are administered systemically. Local administration includes, but is not limited to, injection into an organ, optionally in a depot or sustained release formulation. Systemic administration includes, but is not limited to, oral administration or intravenous administration. In other embodiments, lysosomotropic agents or pharmaceutical compositions described herein are administered in a targeted drug delivery system, such as, by way of example only, in a liposome coated with organ- specific antibody. The liposome is targeted to and taken up selectively by the organ. In other embodiments, lysosomotropic agents or pharmaceutical compositions described herein are administered in the form of a rapid release formulation, while in other embodiments, lysosomotropic agents or pharmaceutical compositions described herein are administered in the form of an extended release formulation. In other embodiments, lysosomotropic agents or pharmaceutical compositions described herein are administered in the form of an intermediate release formulation. [000119] The therapeutically effective amount will vary depending on, among others, the disease indicated, the severity of the disease, the age and relative health of the subject, the potency of the compound administered, the route of administration and the treatment desired. In certain embodiments, satisfactory results are indicated to be obtained at daily dosages daily dosage of a lysosomotropic agent from about 0.03 to 50 mg/kg per body weight. In certain embodiments, satisfactory results are indicated to be obtained at daily dosages daily dosage of a lysosomotropic agent from about 0.03 to 40 mg/kg per body weight. In certain embodiments, satisfactory results are indicated to be obtained at daily dosages daily dosage of a lysosomotropic agent from about 0.03 to 30 mg/kg per body weight. In certain embodiments, satisfactory results are indicated to be obtained at daily dosages daily dosage of a lysosomotropic agent from about 0.03 to 25 mg/kg per body weight. In certain embodiments, satisfactory results are indicated to be obtained at daily dosages daily dosage of a lysosomotropic agent from about 0.03 to 20 mg/kg per body weight. In certain embodiments, satisfactory results are indicated to be obtained at daily dosages daily dosage of a lysosomotropic agent from about 0.03 to 10 mg/kg per body weight. In certain embodiments, satisfactory results are indicated to be obtained at daily dosages daily dosage of a lysosomotropic agent from about 0.03 to 5 mg/kg per body weight. In certain embodiments, satisfactory results are indicated to be obtained at daily dosages daily dosage of a lysosomotropic agent from about 0.03 to 2.5mg/kg per body weight. In certain embodiments, the daily dosage of a lysosomotropic agent, administered intravitreally, is in the range from 0.05 micrograms per kilogram body weight (μg/kg) to 100 micrograms per kilogram body weight (μg/kg). In certain embodiments, the daily dosage of a lysosomotropic agent, administered ophthalmically, is in the range from 0.05 micrograms per kilogram body weight (μg/kg) to 100 micrograms per kilogram body weight (μg/kg). In other embodiments, the daily dosage of a lysosomotropic agent, administered orally, is in the range from 0.01 micrograms per kilogram body weight (μg/kg) to 100 milligrams per kilogram body weight (mg/kg). In certain embodiments, the daily dosage of a lysosomotropic agent, administered intraperitoneally, is in the range from 0.05 micrograms per kilogram body weight (μg/kg) to 100 micrograms per kilogram body weight (μg/kg). An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5mg to about lOOmg of a lysosomotropic agent, conveniently administered, e.g. in divided doses up to four times a day or in controlled release form. In certain embodiment, unit dosage forms for oral administration comprise from about 1 to 50 mg of a lysosomotropic agent.

[000120] Other aspects provided herein are processes for the preparation of pharmaceutical composition which comprise at least one lysosomotropic agent described herein. In certain embodiments, such processes include admixing a lysosomotropic agent described herein with one or more pharmaceutically acceptable carriers, diluents or excipients. In certain embodiments, the pharmaceutical compositions comprise a lysosomotropic agent in free form or in a pharmaceutically acceptable salt or solvate form. In certain embodiments, the pharmaceutical compositions comprising a lysosomotropic agent in free form or in a pharmaceutically acceptable salt or solvate form, in association with at least one pharmaceutically acceptable carrier, diluent or excipient are manufactured by mixing, dissolving, granulating dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes and/or coating methods. In other embodiments, such compositions are optionally contain excipients, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In other embodiments, such compositions are sterilized. Ophthalmic Administration

[000121] In certain embodiments, the lysosomotropic agents or pharmaceutical composition described herein are ophthalmic ally administered to the eye. Administration to the eye generally results in direct contact of the agents with the cornea, through which at least a portion of the administered agents pass. In certain embodiments, such lysosomotropic agents or pharmaceutical compositions have an effective residence time in the eye of about 2 to about 24 hours. In certain embodiments, such lysosomotropic agents or pharmaceutical compositions have an effective residence time in the eye of about 4 to about 24 hours. In certain embodiments, such lysosomotropic agents or pharmaceutical compositions have an effective residence time in the eye of about 6 to about 24 hours.

[000122] Ophthalmic administration, as used herein, includes, but is not limited to, topical administration, intraocular injection, subretinal injection, intravitreal injection, periocular administration, subconjuctival injections, retrobulbar injections, intracameral injections (including into the anterior or vitreous chamber), sub-Tenon's injections or implants, ophthalmic solutions, ophthalmic suspensions, ophthalmic ointments, ocular implants and ocular inserts, intraocular solutions, use of iontophoresis, incorporation in surgical irrigating solutions, and packs (by way of example only, a saturated cotton pledget inserted in the fornix). In certain embodiments, the lysosomotropic agents or pharmaceutical composition described herein are formulated as an ophthalmic composition and are administered topically to the eye. Such topically administered ophthalmic compositions include, but are not limited to, solutions, suspensions, gels or ointments. [000123] In certain embodiments the pharmaceutical compositions, comprising at least one lysomotrpic agent described herein, used for ophthalmic administration take the form of a liquid where the compositions are present in solution, in suspension or both. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous. In other embodiments, such liquid compositions take the form of an ointment. In certain embodiments pharmaceutical compositions containing at least one lysosomotropic agent are administered ophthamically as eye drops formulated as aqueous solutions that optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. A desired dosage is administered via a known number of drops into the eye. By way of example only, for a drop volume of 25 μl, administration of 1-6 drops delivers 25-150 μl of the composition. In certain embodiments, the aqueous compositions contain from about 0.01% to about 50% weight/volume of a lysosomotropic agent. In other embodiments, the aqueous compositions contain from about 0.1% to about 20% weight/volume of a lysosomotropic agent. In still other embodiments, the aqueous compositions contain from about 0.2% to about 10% weight/volume of a lysosomotropic agent. In certain embodiments, the aqueous compositions contain from about 0.5% to about 5%, weight/volume of a lysosomotropic agent.

[000124] In certain embodiments the aqueous compositions have an ophthalmically acceptable pH and osmolality. In certain embodiments the aqueous compositions include one or more ophthalmically acceptable pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris- hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an ophthalmically acceptable range.

[000125] In certain embodiments the compositions also include also include one or more ophthalmically acceptable salts in an amount required to bring osmolality of the composition into an ophthalmically acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[000126] In certain embodiments the aqueous compositions also contain one or more polymers as suspending agents. Such polymers include, but are not limited to, water-soluble polymers such as cellulosic polymers described herein, (for example only, hydroxypropyl methylcellulose), and water-insoluble polymers described herein (for example only, cross-linked carboxyl-containing polymers). In certain embodiments, the aqueous compositions also include an ophthalmically acceptable mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.

[000127] In certain embodiments the compositions also include ophthalmically acceptable solubilizing agents to aid in the solubility of a lysosomotropic agent. The term "solubilizing agent" generally includes agents that result in formation of a micellar solution or a true solution of the agent. In certain embodiments, ophthalmically acceptable nonionic surfactants including, but not limited to, polysorbate 80 are used as solubilizing agents. In other embodiments, ophthalmically acceptable glycols including, but not limited to, polyglycols, polyethylene glycol 400, and glycol ethers are used as solubilizing agents.

[000128] In certain embodiments the compositions also include one or more ophthalmically acceptable surfactants to enhance physical stability or for other purposes. Such nonionic surfactants include, but are not limited to, polyoxyethylene fatty acid glycerides and vegetable oils (by way of example only, polyoxyethylene (60) hydrogenated castor oil) and polyoxyethylene alkylethers and alkylphenyl ethers (by way of example only, octoxynol 10 and octoxynol 40). [000129] In certain embodiments the compositions also include one or more ophthalmically acceptable preservatives to inhibit microbial activity. Such preservatives include, but are not limited to mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[000130] In certain embodiments the compositions also include one or more antioxidants to enhance chemical stability where required. Such antioxidants include, but are not limited to, ascorbic acid and sodium metabisulfite.

[000131] In certain embodiments, the aqueous compositions provided herein are packaged in single-dose non-reclosable containers, while in other embodiments the aqueous compositions provided herein are packaged in multiple-dose reclosable containers wherein a preservative is included in the composition.

[000132] In certain embodiments, the ophthalmic compositions containing one or more lysosomotropic agents take the form of a solid article that can be inserted between the eye and eyelid or in the conjunctival sac, where it releases the agent. Release is to the lacrimal fluid that bathes the surface of the cornea, or directly to the cornea itself, with which the solid article is generally in intimate contact. Solid articles suitable for implantation in the eye in such fashion are generally composed primarily of polymers and can be biodegradable or non-biodegradable.

Oral Dosage Forms

[000133] In certain embodiments, the pharmaceutical compositions containing at least one lysosomotropic agent are administered orally as discrete dosage forms, wherein such dosage forms include, but are not limited to, capsules, gelatin capsules, caplets, tablets, chewable tablets, powders, pills, dragees, granules, liquids, gels, syrups, flavored syrups, elixirs, slurries, solutions or suspensions in aqueous or non-aqueous liquids, edible foams or whips, and oil-in-water liquid emulsions or water-in-oil liquid emulsions. The capsules, gelatin capsules, caplets, tablets, chewable tablets, powders or granules, used for the oral administration of at least one lysosomotropic agent are prepared by admixing at least one lysosomotropic agent (active ingredient) together with at least one excipient using conventional pharmaceutical compounding techniques. Non-limiting examples of excipients used in oral dosage forms described herein include, but are not limited to, binders, fillers, disintegrants, lubricants, absorbents, colorants, flavors, preservatives and sweeteners.

[000134] Non-limiting examples of such binders include, but are not limited to, corn starch, potato starch, starch paste, pre-gelatinized starch, or other starches, sugars, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose and its derivatives (by way of example only, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxypropyl methylcellulose and microcrystalline cellulose), magnesium aluminum silicate, polyvinyl pyrrolidone and combinations thereof.

[000135] Non-limiting examples of such fillers include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. In certain embodiments, the binder or filler in pharmaceutical compositions provided herein are present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

[000136] Non-limiting examples of such disintegrants include, but are not limited to, agar-agar, alginic acid, sodium alginate, calcium carbonate, sodium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and combinations thereof. In certain embodiments, the amount of disintegrant used in the pharmaceutical compositions provided herein is from about 0.5 to about 15 weight percent of disintegrant, while in other embodiments the amount is from about 1 to about 5 weight percent of disintegrant.

[000137] Non-limiting examples of such lubricants include, but are not limited to, sodium stearate, calcium stearate, magnesium stearate, stearic acid, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, sodium lauryl sulfate, talc, hydrogenated vegetable oil (by way of example only, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, sodium oleate, ethyl oleate, ethyl laureate, agar, silica, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.) and combinations thereof. In certain embodiments, the amount of lubricants used in the pharmaceutical compositions provided herein is in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms.

[000138] Non- limiting examples of such diluents include, but are not limited to, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine or combinations thereof. [000139] In certain embodiments, tablets and capsules are prepared by uniformly admixing at least one lysosomotropic agent (active ingredients) with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary. In certain embodiments, tablets are prepared by compression. In other embodiments, tablets are prepared by molding.

[000140] In certain embodiments, at least one lysosomotropic agent is orally administered as a controlled release dosage form. Such dosage forms are used to provide slow or controlled-release of one or more lysosomotropic agents. Controlled release is obtained using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof. In certain embodiments, controlled-release dosage forms are used to extend activity of the lysosomotropic agent, reduce dosage frequency, and increase patient compliance. [000141] Administration of lysosomotropic agent as oral fluids such as solution, syrups and elixirs are prepared in unit dosage forms such that a given quantity of solution, syrups or elixirs contains a predetermined amount of a lysosomotropic agent. Syrups are prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions are formulated by dispersing the compound in a nontoxic vehicle. Non- limiting examples of excipients used in as oral fluids for oral administration include, but are not limited to, solubilizers, emulsifiers, flavoring agents, preservatives, and coloring agents. Non- limiting examples of solubilizers and emulsifiers include, but are not limited to, water, glycols, oils, alcohols, ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers. Non-limiting examples of preservatives include, but are not limited to, sodium benzoate. Non- limiting examples of flavoring agents include, but are not limited to, peppermint oil or natural sweeteners or saccharin or other artificial sweeteners.

Parenteral Dosage Forms

[000142] In certain embodiments pharmaceutical compositions containing at least one lysosomotropic agent are administered parenterally by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. [000143] Such parenteral dosage forms are administered in the form of sterile or sterilizable injectable solutions, suspensions, dry and/or lyophylized products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection (reconstitutable powders) and emulsions. Vehicles used in such dosage forms include, but are not limited to, Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, physiological saline buffer, Ringer's Injection solution, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection solution; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[000144] In certain embodiments, a lysosomotropic agent or composition containing one or more lysosomotropic agents is parenteral administration by bolus injection. In other embodiments, a lysosomotropic agent or composition containing one or more lysosomotropic agents is parenteral administration by continuous infusion. Formulations for injection are presented in unit dosage form, by way of example only, in ampoules or formulations for injection are presented in multi- dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Transdermal Administration

[000145] In certain embodiments pharmaceutical compositions containing at least one lysosomotropic agent are administered transdermally. Such transdermal dosage forms include "reservoir type" or "matrix type" patches, which are applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of a lysosomotropic agent. By way of example only, such transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. In other embodiments, matrix transdermal formulations are used. In certain embodiments transdermal administration is used to provide continuous, while in other embodiments transdermal administration is used to provide discontinuous infusion of a lysosomotropic agent in controlled amounts. [000146] In certain embodiments, the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. In certain embodiments, transdermal delivery is via a transdermal patches placed over different portions of the patient's body, including over the eye.

[000147] Formulations for transdermal delivery of a lysosomotropic agent include an effective amount of a lysosomotropic agent, a carrier and an optional diluent. A carrier includes, but is not limited to, absorbable pharmacologically acceptable solvents to assist passage through the skin of the host, such as water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1, 3 -diol, isopropyl myristate, isopropyl palmitate, mineral oil, and combinations thereof. [000148] In certain embodiments, such transdermal delivery systems include penetration enhancers to assist in delivering one or more lysosomotropic agent to the tissue. Such penetration enhancers include, but are not limited to, acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).

[000149] In other embodiments, the pH of such a transdermal pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, is adjusted to improve delivery of one or more lysosomotropic agent. In other embodiments, the polarity of a solvent carrier, its ionic strength, or tonicity are adjusted to improve delivery. In other embodiments, compounds such as stearates are added to advantageously alter the hydrophilicity or lipophilicity of one or more lysosomotropic agent so as to improve delivery. In certain embodiments, such stearates serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent. In other embodiments, different salts, hydrates or solvates of the lysosomotropic agent are used to further adjust the properties of the resulting composition.

[000150] In other embodiments, transdermal delivery of the lysosomotropic agent is accomplished by means of iontophoretic patches and the like

Topical Dosage Forms

[000151] In certain embodiments at least one lysosomotropic agent is administered by topical application of pharmaceutical composition containing at least one lysosomotropic agent in the form of lotions, gels, ointments solutions, emulsions, suspensions or creams. Suitable formulations for topical application to the skin are aqueous solutions, ointments, creams or gels, while formulations for ophthalmic administration are aqueous solutions. Such formulations optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. [000152] Such topical formulations include at least one carrier, and optionally at least one diluent. Such carriers and diluents include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1, 3 -diol, isopropyl myristate, isopropyl palmitate, mineral oil, and combinations thereof.

[000153] In certain embodiments, such topical formulations include penetration enhancers to assist in delivering one or more lysosomotropic agent to the tissue. Such penetration enhancers include, but are not limited to, acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).

Pulmonary Administration

[000154] In certain embodiments pharmaceutical compositions containing at least one lysosomotropic agent are administered by inhalation. Dosage forms for inhaled administration are formulated as aerosols or dry powders. Aerosol formulations for inhalation administration comprise a solution or fine suspension of at least one lysosomotropic agent in a pharmaceutically acceptable aqueous or non-aqueous solvent. In addition, such pharmaceutical compositions optionally comprise a powder base such as lactose, glucose, trehalose, mannitol or starch, and optionally a performance modifier such as L-leucine or another amino acid, and/or metals salts of stearic acid such as magnesium or calcium stearate.

[000155] In certain embodiments, lysosomotropic agent are be administered directly to the lung by inhalation using a Metered Dose Inhaler ("MDI"), which utilizes canisters that contain a suitable low boiling propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or a Dry Powder Inhaler (DPI) device which uses a burst of gas to create a cloud of dry powder inside a container, which is then be inhaled by the patient. In certain embodiments, capsules and cartridges of gelatin for use in an inhaler or insufflator are formulated containing a powder mixture of a lysosomotropic agent and a powder base such as lactose or starch. In certain embodiments, lysosomotropic agent are delivered to the lung using a liquid spray device, wherein such devices use extremely small nozzle holes to aerosolize liquid drug formulations that can then be directly inhaled into the lung. In other embodiments, lysosomotropic agent are delivered to the lung using a nebulizer device, wherein a nebulizers creates an aerosols of liquid drug formulations by using ultrasonic energy to form fine particles that can be readily inhaled. In other embodiments, lysosomotropic agent are delivered to the lung using an electrohydrodynamic ("EHD") aerosol device wherein such EHD aerosol devices use electrical energy to aerosolize liquid drug solutions or suspensions. [000156] In certain embodiments, the pharmaceutical composition containing at least one lysosomotropic agent, or pharmaceutically acceptable salts and solvates thereof, described herein, also contain one or more absorption enhancers. In certain embodiments, such absorption enhancers include, but are not limited to, sodium glycocholate, sodium caprate, N-lauryl-β-D- maltopyranoside, EDTA, and mixed micelles.

[000157] In certain embodiments pharmaceutical compositions containing at least one lysosomotropic agent are administered nasally. The dosage forms for nasal administration are formulated as aerosols, solutions, drops, gels or dry powders.

Rectal Administration

[000158] In certain embodiments pharmaceutical compositions containing at least one lysosomotropic agent are administered rectally in the form of suppositories, enemas, retention enemas ointment, creams rectal foams or rectal gels. In certain embodiments such suppositories are prepared from fatty emulsions or suspensions, cocoa butter or other glycerides. Depot Administration

[000159] In certain embodiments pharmaceutical compositions containing at least one lysosomotropic agent are formulated as a depot preparation. Such long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, such formulations include polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[000160] In certain embodiments injectable depot forms are made by forming microencapsulated matrices of the lysosomotropic agent in biodegradable polymers. The rate of lysosomotropic agent release is controlled by varying the ratio of lysosomotropic agent to polymer and the nature of the particular polymer employed. In other embodiments, depot injectable formulations are prepared by entrapping the lysosomotropic agent in liposomes or microemulsions. In certain embodiments, posterior juxtascleral depots are used as a mode of administration of lysosomotropic agents. In other embodiments, a lysosomotropic agent is administered as a depot into the scleral layer of the eye by injection through a cannula with small diameter suitable for injection into the scleral layer. The sclera is a thin avascular layer, comprised of highly ordered collagen network surrounding most of vertebrate eye. Since the sclera is avascular it can be utilized as a natural storage depot from which injected material cannot rapidly removed or cleared from the eye.

Otic Administration

[000161] In certain embodiments pharmaceutical compositions containing at least one lysosomotropic agent are administered otically as ear drops. Such formulations are aqueous solutions that optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

Cosolvent Administration

[000162] In certain embodiments, the lysosomotropic agents are hydrophobic and a cosolvent system is used as pharmaceutical carrier for the hydrophobic lysosomotropic agent. Such cosolvent systems include benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. In certain embodiments, the cosolvent system is 10% ethanol, 10% polyethylene glycol 300, 10% polyethylene glycol 40 castor oil (PEG-40 castor oil) with 70% aqueous solution.

Treatment of Lysosomal Storage Diseases

[000163] Provided herein are lysosomotropic agent and pharmaceutical compositions containing at least one lysosomotropic agent for use in removing/clearing toxic, incompletely metabolized compounds from lysosomes, and thereby are used to in the prevention or treatment of lysosomal storage diseases described herein. In certain embodiments, the lysosomal storage disease is a macular degeneration disease. In certain embodiments, the lysosomal storage disease is Stargardt's Disease. In certain embodiments, the lysosomal storage disease is Tay-Sachs disease. In certain embodiments, the lysosomal storage disease is Batten Disease. In certain embodiments, the lysosomal storage disease is Krabbe Disease. In certain embodiments, the lysosomal storage disease is Pompe disease. In certain embodiments, the lysosomal storage disease is Gaucher Disease. In certain embodiments, the lysosomal storage disease is Mucopolysacchiradosis I (MPS I/Hurler/Hurler-Scheie/Scheie). In certain embodiments, the lysosomal storage disease is Mucopolysacchiradosis II (MPS II/Hunter Disease). In certain embodiments, the lysosomal storage disease is Fabry Disease. In certain embodiments, the lysosomal storage disease is leukodystrophies. In certain embodiments, the lysosomal storage disease is Niemann-Pick Disease. [000164] Also provided herein are methods for the treatment of a subject suffering from a lysosomal storage disease, wherein the methods include administering to the subject an effective amount of a lysosomotropic agent or a pharmaceutically acceptable salt, solvate, either alone or as part of a pharmaceutical composition as described herein.

[000165] Provided herein is the use of a lysosomotropic agent, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment of a lysosomal storage disease. In certain embodiments, the lysosomotropic agent or a pharmaceutically acceptable salt or solvate thereof, is used in the preparation of a medicament for the treatment of a lysosomal storage disease selected from a macular degeneration disease, Stargardt's Disease, Tay-Sachs disease, Batten Disease, Krabbe Disease, Pompe disease, Gaucher Disease, Mucopolysacchiradosis I (MPS I/Hurler/Hurler-Scheie/Scheie), Mucopolysacchiradosis II (MPS II/Hunter Disease), Fabry Disease leukodystrophies and Niemann-Pick Disease.

[000166] Provided herein is the use of a lysosomotropic agent, or a pharmaceutically acceptable salt or solvate thereof, in the treatment of a lysosomal storage disease. In certain embodiments, the lysosomotropic agent or a pharmaceutically acceptable salt or solvate thereof, is used in the treatment of a lysosomal storage disease selected from a macular degeneration disease, Stargardt's Disease, Tay-Sachs disease, Batten Disease, Krabbe Disease, Pompe disease, Gaucher Disease, Mucopolysacchiradosis I (MPS I/Hurler/Hurler-Scheie/Scheie), Mucopolysacchiradosis II (MPS II/Hunter Disease), Fabry Disease leukodystrophies and Niemann-Pick Disease. [000167] In certain embodiments, a lysosomotropic agent, or a pharmaceutical compositions comprising at least one lysosomotropic agent, are adapted for oral administration for the treatment of a lysosomal storage disease. In other embodiments, a lysosomotropic agent, or a pharmaceutical compositions comprising at least one lysosomotropic agent, are adapted for oral administration for the treatment of a lysosomal storage disease selected from a macular degeneration disease, Stargardt's Disease, Tay-Sachs disease, Batten Disease, Krabbe Disease, Pompe disease, Gaucher Disease, Mucopolysacchiradosis I (MPS I/Hurler/Hurler-Scheie/Scheie), Mucopolysacchiradosis II (MPS II/Hunter Disease), Fabry Disease leukodystrophies and Niemann-Pick Disease.

[000168] In certain embodiments, a lysosomotropic agent, or a pharmaceutical compositions comprising at least one lysosomotropic agent, are administered as eye drops for the treatment of a lysosomal storage disease. In other embodiments, a lysosomotropic agent, or a pharmaceutical compositions comprising at least one lysosomotropic agent, are administered as eye drops for the treatment of a lysosomal storage disease selected from a macular degeneration disease, Stargardt' s Disease, Tay-Sachs disease, Batten Disease, Krabbe Disease, Pompe disease, Gaucher Disease, Mucopolysacchiradosis I (MPS I/Hurler/Hurler-Scheie/Scheie), Mucopolysacchiradosis II (MPS II/Hunter Disease), Fabry Disease leukodystrophies and Niemann-Pick Disease. [000169] In certain embodiments, a lysosomotropic agent, or a pharmaceutical compositions comprising at least one lysosomotropic agent, are adapted for intraperitoneal administration for the treatment of a lysosomal storage disease. In other embodiments, a lysosomotropic agent, or a pharmaceutical compositions comprising at least one lysosomotropic agent, are adapted for intraperitoneal administration for the treatment of a lysosomal storage disease selected from a macular degeneration disease, Stargardt's Disease, Tay-Sachs disease, Batten Disease, Krabbe Disease, Pompe disease, Gaucher Disease, Mucopolysacchiradosis I (MPS I/Hurler/Hurler- Scheie/Scheie), Mucopolysacchiradosis II (MPS II/Hunter Disease), Fabry Disease leukodystrophies and Niemann-Pick Disease.

[000170] In certain embodiments, a lysosomotropic agent, or a pharmaceutical compositions comprising at least one lysosomotropic agent, are adapted for topical administration for the treatment of a lysosomal storage disease. In other embodiments, a lysosomotropic agent, or a pharmaceutical compositions comprising at least one lysosomotropic agent, are adapted for topical administration for the treatment of a lysosomal storage disease selected from a macular degeneration disease, Stargardt's Disease, Tay-Sachs disease, Batten Disease, Krabbe Disease, Pompe disease, Gaucher Disease, Mucopolysacchiradosis I (MPS I/Hurler/Hurler-Scheie/Scheie), Mucopolysacchiradosis II (MPS II/Hunter Disease), Fabry Disease leukodystrophies and Niemann-Pick Disease.

[000171] In certain embodiments, a lysosomotropic agent, or a pharmaceutical compositions comprising at least one lysosomotropic agent, are adapted for ophthalmic administration for the treatment of a lysosomal storage disease. In other embodiments, a lysosomotropic agent, or a pharmaceutical compositions comprising at least one lysosomotropic agent, are adapted for ophthalmic administration for the treatment of a lysosomal storage disease selected from a macular degeneration disease, Stargardt's Disease, Tay-Sachs disease, Batten Disease, Krabbe Disease, Pompe disease, Gaucher Disease, Mucopolysacchiradosis I (MPS I/Hurler/Hurler-Scheie/Scheie), Mucopolysacchiradosis II (MPS II/Hunter Disease), Fabry Disease leukodystrophies and Niemann-Pick Disease.

Combination Therapies

[000172] In certain embodiments, lysosomotropic agent described herein, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical composition containing at least one lysosomotropic agent described herein, are administered alone (without an additional therapeutic agent) for the treatment of one or more lysosomal storage diseases described herein. [000173] In other embodiments, the lysosomotropic agent described herein, or a pharmaceutically acceptable salts or solvates thereof, or pharmaceutical composition containing at least one lysosomotropic agent described herein, are administered in combination with one or more additional therapeutic agents or methods for the treatment of one or more lysosomal storage diseases described herein.

[000174] In other embodiments, the lysosomotropic agent described herein, or a pharmaceutically acceptable salts or solvates thereof, or pharmaceutical composition containing at least one lysosomotropic agent described herein, are formulated in combination with one or more additional therapeutic agents and administered for the treatment of one or more lysosomal storage diseases described herein.

[000175] In certain embodiments, the combination treatments provided herein include administration of a lysosomotropic agent described herein, or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing a lysosomotropic agent, sequentially with one or more additional therapeutic agents for the treatment of one or more lysosomal storage diseases described herein. [000176] In other embodiments, the combination treatments provided herein include administration of a lysosomotropic agent described herein, or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing a lysosomotropic agent, prior to administration of one or more additional therapeutic agents for the treatment of one or more lysosomal storage diseases described herein.

[000177] In other embodiments, the combination treatments provided herein include administration of a lysosomotropic agent described herein, or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing a lysosomotropic agent, subsequent to administration of one or more additional therapeutic agents for the treatment of one or more lysosomal storage diseases described herein.

[000178] In certain embodiments, the combination treatments provided herein include administration of a lysosomotropic agent described herein, or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing a lysosomotropic agent, concurrently with one or more additional therapeutic agents for the treatment of one or more lysosomal storage diseases described herein.

[000179] In certain embodiments, the combination treatments provided herein include administration of a lysosomotropic agent described herein, or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition formulated with one or more additional therapeutic agents for the treatment of macular degeneration.

[000180] In certain embodiments of the combination therapies described herein, the lysosomotropic agent described herein, or pharmaceutically acceptable salts or solvates thereof, and the additional therapeutics agent(s) act additively. In certain embodiments of the combination therapies described herein, the lysosomotropic agent described herein, or pharmaceutically acceptable salts or solvates thereof, and the additional therapeutics agent(s) act synergistically. [000181] In other embodiments, a lysosomotropic agent described herein, or a pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing a lysosomotropic agent, is administered to a patient who has not previously undergone or is not currently undergoing treatment with another therapeutic agent.

[000182] In other embodiments, a lysosomotropic agent described herein, or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing a lysosomotropic agent, are administered for prophylactic treatments. In other embodiments, a lysosomotropic agent described herein, or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing a lysosomotropic agent in combination with one or more additional therapeutic agents or methods, are administered for prophylactic treatments. In other embodiments, a lysosomotropic agent described herein, or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing a lysosomotropic agent, are administered for therapeutic treatments. In other embodiments, a lysosomotropic agent described herein, or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing a lysosomotropic agent in combination with one or more additional therapeutic agents or methods, are administered for therapeutic treatments.

[000183] In certain embodiments, a lysosomotropic agent described herein, or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing a lysosomotropic agent is administered chronically either alone or in combination with one or more additional therapeutic agents or methods. Chronic administration is for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition. In other embodiments, the administration of the compounds is temporarily suspended for a certain length of time (i.e., a "drug holiday"). [000184] The additional therapeutic methods used in combination with at least one lysosomotropic agent described herein, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, photodynamic therapy (PDT), low dose radiation therapy, submacular surgery, RPE transplantation, macular translocation surgery, implantable miniature telescopes, laser photocoagulation of drusen, microstimulation therapy and laser treatment of drusen.

[000185] The additional therapeutic agents used in combination with at least one lysosomotropic agent described herein, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to an effective amount of a retinyl derivative, including derivatives of all-trans-retinal and 13-cis-retinal, fenretinide and its active metabolites, an adjuvant, at least one compound that modulates RBP or TTR levels or activity, nitric oxide (NO) inducers, statins, negatively charged phospholipids, anti-oxidants, minerals, anti-inflammatory agents, anti-angiogenic agents, matrix metalloproteinase inhibitors, and carotenoids.

[000186] The anti-oxidants used in combination with at least one lysosomotropic agent described herein, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, vitamin C, vitamin E, beta-carotene and other carotenoids, coenzyme Q, 4-hydroxy-2,2,6,6- tetramethylpiperidine-N-oxyl (also known as Tempol), lutein, butylated hydroxytoluene, resveratrol, a trolox analogue (PNU-83836-E), and bilberry extract.

[000187] The minerals used in combination with at least one lysosomotropic agent described herein, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, copper-containing minerals, such as cupric oxide (by way of example only); zinc-containing minerals, such as zinc oxide (by way of example only); and selenium-containing compounds. [000188] The negatively-charged phospholipids used in combination with at least one lysosomotropic agent described herein, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, cardiolipin and phosphatidylglycerol. In certain embodiments, positively-charged and/or neutral phospholipids also provide benefit for patients with macular degenerations and dystrophies when used in combination with at least one lysosomotropic agent described herein, or a pharmaceutically acceptable salt or solvate thereof.

[000189] Carotenoids are naturally-occurring yellow to red pigments of the terpenoid group that can be found in plants, algae, bacteria, and certain animals, such as birds and shellfish. Carotenoids are a large class of molecules in which more than 600 naturally occurring carotenoids have been identified. The use of carotenoids has been correlated with the maintenance of photoprotection necessary in photoreceptor cells. The carotenoids used in combination with at least one lysosomotropic agent described herein, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, hydrocarbons (carotenes) and their oxygenated, alcoholic derivatives (xanthophylls), actinioerythrol, astaxanthin, canthaxanthin, capsanthin, capsorubin, .beta.-8'-apo-carotenal (apo-carotenal), β-12'-apo-carotenal, α-carotene, β-carotene, "carotene" (a mixture of α- and β-carotenes), γ-carotenes, β-cyrptoxanthin, lutein, lycopene, violerythrin, zeaxanthin, and esters of hydroxyl- or carboxyl-containing members thereof. In certain embodiments the carotenoids are in cis-isomeric form, while in other embodiments the carotenoids are in trans-isomeric form. In certain embodiments the carotenoids are a racemic mixture. [000190] The nitric oxide inducers used in combination with at least one lysosomotropic agent described herein, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, compounds that stimulate endogenous NO or elevate levels of endogenous endothelium-derived relaxing factor (EDRFj in vivo or are substrates for nitric oxide synthase. EDRF is a vascular relaxing factor secreted by the endothelium, and has been identified as nitric oxide or a closely related derivative thereof. Such compounds include, bit are not limited to, L- arginine, L-homoarginine, and N-hydroxy-L-arginine, including their nitrosated and nitrosylated analogs (e.g., nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosated L-homoarginine and nitrosylated L-homoarginine), precursors of L-arginine and/or physiologically acceptable salts thereof, including, for example, citrulline, ornithine, glutamine, lysine, polypeptides comprising at least one of these amino acids, inhibitors of the enzyme arginase (e.g., N-hydroxy-L-arginine and 2(S)-amino-6-boronohexanoic acid) and the substrates for nitric oxide synthase, cytokines, adenosine, bradykinin, calreticulin, bisacodyl, and phenolphthalein.

[000191] The nitric oxide inducers used in combination with at least one lysosomotropic agent described herein, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, statins such as, by way of example only, rosuvastatin, pitivastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, compactin, lovastatin, dalvastatin, fluindostatin, atorvastatin, atorvastatin calcium (which is the hemicalcium salt of atorvastatin), and dihydrocompactin.

[000192] The anti-inflammatory agents used in combination with at least one lysosomotropic agent described herein, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, cromolyn, nedocromil, theophylline, zileuton, zafirlukast, montelukast, pranlukast, indomethacin, and lipoxygenase inhibitors; non-steroidal antiinflammatory drugs (NSAIDs) (such as ibuprofen and naproxin); prednisone, dexamethasone, cyclooxygenase inhibitors (i.e., COX-I and/or COX-2 inhibitors such as NAPROXEN™, or CELEBREX™); statins (by way of example only, rosuvastatin, pitivastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, compactin, lovastatin, dalvastatin, fluindostatin, atorvastatin, atorvastatin calcium (which is the hemicalcium salt of atorvastatin), and dihydrocompactin); disassociated steroids, non-steroidal anti-inflammatory drugs such as salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac, ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam, nabumetome, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, apazone and nimesulide, leukotriene antagonists including, but not limited to, zileuton, aurothioglucose, gold sodium thiomalate and auranofin, steroids including, but not limited to, alclometasone diproprionate, amcinonide, beclomethasone dipropionate, betametasone, betamethasone benzoate, betamethasone diproprionate, betamethasone sodium phosphate, betamethasone valerate, clobetasol proprionate, clocortolone pivalate, hydrocortisone, hydrocortisone derivatives, desonide, desoximatasone, dexamethasone, flunisolide, flucoxinolide, flurandrenolide, halcinocide, medrysone, methylprednisolone, methprednisolone acetate, methylprednisolone sodium succinate, mometasone furoate, paramethasone acetate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebuatate, prednisone, triamcinolone, triamcinolone acetonide, triamcinolone diacetate, and triamcinolone hexacetonide and other anti-inflammatory agents including, but not limited to, methotrexate, colchicine, allopurinol, probenecid, thalidomide or a derivative thereof, 5 -aminosalicylic acid, retinoid, dithranol or calcipotriol, sulfinpyrazone and benzbromarone.

[000193] The matrix metalloproteinases (MMPs) inhibitors used in combination with at least one lysosomotropic agent described herein, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, Tissue Inhibitors of Metalloproteinases (TIMPs) (e.g., TIMP-I, TIMP-2, TIMP-3, or TIMP4), 0C₂-macroglobulin, tetracyclines (e.g., tetracycline, minocycline, and doxycycline), hydroxamates (e.g., batimistat, marimistat and TROCADE™), chelators (e.g., EDTA, cysteine, acetylcysteine, D-penicillamine, and gold salts), synthetic MMP fragments, succinyl mercaptopurines, phosphonamidates, hydroxaminic acids, the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase, collagenase- 1 (MMP-I), collagenase-2 (MMP-8), collagenase-3 (MMP- 13), stromelysin- 1 (MMP-3), stromelysin-2 (MMP-IO), and stromelysin-3 (MMP-Il) andMMP-9 and MMP- 12.

[000194] The antiangiogenic or anti-VEGF drugs used in combination with at least one lysosomotropic agent described herein, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, Rhufab V2 (LUCENTIS™), Tryptophanyl-tRNA synthetase (TrpRS), EyeOOl (Anti-VEGF Pegylated Aptamer), squalamine, RETAANE™ (anecortave acetate for depot suspension; Alcon, Inc.), Combretastatin A4 Prodrug (CA4P), MACUGEN™, MIFEPREX™ (mifepristone-ru486), subtenon triamcinolone acetonide, intravitreal crystalline triamcinolone acetonide, Prinomastat (AG3340— synthetic matrix metalloproteinase inhibitor, Pfizer), fluocinolone acetonide (including fluocinolone intraocular implant, Bausch & Lomb/Control Delivery Systems), VEGFR inhibitors (Sugen), VEGF-Trap (Regeneron/Aventis), anti-vascular endothelial cell growth factor antibody bevacizumab (AVASTIN™), VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo- 2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4- ylmethoxy)quinazoline (ZD6474), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3- pyrrolidin- 1 -ylpropoxy)quinazoline (AZD2171), vatalanib (PTK787) and SUl 1248 (sunitinib), linomide, and inhibitors of integrin αvβ3 function and angiostatin. [000195] Other pharmaceutical therapies used in combination with at least one lysosomotropic agent described herein, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, VISUD YNE™ with use of a non-thermal laser, PKC 412, Endovion (NeuroSearch A/S), neurotrophic factors, including by way of example Glial Derived Neurotrophic Factor and Ciliary Neurotrophic Factor, diatazem, dorzolamide, Phototrop, 9-cis-retinal, eye medication (including Echo Therapy) including phospholine iodide or echothiophate or carbonic anhydrase inhibitors, AE-941 (AEterna Laboratories, Inc.), Sirna-027 (Sima Therapeutics, Inc.), pegaptanib (NeXstar Pharmaceuticals/Gilead Sciences), neurotrophins (including, by way of example only, NT-4/5, Genentech), Cand5 (Acuity Pharmaceuticals), ranibizumab (Genentech), INS-37217 (Inspire Pharmaceuticals), integrin antagonists (including those from Jerini AG and Abbott Laboratories), EG-3306 (Ark Therapeutics Ltd.), BDM-E (BioDiem Ltd.), thalidomide (as used, for example, by EntreMed, Inc.), cardiotrophin- 1 (Genentech), 2-methoxyestradiol (Allergan/Oculex), DL-8234 (Toray Industries), NTC-200 (Neurotech), tetrathiomolybdate (University of Michigan), LYN-002 (Lynkeus Biotech), microalgal compound (Aquasearch/Albany, Mera Pharmaceuticals), D-9120 (Celltech Group pic), ATX-SlO (Hamamatsu Photonics), TGF-beta 2 (Genzyme/Celtrix), tyrosine kinase inhibitors (Allergan, SUGEN, Pfizer), NX-278-L (NeXstar Pharmaceuticals/Gilead Sciences), Opt-24 (OPTIS France SA), retinal cell ganglion neuroprotectants (Cogent Neurosciences), N-nitropyrazole derivatives (Texas A&M University System), KP-102 (Krenitsky Pharmaceuticals), cyclosporin A, "limited retinal translocation", photodynamic therapy, (including, by way of example only, receptor- targeted PDT, Bristol-Myers Squibb, Co.; porfimer sodium for injection with PDT; verteporfin, QLT Inc.; rostaporfin with PDT, Miravent Medical Technologies; talaporfin sodium with PDT, Nippon Petroleum; motexafin lutetium, Pharmacyclics, Inc.), antisense oligonucleotides (including, by way of example, products tested by Novagali Pharma SA and ISIS- 13650, Isis Pharmaceuticals), laser photocoagulation, drusen lasering, macular hole surgery, macular translocation surgery, implantable miniature telescopes, Phi-Motion Angiography (also known as Micro-Laser Therapy and Feeder Vessel Treatment), Proton Beam Therapy, microstimulation therapy, Retinal Detachment and Vitreous Surgery, Scleral Buckle, Submacular Surgery, Transpupillary Thermotherapy, Photosystem I therapy, use of RNA interference (RNAi), extracorporeal rheopheresis (also known as membrane differential filtration and Rheotherapy), microchip implantation, stem cell therapy, gene replacement therapy, ribozyme gene therapy (including gene therapy for hypoxia response element, Oxford Biomedica; Lentipak, Genetix; PDEF gene therapy, GenVec), photoreceptor/retinal cells transplantation (including transplantable retinal epithelial cells, Diacrin, Inc.; retinal cell transplant, Cell Genesys, Inc.), and acupuncture. [000196] In certain embodiments, the subject, in conjunction with administration of a lysosomotropic agent, pharmaceutical composition or combination therapy described herein are also monitored for physiological manifestations of lysosomal storage diseases. In certain embodiments the subject, in conjunction with administration of a lysosomotropic agent, pharmaceutical composition or combination therapy described herein are also monitored for physiological manifestations of retinoid-related disease processes. By way of example only, the subject may be monitored for physiological manifestations of age-related macular degenerations or dystrophies, including the formation of drusen in the eye of the subject, measuring the levels of lipofuscin in the eye of the subject, measuring the auto-fluorescence of A2E and precursors of A2E, and measuring N-retinylidene-N-retinylethanolamine levels in the eye of the subject. In certain embodiments, the subject is monitored for changes or perturbations in vitamin A levels, as well as RBP and TTR levels or activity in a biological sample. Kits

[000197] Also provided herein are pharmaceutical packs or kits that include one or more containers containing a lysosomotropic agent useful for the treatment or prevention of a lysosomal storage disease. In other embodiments, such pharmaceutical packs or kits include one or more containers containing a lysosomotropic agent useful for the treatment or prevention of a lysosomal storage disease and one or more containers containing an additional therapeutic agent, including but not limited to those listed above. In certain embodiments, such pharmaceutical packs or kits optionally include instructions for its administration of a lysosomotropic agent as disclosed herein. [000198] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

Examples

Cell -based Assays: A2E clearance

[000199] An immortalized human retinal pigment epithelium (RPE) cell line, ARPE- 19 cells, is used in the cell-based assays for evaluation of A2E clearance. Cells are grown at 37°C in DMEM/F12 (antibiotics) medium in 5% CO₂ and 95% O₂. Cells are pre-loaded with 8 μM A2E, which was added directly to the culture medium and incubated overnight. The following day the culture medium is replaced with fresh medium. To test for A2E clearance the A2E pre-loaded RPE cells are treated with 100 μM chlorpromazine (CPZ) in DMSO or are treated with DMSO alone, which are directly added to the culture medium. The A2E fluorescence is visualized by fluorescence microscopy on the Opera™ confocal microplate imager (Perkin Elmer) and on the ViewLux™ microplate imager (Perkin Elmer) with excitation at 488nm and emission at 540nm or 590nm. Additionally, A2E inside the cells and A2E released in the medium are quantified by centrifuging the cells in a clinical centrifuge for 10 minutes, separating the pellet (cells) and the supernatant (cell culture medium), extracting each with 3 volumes acetonitrile, and analyzing the extracts by HPLC on an Agilent 1100 system. Purified synthetic A2E standards are used to calibrate the HPLC for A2E quantification. Analysis of the A2E fluorescence by microscopy shows that the A2E signal of CPZ treated cells is significantly reduced compared to DMSO-treated cells, indicating A2E clearance (Figure 1). Figure l(A) are photographs taken with the Opera™ confocal microplate imager (Perkin Elmer), wherein ARPE- 19 cells are incubated with 8 μM A2E overnight and then are treated either with DMSO or with 100 μM CPZ in DMSO for 4 hours, washed in PBS, and photographed. Figure 1(B: left) are photographs taken with the ViewLux™ microplate imager (Perkin Elmer), wherein ARPE- 19 cells preloaded with A2E as above are incubated with 100 μM CPZ for 2 hours. Figure 1(B: right) is the quantification of the A2E fluorescence with the ViewLux™ microplate imager (Perkin Elmer) and it shows a more than 2- fold reduction in A2E signal upon treatment with CPZ.

[000200] In addition, analysis of A2E content of cell lysates and the A2E content of the culture media using HPLC shows that CPZ treatment reduces A2E in cells and increased A2E content in the media (Figure 4). ARPE- 19 cells are incubated with 8 μM A2E overnight and then are treated either with DMSO or with 50 μM CPZ in DMSO for 4 hours. Cells are pelleted, and the A2E content of cell lysates and the culture media are determined by HPLC analysis. For each treatment group, A2E content is expressed as percent total A2E, that is, the A2E in the lysates relative to the A2E in the lysates plus the A2E in media, or the A2E in the media relative to the A2E in the lysates plus the A2E in media. In the CPZ treated cells, A2E content in cell lysates was lower and the A2E content in the media was higher compared to that with DMSO-treated cells (control).

Dose Response of A2E clearance by CPZ

[000201] ARPE- 19 cells were loaded with 8 μM A2E overnight. The following day, cells were incubated overnight with 0 μM CPZ, 25 μM CPZ or 50 μM CPZ. Cells were then processed for analysis for A2E autofluorescence with the Opera™ confocal microplate imager (Perkin Elmer) as described above. Figure 5 (A) shows inverted pictures taken with the Opera™ confocal microplate imager (Perkin Elmer). Note progressively reduced staining (dark perinuclear stains) with increasing CPZ concentrations in the top row. The bottom row shows magnified images of the rectangular areas marked in the top row. Note punctate labeling by A2E, presumably within lysosomoes. This punctate labeling is reduced after treatment with CPZ. Figure 5 (B) shows the level of A2E autofluorescence intensity after each treatment. Note reduction in intensity with increasing concentrations of CPZ.

Cell -based Assays: LysoTracker® green clearance

[000202] An immortalized human retinal pigment epithelium (RPE) cell line, ARPE- 19 cells, is used in the cell-based assays for evaluation of LysoTracker® green clearance. Cells are grown at 37°C in DMEM/F12 medium (antibiotics) in 5% CO₂ and 95% O₂. Cells are pre-loaded with 0.3 μM LysoTracker® green, which was added directly to the culture medium and incubated for 4 hours. Then the culture medium is replaced with fresh medium. To test for LysoTracker® green clearance the LysoTracker® green pre-loaded RPE cells are treated with 100 μM chlorpromazine (CPZ) in DMSO or are treated with DMSO alone, which are directly added to the culture medium. The LysoTracker® green fluorescence, is visualized by fluorescence microscopy on the Opera™ confocal microplate imager (Perkin Elmer) and on the ViewLux™ microplate imager (Perkin Elmer) with excitation at 488nm and emission at 540nm or 590nm. Additionally, LysoTracker® green inside the cells and A2E released in the medium are quantified by centrifuging the cells in a clinical centrifuge for 10 minutes, separating the pellet (cells) and the supernatant (cell culture medium), extracting each with 3 volumes acetonitrile, and analyzing the extracts by HPLC on an Agilent 1100 system. LysoTracker® green standards are used to calibrate the HPLC for LysoTracker® green quantification. Analysis of the A2E fluorescence by microscopy shows that the LysoTracker® green signal of CPZ treated cells is significantly reduced compared to DMSO- treated cells, indicating LysoTracker® Green clearance (Figure 2). Figure 2(A) are photographs taken with Opera™ confocal microplate imager (Perkin Elmer), wherein ARPE- 19 cells are incubated with 250 nM LysoTracker® Green for 2 hours and then are treated either with DMSO or with 50 μM CPZ in DMSO for 4 hours, washed in PBS, and photographed. Figure 2(B: left) are photographs taken with the ViewLux™ microplate imager (Perkin Elmer), wherein ARPE- 19 cells preloaded with LysoTracker® Green as above are incubated with 100 μM CPZ for 2 hours. Figure 2(B: right) is the quantification of the A2E fluorescence with the ViewLux™ microplate imager (Perkin Elmer) and it shows a more than 2-fold reduction in A2E signal upon treatment with CPZ.

Evaluation of possible quenching of A2E by chlorpromazine (CPZ)

[000203] Possible quenching of A2E by CPZ is evaluated using a cell-free system and titrating

A2E with CPZ or titrating CPZ with A2E (Figure 3). Various concentrations of A2E are mixed with DMSO or 100 μM CPZ in DMSO in a cell-free system and incubated for 2 hours at room temperature. The A2E fluorescence is then quantified by the ViewLux™ microplate imager

(Perkin Elmer).

[000204] No significant quenching effect is observed. For the solution based titration the A2E and CPZ are mixed in cell culture media or in PBS, for the same length of time as the above assays, and then analyzed with the Opera™ confocal microplate imager (Perkin Elmer) or with the

ViewLux™ microplate imager (Perkin Elmer).

Effect of various lysosomotropes on A2E clearance in ARPE- 19 cells

[000205] ARPE- 19 cells were loaded with 8 uM A2E overnight. The following day, cells were incubated overnight with 25 μM CPZ, or with 50 μM or 100 μM of the other compounds shown in Figure 6. Drugs were tested at concentrations that were not significantly cytotoxic. Drug stocks were made in DMSO; final DMSO concentration in culture media was 1% (v/v) or less. Cells treated with DMSO served as control. Treated cells were then processed for analysis for A2E autofluorescence with the Opera™ confocal microplate imager (Perkin Elmer). Figure 6A shows inverted pictures taken with the Opera™ confocal microplate imager (Perkin Elmer). Note reduced staining (dark perinuclear stains) with CPZ (middle) and 4-benzyloxy-2-azetidinone (right) compared to that in DMSO treated cells (left). Figure 6B shows the level of A2E autofluorescence intensity after treatment with each lysosomotrope. Upper and lower dashed lines show level of intensity after treatment with vehicle and CPZ, respectively.

Mouse model Assays: A2E clearance

[000206] To determine the in vivo efficacy of A2E clearance, abca4-/- mice, which have elevated A2E levels, are treated with chlorpromazine (CPZ) using the following regimens and with various administration routes listed below. Both pigmented (B 6.129 background) and non-pigmented (BALB/c background) abca4-/- mice are tested, as chlorpromazine has been shown to bind melanin. To analyze A2E clearance, the eyes from euthanized mice are extracted with acetonitrile/PBS (3:1), and the extracts are analyzed for A2E content by LC-MS and quantitated by reference to purified A2E standards. In addition, eyes are analyzed by fluorescence microscopy and the level of lipofuscin autofluorescence (which contains A2E) is determined.

A) In one study abca4-/- mice are dosed orally with various doses up to 50 mg/kg of chlorpromazine (CPZ) in a vehicle of saline or water, or dosed with the vehicle alone, for 1 to 112 days.

B) In another study, abca4-/- mice are dosed with chlorpromazine (CPZ) in Alzet pumps implanted intraperitoneally or subcutaneously and reared in the dark. Since A2E production is light-dependent (i.e. retinoid cycle dependent), A2E biosynthesis should be minimal in the dark. Thus any reduction in A2E with CPZ treatment is due to clearance of A2E out of the eye, rather than due to a slower rate of A2E biosynthesis affected by CPZ.

C) In another study, abca4-/- mice are intravitreally injected with chlorpromazine (CPZ) in saline, up to 50 mg/kg, or with saline alone, and euthanized 1 or several days later and analyzed for A2E content of eyes.

D) Eyecups are prepared from euthanized abca4-/- mice and treated in culture medium (e.g. DMEM/F-12, containing FBS and antibiotics) containing various concentrations of chlorpromazine for several hours to several days in an 37 ⁰C incubator.

E) Studies A-D are repeated using other lysosomotropic agents including lysosomotropic agents selected from LysoTracker® green, LysoTracker® red, amantadine, 4-aminoquinoline, amiodarone, amodiaquine, azithromycin, chloroquine, clindamycin, N- (3-[(2,4-dinitrophenyl)-amino]-propyl)-N-(3-aminopropyl-methylamine)dihydrochloride (DAMP), imipramine, methylamine, monensin, monodansylcadaverine, NH₄Cl, perhexilene, phenylalanine methyl ester, primaquine, quinacrine, suramin, thioridazine, tilorone, tributylamine, and ketotifen fumarate.

Claims

WE CLAIM:

1. A pharmaceutical composition for treating a lysosomal-storage disease comprising a therapeutically effective amount of a lysosomotropic agent and a pharmaceutically acceptable excipient.

2. A pharmaceutical composition for reducing the concentration of a toxic metabolite in a lysosome comprising an effective amount of a lysosomotropic agent and a pharmaceutically acceptable carrier, wherein the toxic metabolite is associated with a lysosomal-storage disease.

3. A pharmaceutical composition for reducing the concentration of N-retinylidene-N- retinylethanolamine (A2E) in an eye of a mammal comprising an effective amount of a lysosomotropic agent and a pharmaceutically acceptable carrier.

4. A pharmaceutical composition for reducing the concentration of lipofusion in an eye of a mammal comprising an effective amount of a lysosomotropic agent and a pharmaceuticall acceptable carrier.

5. A pharmaceutical composition for treating dry form age-related macular degeneration in an eye of a mammal comprising an effective amount of a lysosomotropic agent and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition of claim 1 or claim 2, wherein the lysosomal-storage disease is selected from Tay-Sachs disease, Batten Disease, Krabbe Disease, Pompe disease, Gaucher Disease, Mucopolysacchiradosis I (MPS I/Hurler/Hurler-Scheie/Scheie), Mucopolysacchiradosis II (MPS II/Hunter Disease), Fabry Disease, leukodystrophies, Niemann- Pick Disease, Stargardt' s Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration.

7. The pharmaceutical composition of claim 1, wherein the lysosomal-storage disease is a macular degeneration disease.

8. The pharmaceutical composition of claim 7, wherein the macular degeneration disease is selected from Stargardt' s Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration.

9. The pharmaceutical composition of any of claims 1-8, wherein the lysosomotropic agent is selected from chlorpromazine, 7-(3-(2-(dimethylamino)ethylamino)-3- oxopropyl)-5,5-difluoro-l,3-dimethyl-2,5-dihydro-lH-dipyrrolo[l,2-c:l',2'- f][l,3,2]diazaborinin-4-ium-5-uide, (7-(3-(2-(dimethylamino)ethylamino)-3-oxopropyl)- 5,5-difluoio-3-(lH-pyiTOl-2-yl)-2,5-dihydio-lH-dipyiTOlo[l,2-c: l',2'- f][l,3,2]diazaborinin-4-ium-5-uide, amantadine, 4-aminoquinoline, amiodarone, amodiaquine, azithromycin, chloroquine, clindamycin, N-(3-[(2,4-dinitrophenyl)-amino]- propyl) -N- (3 - aminopropyl-methylamine)dihydrochloride (D AMP) , imipramine , methylamine, monensin, monodansylcadaverine, NH₄Cl, perhexilene, phenylalanine methyl ester, primaquine, quinacrine, suramin, thioridazine, tilorone, tributylamine, and ketotifen fumarate.

10. The pharmaceutical composition of any of claims 1-9, wherein the pharmaceutical composition further comprises a compound selected from the group consisting of fenretinide, an inducer of nitric oxide production, an antioxidant, an anti-inflammatory agent, a mineral, an anti-oxidant, a carotenoid, a negatively charged phospholipid and a statin.

11. The pharmaceutical composition of any of claims 1-9, wherein the pharmaceutical composition further comprises fenretinide.

12. A medicament for treating a lysosomal-storage disease, wherein the medicament comprises a therapeutically effective amount of a lysosomotropic agent.

13. The medicament of claim 12, wherein the lysosomal-storage disease is selected from Tay-Sachs disease, Batten Disease, Krabbe Disease, Pompe disease, Gaucher Disease, Mucopolysacchiradosis I (MPS I/Hurler/Hurler-Scheie/Scheie), Mucopolysacchiradosis II (MPS II/Hunter Disease), Fabry Disease, leukodystrophies, Niemann-Pick Disease, Stargardt's Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration.

14. The medicament of claim 12, wherein the lysosomal-storage disease is a macular degeneration disease.

15. The medicament of claim 14, wherein the macular degeneration disease is selected from Stargardt's Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration.

16. The medicament of any of claims 11-15, wherein the lysosomotropic agent is selected from chlorpromazine, 7-(3-(2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-l,3- dimethyl-2,5-dihydro-lH-dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5-uide, 7-(3- (2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-3-(lH-pyrrol-2-yl)-2,5- dihydro- lH-dipyrrolo[ 1 ,2-c : 1 ' ,2' -f] [ 1 ,3 ,2]diazaborinin-4-ium-5-uide, amantadine, 4- aminoquinoline, amiodarone, amodiaquine, azithromycin, chloroquine, clindamycin, N-(3- [(2,4-dinitrophenyl)-amino]-propyl)-N-(3-aminopropyl-methylamine)dihydrochloride (DAMP), imipramine, methylamine, monensin, monodansylcadaverine, NH₄Cl, perhexilene, phenylalanine methyl ester, primaquine, quinacrine, suramin, thioridazine, tilorone, tributylamine, and ketotifen fumarate.

17. The medicament of any of claims 12-16, wherein the medicament further comprises a compound selected from the group consisting of fenretinide, an inducer of nitric oxide production, an antioxidant, an anti-inflammatory agent, a mineral, an anti-oxidant, a carotenoid, a negatively charged phospholipid and a statin.

18. The medicament of any of claims 12-17, wherein the medicament further comprises fenretinide.

19. Use of a lysosomotropic agent in the manufacture of a medicament for treating a lysosomal- storage disease.

20. A method for treating a lysosomal-storage disease comprising administering to a subject in need thereof, a therapeutically effective amount of a lysosomotropic agent.

21. A method for reducing the concentration of a toxic metabolite in a lysosome comprising administering of an effective amount of a lysosomotropic agent thereby reducing the concentration of the toxic metabolite in the lysosome, and wherein the toxic metabolite is associated with a lysosomal-storage disease.

22. The method of claim 20 or claim 21, wherein the lysosomal-storage disease is selected from Tay-Sachs disease, Batten Disease, Krabbe Disease, Pompe disease, Gaucher Disease, Mucopolysacchiradosis I (MPS I/Hurler/Hurler-Scheie/Scheie), Mucopolysacchiradosis II (MPS II/Hunter Disease), Fabry Disease, leukodystrophies, Niemann- Pick Disease, Stargardt' s Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration.

23. The method of claim 20 or claim 21, wherein the lysosomal-storage disease is a macular degeneration disease.

24. The method of claim 23, wherein the macular degeneration disease is selected from Stargardt's Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration.

25. A method for reducing the concentration of N-retinylidene-N-retinylethanolamine (A2E) in an eye of a mammal comprising administering to the mammal at least once an effective amount of a lysosomotropic agent.

26. A method for reducing the concentration of lipofusion in an eye of a mammal comprising administering to the mammal an effective amount of a lysosomotropic agent.

27. A method for treating dry form age-related macular degeneration in an eye of a mammal comprising administering to the mammal an effective amount of a lysosomotropic agent.

28. The method of any of claims 20-27, wherein the lysosomotropic agent is selected from chlorpromazine, 7-(3-(2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-l,3- dimethyl-2,5-dihydro-lH-dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5-uide, 7-(3- (2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-3-(lH-pyrrol-2-yl)-2,5- dihydro- lH-dipyrrolo[ 1 ,2-c : 1 ' ,2' -f] [ 1 ,3 ,2]diazaborinin-4-ium-5-uide, amantadine, 4- aminoquinoline, amiodarone, amodiaquine, azithromycin, chloroquine, clindamycin, N-(3- [(2,4-dinitrophenyl)-amino]-propyl)-N-(3-aminopropyl-methylamine)dihydrochloride (DAMP), imipramine, methylamine, monensin, monodansylcadaverine, NH₄Cl, perhexilene, phenylalanine methyl ester, primaquine, quinacrine, suramin, thioridazine, tilorone, tributylamine, and ketotifen fumarate.

29. The method of any of claims 20-28, wherein the method further comprises the administration a second compound selected from the group consisting of fenretinide, an inducer of nitric oxide production, an antioxidant, an anti-inflammatory agent, a mineral, an anti-oxidant, a carotenoid, a negatively charged phospholipid and a statin.

30. A method of identifying a lysosomotropic agent for the treatment of lysosomal- storage disease comprising incubating a cell sample comprising a fluorescent compound with at least one candidate lysosomotropic agent and measuring the emission spectra of the fluorescent compound, wherein the candidate lysosomotropic agent decreases the emission spectra of the fluorescent compound in the cell sample after incubation.

31. The method of claim 32, wherein the lysosomotropic agent is selected from chlorpromazine, 7-(3-(2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-l,3- dimethyl-2,5-dihydro-lH-dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5-uide, 7-(3- (2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-3-(lH-pyrrol-2-yl)-2,5- dihydro-lH-dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5-uide, amantadine, 4- aminoquinoline, amiodarone, amodiaquine, azithromycin, chloroquine, clindamycin, N-(3- [(2,4-dinitrophenyl)-amino]-propyl)-N-(3-aminopropyl-methylamine)dihydrochloride (DAMP), imipramine, methylamine, monensin, monodansylcadaverine, NH₄Cl, perhexilene, phenylalanine methyl ester, primaquine, quinacrine, suramin, thioridazine, tilorone, tributylamine, and ketotifen fumarate.

32. The method of claim 32 or claim 33, wherein the fluorescent compound absorbs at between 300 nm and 550 nm and emits at between 520 nm and 700 nm.

33. The method of any of claims 32-35, wherein the fluorescent compound is N- retinylidene-N-retinyl-phosphatidylethanolamine (A2E).

34. The method of any of claims 32-36, wherein the cell sample comprises a RPE cell.

35. A compound for use in a method of medical treatment, wherein the method of medical treatment is for treating a lysosomal-storage disease, wherein the lysosomal- storage disease is sleeted from Tay-Sachs disease, Batten Disease, Krabbe Disease, Pompe disease, Gaucher Disease, Mucopolysacchiradosis I (MPS I/Hurler/Hurler-Scheie/Scheie), Mucopolysacchiradosis II (MPS II/Hunter Disease), Fabry Disease, leukodystrophies, Niemann- Pick Disease, Stargardt's Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration, and wherein the compound is a lysosomotropic agent.

36. The compound of claim 37, wherein the lysosomotropic agent is selected from chlorpromazine, 7-(3-(2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-l,3- dimethyl-2,5-dihydro-lH-dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5-uide, 7-(3- (2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-3-(lH-pyrrol-2-yl)-2,5- dihydro-lH-dipyrrolo[l,2-c:l',2'-f][l,3,2]diazaborinin-4-ium-5-uide, amantadine, 4- aminoquinoline, amiodarone, amodiaquine, azithromycin, chloroquine, clindamycin, N-(3- [(2,4-dinitrophenyl)-amino]-propyl)-N-(3-aminopropyl-methylamine)dihydrochloride (DAMP), imipramine, methylamine, monensin, monodansylcadaverine, NH₄Cl, perhexilene, phenylalanine methyl ester, primaquine, quinacrine, suramin, thioridazine, tilorone, tributylamine, and ketotifen fumarate.

37. The compound of claim 37 or claim 38, wherein the method of medical treatment further comprises the use a second compound selected from the group consisting of fenretinide, an inducer of nitric oxide production, an antioxidant, an anti-inflammatory agent, a mineral, an anti-oxidant, a carotenoid, a negatively charged phospholipid and a statin.