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WO2018017639A1 - Méthodes de traitement du syndrome de rett - Google Patents

Méthodes de traitement du syndrome de rett Download PDF

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Publication number
WO2018017639A1
WO2018017639A1 PCT/US2017/042710 US2017042710W WO2018017639A1 WO 2018017639 A1 WO2018017639 A1 WO 2018017639A1 US 2017042710 W US2017042710 W US 2017042710W WO 2018017639 A1 WO2018017639 A1 WO 2018017639A1
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thip
mice
mecp2
administered
neurons
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Chun Jiang
Weiwei ZHONG
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Georgia State University Research Foundation Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • MECP2 The role of MECP2 in disease is primarily associated with either a loss of function
  • Rett syndrome has a high prevalence in females affecting about 1 in every 10,000. Subjects are born with signs of this disorder, but after about six months to a year and half, speech and motor function capabilities start to decrease. This is followed by seizures, growth retardation and cognitive and motor impairment in infancy.
  • the genetic loss of MECP2 has been identified as changing the properties of cells in the locus ceruleus (LC) the exclusive source of noradrenergic innervation to the cerebral cortex and hippocampus (Taneja P et al, "Pathophysiology of locus ceruleus neurons in a mouse model of Rett syndrome," The Journal ofNeuroscience 29, 12187-12195 (2009)). Therefore, these neurons are a pivotal source of norepinephrine throughout the brainstem and forebrain and are involved in the regulation of diverse functions disrupted in Rett syndrome, such as respiration and cognition. As such, the locus ceruleus is a critical site at which loss of MECP2 results in CNS dysfunction.” BRIEF DESCRIPTION OF THE FIGURES
  • Figure 1 depicts the excitability of LC neurons in compares the neuronal activity of wild type mice versus Mecp2-mA ⁇ mice.
  • Figure IA1-IC2 shows the age dependency of neuronal hyperexcitability.
  • P45 Figure B2
  • Mecp2-mA ⁇ mice showed significant firing activity of locus coeruleus (LC) neurons.
  • Figure O shows that administration of 4,5,6,7- tetrahydroisoxazolo[5,4-c]pyridin-3(2H)-one ( ⁇ ) resulted in recovery to a level consistent with controls.
  • Figures ID and IE show the increased LC neuronal excitability in Mecp2-null mice was significantly different from the WT, and showed age dependence.
  • Figure 2 relates to the hyperexcitability of Me5 neurons in Mecp2-mA ⁇ mice and effects of ⁇ .
  • Figure 2Ai and 2A2 show that Me5 neurons did not fire action potentials spontaneously. With step depolarizing current injections, most Me5 neurons in Mecp2-nu ⁇ mice fired multiple action potentials, most WT Me5 neurons did not. This tendency of hyperexcitability became less obvious with ⁇ treatment.
  • Figure 3A-3C are typical recordings of breathing activity from both WT and Mecp2-mA ⁇ mice at different ages.
  • Figure 4Ai and Figure 4Ai depict the typical records of breathing activity from both WT d Mecp2-nu ⁇ mice with and without THIP administration.
  • Figure 4D and Figure 4E depict the effects of THIP treatment on breathing frequency variation that was observed in these mice.
  • Figures 5A-D depict the improvement of TH and DBH expressions with THIP administration Mecp2-mA ⁇ mice.
  • Figures 7A-D demonstrate that THIP administration alleviated the defects of social behaviors Mecp2-mx ⁇ mice.
  • Figures 7B-D show the results of the three chamber test wherein both WT and null mice spent similar times in either side of the chambers. After introducing a mouse in the test area, in comparison to the WT, Mecp2-mx ⁇ mice spent significant less the time with the mice. THIP treatment eliminated the difference.
  • Figures 8A-E demonstrate that THIP administration expanded the lifespan of Mecp2-mA ⁇ mice.
  • Figure 8B indicates the percentage of survival in the test mice.
  • Figure 8C discloses that in the sham group, 50% Mecp2-mA ⁇ mice died within 52 days, while THIP treatment expanded the 50% lifespan to 81 days.
  • Figure 8D and Figure 8E demonstrates that the fatality oiMecp2-mA ⁇ mice was significantly reduced with oral THIP administration at 8 weeks old and the THIP effect remained at 9 weeks old.
  • Figure 9 shows the effects of THIP on neuronal excitability one week after withdrawal (P61).
  • the hyperexcitability of LC neurons was significantly in lower in Mecp2-mA ⁇ mice with THIP treatment than in those without ( Figure 9A).
  • ⁇ nMecp2-mA ⁇ Me5 neurons the suppression of neuronal excitability by THIP was remained ( Figures 9B and 9C).
  • Figure 10 shows the effects of THIP on breathing activity one week after THIP withdrawal.
  • Figures IOA1-A2 are typical recordings of breathing activity from both WT dMecp2-nu ⁇ mice at P61.
  • the apnea count ( Figure 10B) and breathing frequency variation (Figure IOC) in mice at P61 were significantly reduced in comparison to the sham control.
  • Ranges may be expressed herein as from “about” one particular value, and/or to "about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
  • the term “comprising” and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and/or steps.
  • the foregoing also applies to words having similar meanings such as the terms, “including”, “having” and their derivatives.
  • the term “consisting” and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but exclude the presence of other unstated features, elements, components, groups, integers and/or steps.
  • the second component as used herein is chemically different from the other components or first component.
  • a “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different.
  • suitable means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, and the identity of the molecule(s) to be transformed, but the selection would be well within the skill of a person trained in the art. All process/method steps described herein are to be conducted under conditions sufficient to provide the product shown. A person skilled in the art would understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so.
  • subject includes all members of the animal kingdom including mammals, and suitably refers to humans, companion animals (e.g. dogs, cats, rodents, rabbits etc.) and livestock (e.g. cattle, sheep, pigs, goats, equines such as horses, mules and donkeys etc.).
  • companion animals e.g. dogs, cats, rodents, rabbits etc.
  • livestock e.g. cattle, sheep, pigs, goats, equines such as horses, mules and donkeys etc.
  • pharmaceutically acceptable means compatible with the treatment of subjects such as humans, companion animals and livestock.
  • pharmaceutically acceptable salt means an acid addition salt that is suitable for, or compatible with, the treatment of subjects or a base addition salt that is suitable for, or compatible with, the treatment of subjects.
  • administered means administration of an effective amount of one or more compounds of the application to a cell either in cell culture or in a subject.
  • an effective amount of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3(2H)-one is an amount that, for example, reduces the symptoms of Rett Syndrome in a subject compared to the symptoms without administration of ⁇ .
  • reducing the symptoms it is meant, for example, reducing the amount and/or frequency of behavior attributable to autonomic dysfunction and the impairment of brainstem motor controls.
  • the benefits of the effective amount includes, but is not limited to, stabilized neuronal excitability, alleviated breathing abnormalities, enhanced motor function, improved social behaviors, and extended lifespan.
  • Effective amounts may vary according to factors such as the disease state, age, sex, weight and/or species of the subject.
  • the amount of ⁇ that will correspond to such an amount will vary depending upon various factors, such as the pharmaceutical formulation, the route of administration, the type of Rett Syndrome manifestation, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.
  • to treat means an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms of Rett Syndrome, diminishment of the extent of the disease manifestations, stabilized (i.e. not worsening) state of a symptom or manifestation
  • To treat can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Treatment and “treatment” as used herein also include prophylactic treatment. For example, a subject with early symptoms of Rett Syndrom can be treated to prevent progression, or alternatively a subject in remission can be treated with ⁇ to prevent recurrence.
  • prevent or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed. Because Rett's Syndrome has been identified as being caused by a genetic mutation, especially of the MECP2 gene, a subject which is tested for a genetic abnormality, can be treated for Rett's Syndrome prophylactically. Therefore, disclosed are methods for prevention.
  • Treatment methods comprise administering to a subject a therapeutically effective amount of THIP, optionally consisting of a single administration, or alternatively comprising a series of administrations.
  • THIP is administered at least once a week.
  • THIP is administered to the subject from about one time per three weeks, or about one time per week to about once daily for a given treatment.
  • THIP is administered 2, 3, 4, 5 or 6 times daily.
  • the length of the treatment period depends on a variety of factors, such as the severity of the disease, the age of the subject, and the concentration of THIP in a formulation.
  • the effective dosage of THIP used for the treatment can increase or decrease over the course of a particular treatment regime. Changes in dosage can result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration is required.
  • THIP is administered in an amount and for a duration sufficient to treat the subject.
  • Rett Syndrome is manifested by the increased membrane excitability in the brainstem neurons which are due to abnormal intrinsic membrane properties and deficiency in GABAergic synaptic inhibitions (X. Zhang et al., "Intrinsic membrane properties of locus coeruleus neurons in Mecp2-null mice,” American Journal of Physiology. Cell Physiology 298, C635-646 (2010). As such, both GABAA and GABAB synaptic currents are reduced in LC neurons ofMecp2-nu ⁇ mice (X. Jin et al, "GABAergic synaptic inputs of locus coeruleus neurons in wild-type and Mecp2-null mice,” American Journal of Physiology.
  • GABAARS synaptic GABA receptors
  • THIP tetrahydroisoxazolo [5,4-c]-pyridin-3-ol
  • One aspect of the disclosure relates to administering to a subject diagnosed with Rett Syndrome from about 1 mg/kg to about 10 mg/kg of THIP. In one iteration from about 2.5 mg/kg to about 10 mg/kg of body weight of THIP is administered. In one embodiment
  • THIP is administered once daily. In another embodiment THIP is administered twice daily.
  • THIP is administered once daily. In another embodiment THIP is administered twice daily.
  • THIP is administered to a subject in need of treatment two or more times per day wherein the total amount of THIP administered is from about 1 to about 10 mg/kg of the subject's body weight. In one iteration from about 2.5 to about 10 mg/kg total is administered. In a further iteration from about 5 to about 10 mg/kg of body weight is administered.
  • Me5 neurons were also hyperexcitable in Mecp2-mA ⁇ mice, although they were silent at basal condition without current injection in both WT dMecp2-nu ⁇ mice. In response to depolarizing current injection, the Me5 neurons in Mecp2-mA ⁇ mice tended to fire multiple action potentials with higher firing frequency than their WT counterparts (Figure 2Ai).
  • THIP extrasynaptic GABAAR agonist
  • Mecp2-mA ⁇ mice developed breathing abnormalities showing significantly high apnea rate and high breathing frequency variation ( Figures 3A-D). These RTT-like symptoms started at 2 - 4 weeks, and deteriorated with growth ( Figures 3A-C and 3F). Both were similar to the alterations in LC neuronal hyperexcitability.
  • Statistical correlation of breathing abnormalities with LC neuronal activity in 6-8 week-old Mecp2-mx ⁇ mice indicate a strong association of the excitability of LC neurons with the apnea rate (Figure 3H) and breathing frequency variation ( Figure 31). Inhibition of LC neuronal hyperexcitability by THIP also affects breathing abnormalities.
  • Mecp2 disruption leads to reductions in NE content in the CNS and expression levels of the rate-limiting enzymes tyrosine hydroxylase (TH) and dopamine ⁇ hydroxylase (DBH) for NE biosynthesis.
  • Persistent hyperexcitation of LC neurons interferes with the homeostatic state in NE biosynthesis and release, affecting expression of TH and DBH in Mecp2-mA ⁇ mice.
  • Moderation of LC neuronal hyperexcitability improves the expression of TH and DBH Mecp2-mA ⁇ mice.
  • Disclosed herein are results for the expression of TH and DBH at mRNA and protein levels.
  • LC neurons project to multiple regions in the CNS, such as the cortex, cerebellum, medulla and spinal cord.
  • the improvements in neuronal excitability and NE biosynthesis in these cells affects other behaviors mMecp2-nu ⁇ mice, including motor function and social behaviors, defects of which have been reported in people with RTT as well as Mecp2-mx ⁇ mice.
  • Mecp2 disruption causes an age-dependent increase in neuronal excitability of LC and Me5 neurons, which is closely associated with breathing abnormalities.
  • THIP neuronal excitability leading to several beneficial effects on breathing abnormalities, NE biosynthetic enzymes, motor function, behaviors, and lifespan oiMecp2- null mice.
  • Some of the THIP effects last at least a week after drug withdrawal. Therefore, early exposure of Mecp2-mA ⁇ mice to low-dose THIP is a means of treating RTT-like symptoms.
  • inhibitory postsynaptic currents of both GABAARS and GABABRS are markedly reduced with inadequate GABA release from presynaptic terminals (Jin X et al., " GABAergic synaptic inputs of locus coeruleus neurons in wild-type and Mecp2-null mice," American Journal of
  • Mecp2 ablation in a subset of forebrain GABAergic neurons recapitulates many features of RTT including breathing disturbances.
  • Voituron et al. have demonstrated that administration of benzodiazepine or GABA reuptake blocker together with a serotonin receptor la agonist suppresses breathing defects ofMecp2-nu ⁇ mice (Voituron N et al, "The benzodiazepine Midazolam mitigates the breathing defects of Mecp2-deficient mice," Respiratory Physiology & Neurobiology 177, 56-60 (2011). Therefore, interventions to the synaptic GABAARS can lead to a control of neuronal hyperexcitability.
  • mice Female heterozygous mice (Genotype: Mecp2 + ; Strain name: B6.129P2(C)- IBird/J; Stock number 003890) from Jackson Lab were crossbred with male C57BL/6 mice (WT) to produce the RTT model mice with the genotype Mecp2 ⁇ ri .
  • the PCR protocol from Jackson Lab was used to identify the genotype. All experimental procedures in mice were conducted in accordance with the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals and were approved by the Georgia State University Institutional Animal Care and Use Committee. All experiments were done in male mice because the Mecp2r ri males offer a completely Mecp2- A ⁇ condition that is not always available in Mecp2 + females owing to uncontrolled X- chromosome inactivation.
  • NASH National Institutes of Health
  • mice were decapitated after deep anesthesia with inhalation of saturated isoflurane.
  • the brain stem was obtained and immediately placed in an ice-cold and sucrose- rich aCSF (in mM) containing 220 sucrose, 1.9 KC1, 0.5 CaCh, 6 MgCh, 33 NaHC0 3 , 1.2 NaH2P04 and 10 D-glucose.
  • the solution was bubbled with 95% O2 balanced with 5% CO2 (pH 7.40).
  • the transverse pontine sections (150-250 ⁇ ) containing the LC or Me5 area were obtained using a vibratome sectioning system and then recovered at 33°C for 60min in normal aCSF (in mM) containing 124 NaCl, 3 KC1, 2 CaCh, 2 MgCh, 26 NaHC0 3 , 1.3 NaH2P04 and 10 D-glucose.
  • the brain slices were kept at room temperature before being used. At recording, the slices were perfused with oxygenated aCSF at a rate of 2 ml/min and maintained at 34°C in a recording chamber by a dual automatic temperature control (Warner Instruments).
  • Breathing activities of unanesthetized mice were recorded by the plethysmograph system with a ⁇ 40ml plethysmograph chamber and a connected reference chamber.
  • the individual animal was kept in the plethysmograph chamber flowed by air at a rate of 60ml/min for at least 20 min for adaptation followed by a 20 min recording.
  • the breathing activity was recorded continuously as the barometrical changes between the
  • mice at age 6-7 weeks were tested in a 25 cm smooth, transparent tube with an internal diameter of 3.2 cm. On the testing day, all the tested mice were placed in the test room for 30 minutes for habituation. Two mice were randomly placed in opposite ends of the tube and released into the tube simultaneously. They tended to interact in the middle of the tube. The animal retreating fully from the tube was counted as loser (score 0), while the animal stayed inside the tube was counted as winner (score 1). Only all four paws out of tube was considered as a full retreat. The maximum test period was 2 minutes. Experiment failure was considered when both of the mice remained inside the tube over 2 minutes. All the mice were tested at approximately the same time of each day and only the strangers (animals from different litters) with age difference smaller than 5 days were matched for the experiments (35).
  • mice age 6-7 weeks, were tested in a three-chambered box (60 cm ⁇ 30 cm ⁇ 40 cm) with doors between each chamber. On the test day, mice were placed in the test room for 30 minutes for habituation. The procedures were performed sequentially. Firstly, the tested mouse was placed in the center chamber for 10 min, allowing the mouse to move freely over all three chambers. Its preference of a particular chamber to the rest was analyzed by the time spent in each chamber. Secondly, the social behavior test was performed by introducing a random littermate in one side chamber of the apparatus for 10 min, while times that the tested mice spent with the mice were measured. The littermate was randomly assigned in either side of the chamber to avoid the side bias. Lastly, the social novelty test was performed by introducing a new stranger mouse in the chamber and switching the littermate into the other chamber. The time spent in both side the chambers were analyzed (36).
  • Mecp2 ⁇ IY mice in the experiment were randomly selected from litters. Half of them were treated with THIP containing water, and equal number of mice treated with regular water as sham control. Their lifespan were monitored. Death date of each mouse was recorded when it died naturally or reached the humane end point as determined by the animal facility in Georgia State University. One outlier at each end was removed from each group to minimize data variations.
  • the animals used in the study were randomly separated into sham group and THIP group. All the patch experiments were done double-blindly by three people. All the behavior experiments, including breathing activity, motor function and social behavior were done double-blindly by more than one person.

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Abstract

L'invention concerne des méthodes de traitement du syndrome de Rett et de troubles associés au syndrome de Rett.
PCT/US2017/042710 2016-07-19 2017-07-19 Méthodes de traitement du syndrome de rett Ceased WO2018017639A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150352085A1 (en) * 2014-06-06 2015-12-10 Ovid Therapeutics Inc. Methods of increasing tonic inhibition and treating secondary insomnia
US20160199366A1 (en) * 2011-05-19 2016-07-14 Gilrose Pharmaceuticals, Llc Pre-frontal cortex processing disorder gait and limb impairments treatment

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160199366A1 (en) * 2011-05-19 2016-07-14 Gilrose Pharmaceuticals, Llc Pre-frontal cortex processing disorder gait and limb impairments treatment
US20150352085A1 (en) * 2014-06-06 2015-12-10 Ovid Therapeutics Inc. Methods of increasing tonic inhibition and treating secondary insomnia

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DRASBEK ET AL.: "THIP, a Hypnotic and Antinociceptive Drug, Enhances an Extrasynaptic GABAA Receptor-mediated Conductance in Mouse Neocortex", CEREBRAL CORTEX, vol. 16, no. 8, August 2006 (2006-08-01), pages 1134 - 1141, XP055452816 *

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