WO2011031948A2

WO2011031948A2 - Prevention of myopia

Info

Publication number: WO2011031948A2
Application number: PCT/US2010/048397
Authority: WO
Inventors: Bruce H. Dewoolfson; Dale P. Devore; George E. Glady; Joann Simonsen Glady; Le Thi
Original assignee: Euclid Systems Corp
Current assignee: Euclid Systems Corp
Priority date: 2009-09-11
Filing date: 2010-09-10
Publication date: 2011-03-17
Anticipated expiration: 2012-03-11
Also published as: WO2011031948A3

Abstract

Methods of preventing development of myopia by applying an orthokeratology style lens alone or in combination with administration of stabilizing molecules or by administration of stabilizing molecules, including SLRPS and FACITS, without orthokeratology style lens wear to maintain shape and structure, are disclosed. Also described are methods of identifying subject who are predisposed to development of myopia but who have not yet developed myopia.

Description

PREVENTION OF MYOPIA

FIELD OF THE INVENTION

[0001 ] This application claims priority to U.S. Provisional Application No. 61/241 ,607 filed September 1 1 , 2009, the contents of which are incorporated herein by reference.

[0002] The present invention relates to methods of preventing myopia by the temporary wear of orthokeratology style contact lenses, temporary wear of orthokeratology style contact lenses in combination with the application of molecules shown to stabilize corneal collagen structure, or by the sole application of biological molecules shown to stabilize corneal collagen structure. It also relates to methods of identifying subjects at risk of developing myopia.

BACKGROUND

[0003] General Information. Myopia or shortsightedness is the most common human eye disorder in the world, and its public health and economic impact are considerable. The prevalence of myopia varies because of varied definitions, but in the U.S. adult population the estimated prevalence of at least 25% is supported by multiple studies. Females are reported to have an earlier onset and a slightly higher prevalence than males. Whites have a significantly higher prevalence than black. Chinese and Japanese populations have high myopia prevalence rates of >50 to 70%. Ashkenazi Jews, especially Orthodox Jewish males, have shown a higher prevalence than other white U.S. and European populations.

[0004] Myopia is a significant public health problem, as it is associated with increased risk for visual loss. Myopic chorioretinal degeneration is the fourth most frequent cause of blindness leading to visual services and disability registration, and accounts for 8.8% of all causes of blindness. An estimated 5.6% of blindness among schoolchildren in the U.S. is attributable to myopia. Substantial resources are required for optical correction of myopia with spectacles, contact lenses, and, more recently, surgical procedures such as LAS IK. [0005] The market for optical aids in the U.S. was estimated to exceed $8 billion in annual sales in 1990; most dollars were spent for the correction of myopia. The development of methods for preventing or slowing the onset of myopia, or for limiting its progression is of high significance.

[0006] Myopia is defined as refractive error where parallel rays of light come to focus in front of the retina due to axial elongation of the eyeball, resulting in blurred vision. Any refraction with negative convergence or any negative diopter number is considered myopic. The mechanism underlying myopia is not well understood but is thought to be due to molecular changes in the sclera via a process known as "scleral remodeling". During this process, thinning and altered architecture of the sclera leads to increased axial elongation. This in turn leads to not only refractive error in the optical system of the eye but also to stress on the tissues of the eye due to the resulting anatomical defect. This stress can lead to other complications during aging. Refractive error is a symptom of underlying pathological changes potentially leading to long-term complications such as retinal detachment, retinal degeneration, cataracts, and glaucoma.

[0007] Scleral remodeling results from alterations in the composition of collagen content, which is regulated by both matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP).

[0008] There are different theories as to what behaviors may trigger or worsen myopia. However, it is generally accepted within the medical community that nearsightedness is an inherited trait. Nearsighted people have eyes that are elongated (axial myopia) or corneas that are more steeply curved (corneal myopia) than those of the average person, causing incoming light to focus at a point in front of the retina, rather than on it. This type of refractive error is most commonly found in those who have a direct relative with the same condition.

[0009] Juvenile onset myopia is one form of myopia. It generally occurs during the ages of 6- 6 years. It has a mean cessation age of from 14.4 to 15.3 years in females and 15 to 16.5 years in males. [0010] Progression of myopia: Once myopia is identified in a child, it almost always increases in severity. A progression rate of -0.45 diopters per year has been observed in Caucasian juveniles 8 to 12 years of age.

Progression in Asians (i.e. , how quickly the myopia worsens as seen by an increase in negative diopter) is twice that observed in Caucasians.

[001 1 ] Role of Genetics in Myopic Development: Generally the causes of myopia are classified as either environmental or genetic. Studies have shown that the prevalence of myopia in children with two myopic parents is 32.9%, decreasing to 18.2% in children with only one myopic parent, and to less than 6.3% in children with no myopic parents.

[0012] Candidate gene studies underscore that the genetics underlying myopia are very complex, in fact, so complex that single candidate gene studies are unlikely to demonstrate the type of relationships needed to account for the majority of susceptibility genes. Several clinical trials have been conducted to better understand the role of genetics in myopia development, including the Family Myopia Study sponsored by the National Human Genome Research Institute (NHGR) and Genomewide Screening of Pathological Myopia sponsored by National Taiwan National Hospital.

[0013] Although the genetics of myopia are complex, multiple familial aggregation studies report a positive correlation between parental myopia and myopia in their children, indicating heritable myopia susceptibility. Children with a family history of myopia had on average less hyperopia, deeper anterior chambers, and longer vitreous chambers even before becoming myopic. Multiple familial studies support a high genetic effect for myopia. A high degree of familial aggregation of refraction, particularly myopia, was reported in the Beaver Dam Eye Study population after accounting for the effects of age, sex, and education. Segregation analysis suggested the involvement of multiple genes, rather than a single major gene effect.

[0014] Twin studies provide the most compelling evidence that myopia is inherited. Multiple studies note an increased concordance of refractive error as well as refractive components (AL, corneal curvature, lens power) in monozygotic twins compared with dizygotic twins. Twin studies estimate a high heritability value for myopia, (the proportion of the total phenotypic variance that is attributed to genetic variance) of between 0.5 and 0.96.

[0015] Slowing progression of myopia: In the past, several techniques have demonstrated limited success in myopia control. The use of bifocals and reading glasses have yielded minimal success. Chronic use of atropine has been successful in stopping the progression of myopia; however, this treatment is not well accepted because of significant systemic, visual and ocular side effects.

[00 6] More recently controlled studies have shown that

orthokeratology lens wear can stop the progression of myopia. The

Longitudinal Orthokeratology Research in Children (LORIC) study in Hong Kong measured refractive error, axial length and vitreous chamber depth. After 24 months, when compared with spectacle wearers, patients who wore orthokeratology design contact lenses demonstrated significantly less increase in all measurements. And very recently, participants in both the Corneal Reshaping and Yearly Observation of Nearsightedness (CRAYON) study and the Stabilization of Myopia by Accelerated Reshaping Technique (SMART) study demonstrated comparable visual outcomes to subjects in the LORIC study. Orthokeratology design contact lenses appear to be an effective clinical technique to control the progression of myopia.

[0017] Most myopic children will develop only low to moderate levels of myopia, but some will progress rapidly to high myopia. Risk factors for the development of high myopia include ethnicity, parental refraction, and rate of progression of myopia. In those children at risk, interventions should be considered. Efforts to prevent the progression of myopia date back centuries, and eye exercises, medications, and hygiene have been proposed to prevent weak eyes. Most modern efforts have focused on decreasing the

accommodative requirements of the eyes. Anti-cholinergics such as atropine have been used in combination with bifocals in an attempt to slow the progression of myopia. Although progression is slowed during treatment, the long term effects seem to be a difference of no more than 1 -2 diopters, and no cases of pathological myopia have been prevented with this treatment.

[0018] Anti-cholinergics may act by a direct affect on the retina.

Pirenzepine is a selective antimuscarinic that has no anti-accommodative effects. It has been shown to retard experimental myopia in chickens through a direct effect on the retina and sclera, and its efficacy is currently being investigated in a multicentre trial. Other biochemical modulators of scleral growth are currently being investigated in animal models, and limited human trials are under way.

[0019] Accommodative effort and retinal blur can be minimized by bifocal glasses, which change the focal point for near work. Use of bifocals may slow the rate of progression of myopia; prospective randomized trials are addressing this question.

[0020] Rigid or gas permeable contact lenses may offer a mode of treatment that may be effective in slowing the progression of myopia. The rate of progression of myopia is slower in patients using these contact lenses than in patients using lenses that are placed in spectacles. The exact mechanism by which rigid contact lenses prevent axial myopia from developing is unclear. Laser refractive surgery can eliminate the refractive condition of myopia, but it does not decrease the rate of the blinding conditions of retinal detachment, macular degeneration, and glaucoma associated with high myopia.

[0021 ] Other interventions have included the use of vitamins, scleral surgery to provide shortening of the eye, biofeedback, ocular hypotensives, ocular relaxation techniques, and acupuncture. However, the efficacy of these treatments has not been confirmed in randomized controlled trials.

[0022] The patent art describing methods or devices to prevent myopia is very limited. US Patent 7,543,938 describes an electronic image device to relieve convergence and possibly relieving ciliary muscle spasms that may decrease onset and development of myopia. CN 20 199297 discloses myopia prevention glasses that essentially comprise a connecting section between two eyeglasses and a control circuit, wherein, the edge at the lower part of the connecting section is corresponding to a physiological structure at the upper part of a nose while the width of the middle part is larger than the diameter of a 3V button cell. CN 2715182 also discloses myopia prevention glasses for near use having myopia weakening effect, comprising two eyeglasses. CN 2787064 discloses a telescopic apparatus for preventing myopia, which comprises a table-top fixing seat (5), a bracket (2) and an adjusting rod (14). In the utility model, a telescopic rod (3) is arranged on the adjusting rod (14), and a spring positioning buckle (4) is arranged in the telescopic rod (3); a positioning hole (12) which is matched with the spring positioning buckle (4) is arranged on the adjusting rod (14), and the bracket (2) and the telescopic rod (3) are fixedly connected to be in the shape of a T; positioning teeth (10) are arranged on the adjusting rod (14), and an adjusting seat (6) is fixed to the table-top fixing seat (5); the adjusting rod (14) is inserted to the adjusting seat (6), and a positioning and clamping buckle (7) is hinged on the table-top fixing seat (5); a restoring spring (8) is arranged on the positioning and clamping buckle (7) which cooperates with the positioning teeth (10); anti-support gear teeth (1 ) are arranged on the bracket (2), and the end part of the adjusting rod (14) is provided with a positioning sleeve (1 1 ).

[0023] It is known that orthokeratology style lens wear can slow the progression of myopia, as discussed above. It is also known that certain molecules and recombinant human molecules stabilize corneal structures as described in US Patents 6,946,440 (Euclid Systems Corp.), 7,402,562 (Euclid Systems Corp.) and Patent Application Publication 2009/0105127 (Euclid Systems Corporation). However, neither orthokeratology style lenses nor molecules that stabilize the cornea have been disclosed as capable of preventing development of myopia. SUMMARY OF THE INVENTION

[0024] The inventors have discovered that orthokeratology style lens wear can not only slow progression of myopia in children and adolescents, but that they can prevent development of myopia in subjects who have not yet been diagnosed as having myopia. In addition, the inventors have found that certain molecules that can stabilize cornea structure and increase

biomechanical integrity can be used in combination with orthokeratology style lens wear, or used alone, to prevent development of myopia. Orthokeratology style lens application alone, in combination with natural or stabilizing molecules, or natural stabilizing molecules alone will be particularly beneficial in preventing myopia in children and adolescents genetically predisposed to develop myopia. Accordingly, the methods and uses described represent methods of preventing juvenile onset myopia. As noted above, studies have shown that the prevalence of myopia in children with two myopic parents is 32.9% decreasing to 18.2% in children with one myopic parent and to less than 6.3% in children with no myopic parents. It has also been reported that 70-80% in Asian populations have myopia. In Hong Kong prevalence of myopia is very high, from 1 1 % among 7 year olds, up to 57% in 12 year olds and over 70% in 17 year olds.

[0025] Orthokeratology style lens wear alone, in combination with natural stabilizing molecules, or natural stabilizing molecules alone will be administered before the onset of myopia. The age range at which treatment is initiated will generally be from 6 to 20 years, but is often before age 10.

[0026] In the case of orthokeratology style lens wear, the subject who has not yet developed myopia will be fitted with an orthokeratology style lens, such as those manufactured by Euclid Systems Corporation, to be worn as directed, usually overnight.

[0027] In those cases where stabilizing molecules are administered, the subject will be given a stabilizing composition on a schedule that will be determined by the prescriber, often ranging from once a week to once a month to once a year. The stabilizing agent may be administered as drops following the application of a typical ophthalmic anesthetic such as tetracaine hydrochloride, or following the application of an acylation agent known to transiently open the corneal cell structure to allow penetration into the corneal stroma or may be administered by direct injection into the corneal stroma using fine gauge needles, i.e. 30 or 32 Gauge, or by controlled injection using a unique application device developed by Euclid Systems Corporation (patent pending).

[0028] In the case wherein stabilization eye drops are used, drops may be administered following the application of a typical ophthalmic anesthetic such as tetracaine hydrochloride, or following the application of an acylation agent known to transiently open the corneal cell structure to allow penetration into the corneal stroma. The drops may be administered directly to the cornea using an applicator designed to focus delivery of liquids such as drops to the cornea and to minimize exposure of the non-corneal surface to the drops.

[0029] Natural stabilizing molecules have been described in US Patents 6,946,440 (Euclid Systems Corp.), 7,402,562 (Euclid Systems Corp.) and Patent Application Publication 2009/0105127 (Euclid Systems

Corporation). These molecules include decorin or other small leucine rich proteoglycans know as SLRPs and certain fibril associated collagen molecules with interrupted triple helices such as Type VI collagen known as (FACITs).

[0030] SLRPs also include biglycan, keratocan, lumican, mimican, and fibromodulin. FACITs include Type X, Type XII, and Type XIV collagen.

DETAILED DESCRIPTION

[0031] Additional objects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. In order that the present invention may be more readily understood, certain terms are first defined. Other definitions are set forth throughout the description of the embodiments.

[0032] Orthokeratology is the use of rigid gas-permeable contact lenses, normally worn at night, to improve vision through reshaping of the cornea.

[0033] An Orthokeratology style lens is a contact lens that will maintain the shape of the cornea according to the visual requirements of the individual patient.

[0034] By acylating agent is meant an agent that transfers an acyl group to another nucleophile. Examples of acylation agents include sulfonic acids, anhydrides, sulfonyl chlorides, and acid chlorides. A listing of appropriate anhydrides, acid chlorides, sulfonyl chlorides, and sulfonic acids can be found in the Sigma-Aldrich Chemical company catalogue.

[0035] SLRPs are small leucine-rich proteoglycans. SLRPs includes decorin, biglycan, keratocan, lumican, mimican, and fibromodulin. These proteoglycans, as well as fiber associated collagens, are linked to collagen fibers to control diameter and stabilize stromal architecture. Natural and recombinant forms of SLRPs are included, as is the core protein lacking the glycans, unless context makes clear that one particular form is intended.

[0036] FACITs are fibril associated collagen molecules with interrupted triple helices (FACITs) and includes Type VI , Type X, Type XII, and Type XIV collagen. FACITs are linked to collagen fibers to control diameter and stabilize stromal architecture. FACITs may be derived from natural products or from tissue culture sources.

[0037] Myopia, or shortsightedness, is defined as refractive error where parallel rays of light come to focus in front of the retina due to axial elongation of the eyeball resulting in blurred vision. Any refraction with negative convergence or any negative diopter number is considered myopic.

[0038] The present invention provides methods for preventing myopia. In some cases, the method is accomplished by applying orthokeratology style contact lenses to human cornea to maintain corneal structure and shape. In other cases, stabilizing molecules are administered in combination with orthokeratology style lens wear to further stabilize corneal structure and shape. In still other cases, the stabilizing molecules are administered alone to stabilize corneal structure and shape to prevent development of myopia.

[0039] Thus, in certain embodiments the invention relates to a method of preventing myopia in a subject identified as being predisposed to develop myopia but who has not yet developed myopia by fitting the cornea with an orthokeratology style lens. In this case the orthokeratology style lens is used in the manufacture of a medicament for the prevention of myopia in a subject identified as being predisposed to develop myopia but who has not yet developed myopia.

[0040] In other embodiments, the invention involves a method of preventing myopia in a subject identified as being predisposed to develop myopia but who has not yet developed myopia by fitting the cornea with an orthokeratology style lens and administering at least one agent to stabilize corneal structure. Here, an orthokeratology style lens is used in combination with at least one agent that stabilizes corneal structure to prevent myopia in a subject identified as being predisposed to develop myopia but who has not yet developed myopia.

[0041 ] One example of the use of an orthokeratology style lens in combination with at least one agent that stabilizes corneal structure is a method of preventing myopia that comprises:

a first step comprising wearing an orthokeratology style lens to control corneal tissue shape and structure;

a second step comprising applying to the corneal tissues an agent to facilitate penetration of stabilizing molecules into the cornea stroma; a third step comprising administering a stabilizing agent, optionally using an applicator to control distribution, onto the cornea; and a fourth step comprising rinsing the cornea with physiological buffers, or suitable eye washes. In the case of direct injection of the stabilizing agent, application of an agent to the corneal tissues to facilitate penetration of stabilizing molecules into the cornea stroma is unnecessary.

[0042] Certain other methods of preventing myopia in a subject identified as being predisposed to develop myopia but who has not yet developed myopia involve the administration of least one stabilizing molecule. In these cases the stabilizing molecule or molecules is used in preventing myopia in a subject identified as being predisposed to develop myopia but who has not yet developed myopia. One example of such a use of stabilizing agents that does not involve also using an orthokeratology style lens is a method that comprises:

a first step comprising applying to the corneal tissues an agent to facilitate penetration of stabilizing molecules into the cornea stroma, optionally using an applicator to control distribution to the cornea;

a second step comprising administering a stabilizing agent, optionally into an applicator to control distribution, onto the cornea; and a third step comprising rinsing the cornea with physiological buffers, or suitable eye washes. In the case of direct injection of the stabilizing agent, application of an agent to the corneal tissues to facilitate penetration of stabilizing molecules into the cornea stroma is unnecessary.

[0043] Other methods of preventing myopia in a subject who is predisposed to myopia but who has not yet developed myopia comprise:

conducting an examination of the subject's vision to determine that the patient does not have myopia in either eye;

obtaining a family history to establish that at least one parent is a myope;

fitting the subject with at least one orthokeratology style lenses that is constructed so as to maintain the emmetropic shape of a cornea; and providing the subject with the at least one orthokeratology style lenses. [0044] In some cases the method further comprises administering at least one chemical or biological agent to stabilize the corneal structure.

[0045] In other embodiments, methods of preventing myopia in a subject who is predisposed to myopia but who has not yet developed myopia comprise:

obtaining a family history to establish that at least one parent is a myope; and

administering at least one chemical or biological agent to stabilize the corneal structure.

[0046] In any of those embodiments in which a family history establishes that only one parent is myopic, the method may optionally further include establishing at least one other risk factor for development of myopia. The additional risk factor may be chosen from at least one of Chinese ethnicity, Japanese ethnicity, or the monozygotic twin of a myope.

[0047] Similarly, any of the methods involving obtaining a family history may optionally also further comprise obtaining a family history to establish that both parents are myopic. Still further, the methods may comprise obtaining a family history to establish that one or both parents developed myopia before the age of 15, the age of 16, the age of 17, or the age of 18. The methods may also further comprise obtaining a family history to establish that one or both of the parents developed myopia that began and progressed rapidly during their childhood or adolescences.

[0048] In any of the embodiments involving agents to stabilize corneal structure, the agents can be chosen from at least one SLRP, at least one FACIT, or a combination of at least one SLRP and at least one FACIT. The at least one SLRP is chosen from decorin, biglycan, keratocan, lumican, mimican, or fibromodulin. The at least one FACIT is chosen from Type VI, Type X, Type XII, or Type XIV collagen. In certain embodiments, the at least one SLRP is recombinant human decorin. [0049] The orthokeratology style lens may be provided along with the at least one agent that stabilizes the corneal structure in kit form. Kits may optionally further comprise an agent to facilitate penetration of the stabilizing molecule into the corneal stroma. In the case of direct injection of the stabilizing agent into the corneal stroma, the agent to facilitate penetration of the stabilizing agent into the corneal stroma is not necessary. Instead, the kit may include an injection device to provide controlled administration of the stabilizing agent to the corneal stroma. Thus, kits may comprise one or more orthokeratology style lens, an agent that stabilizes the corneal structure in the shape imparted by the lens, and at least one agent that facilitates the penetration of the stabilizing agent or, instead of the at least one agent that facilitates the penetration of the stabilizing agent, a device to provide controlled injection of the stabilizing agent into the corneal stroma without the need of an agent to facilitate penetration of the stabilizing agent.

Alternatively, kits may comprise one or more orthokeratology style lens and an agent that stabilizes the corneal structure in the shape imparted by the lens. In some embodiments, the kits comprise one or more orthokeratology style lens and decorin. In addition, kits may optionally further comprise at least one washing or rinsing buffers. Other optional portions of the kits include written material indicating the purpose of the kit is for preventing myopia. One non-limiting example of a kit is a kit for preventing myopia in a subject who is predisposed to myopia but who has not yet developed myopia, comprising at least one orthokeratology style lens and at least one agent to stabilize corneal structure. Another non-limiting example of a kit is a kit for preventing myopia in a subject who is predisposed to myopia but who has not yet developed myopia, comprising at least one orthokeratology style lens and recombinant human decorin. Any of the kits may further comprise written material describing the intended use of the kit.

[0050] In the cases where stabilizing molecules are used, drops of a standard topical anesthetic, such as tetracaine HCI, will generally be administered. As mentioned, in some cases an agent that facilitates penetration of the stabilizing may also be used, for example, as described in PCT/US2009/037497. For example, drops of an acylation agent, such as glutaric anhydride may be administered to facilitate penetration of the stabilizing molecules. Before administration of the acylation agent, drops of a slightly alkaline buffer will usually be applied. The eye will generally be thoroughly rinsed with physiological buffer solution, eye drops, or other physiological solution following administration of drops of stabilizing molecule solution.

[0051] When an acylating agent is used to facilitate penetration of the stabilizing molecule, the tissue is often pretreated with a solution exhibiting a pH from 7.5-9.5 prior to addition of the acylating reagent. The solution may be composed of a single component, such as disodium phosphate or sodium pyrophosphate or sodium borate, or may be a buffer composition providing a pH ranging from 7.5-9.5. The concentration of the alkaline solution generally ranges from 0.01 M to 0.2 M, but the concentration is not generally critical unless specifically so indicated.

[0052] In general, the concentrations of the acylation agents can range from 0.1 ng/mL to 50 mg/mL, and the concentration will depend upon the particular acylating agent. In many embodiments, the concentration is between 0.2 Tg/rnL and 20 mg/mL, or between 1 Mg/mL and 10 mg/mL, or even between 0.5 pg/mL and 5 mg/mL.

[0053] Additional methods to stabilize corneal structure have been described in US Patent 6, 161 ,544 and PCT/US2009/036636, including collagen crosslinking using ultraviolet and visible light in combination with a photoinitiator and collagen crosslinking using chemicals such as aldehydes and bifunctional acylation agents. Other potential methods to stabilize corneal tissues include the application of radio waves, thermal radiation, and microwave energy. Still other methods to stabilize cornea tissue via collagen crosslinking include use of epoxy compounds, carbodiimides, naphthalimides, ribose and other reducing sugars, and other known crosslinking substances. It is understood that the method for stabilization must be safe for use in human cornea without causing any irritation or toxicity.

[0054] Orthokeratology style lens wear alone, in combination with stabilizing molecules, or stabilizing molecules alone will be administered before the onset of myopia. Accordingly, the exact age range may vary, so long as the individual has not yet developed myopia. In general the age range will be from 6 to 18 years. For example, individuals identified as candidates for lens wear, treatment with stabilizing molecules, or lens wear in combination with treatment with a stabilizing molecule are often 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, or 18 years of age when therapy is initiated, although it is certainly possible to treat older subjects who are determined to be predisposed to myopia for either genetic or environmental reasons but have not yet developed the condition. Often, therapy will begin before age 10, before age 1 1 , before age 12, before age 13, before age 14, before age 15, or before age 16.

[0055] Myopia can be easily diagnosed during a routine eye exam. Usually, a visual acuity test combined with a refraction assessment can not only identify nearsightedness, but can also determine the degree of myopia. The visual acuity test involves reading a special chart from a specific distance. Based on how much of the chart the patient can read, the doctor is able to determine how clearly the patient can see. During a refraction assessment, the patient is asked to look through a device called a Phoropter while the eye doctor changes lenses and asks the patient questions. This allows the doctor to determine what prescription will most effectively correct the patient's vision. Accordingly, these methods allow those individuals having myopia to be distinguished from individuals that are not myopic at the time of the

examination. An exam result indicating any refraction with negative convergence or any negative diopter number indicates the subject is myopic. For a treatment to be a "prevention" or for the method to be of preventing myopia, the patient must not have negative convergence or a negative diopter number as determined by a standard visual exam at the time treatment begins. Retarding progression of myopia, in contrast, would involve a patient who is at least mildly myopic on a standard visual exam at the time treatment begins.

[0056] In the case of orthokeratology style lens wear, the individual who is not yet myopic but is determined to be predisposed to developing myopia by and of the methods described herein will be fitted with an orthokeratology style lens, such as those manufactured by Euclid Systems Corporation.

Usually the lens is worn overnight, and often the lens is worn each night, however, individual requirements will vary and in some cases the lens may be worn only once a week, twice a week, three times a week, four times a week, five times week, or six times a week. Wear, while often at night, can also be during the day. Lens use may decrease in frequency as the patient ages, or it may increase in frequency. Each use of the lens will often be for a period of at least 6 hours, although shorter periods of at least 3, 4, or 5 hours may be appropriate.

[0057] In the case where stabilizing molecules are administered by eye drops or by injection, the subject will be given appropriate volumes of a stabilizing composition on a schedule appropriate for preventing the development of myopia. The schedule will often range from once a month to once a year, but in some cases more or less frequent application of the eye drops or injections may be appropriate. The prescriber may select a schedule that is daily, weekly, monthly, or even yearly, depending upon the needs of the subject. Thus, the eye drops or injections may be administered once a day, once a week, once a month, or once a year. In addition, treatments schedules may be more frequent when first initiated, then later be adjusted to a less frequent schedule, or conversely, the frequency may be increased as the subject ages. Non-limiting examples of treatment schedules include daily; weekly; monthly; annual; schedules that begin with a daily schedule for a period of several weeks, for example 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 weeks, then transition to a weekly schedule for a period of several months, for example, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 months, or for the duration of the treatment schedule, and which may or may not then transition to a monthly treatment schedule, a quarterly treatment schedule, a semi-annual treatment schedule, or an annual treatment schedule; and schedules that begin with yearly, semi-annual, quarterly, or schedule but then transition to a monthly schedule, to a weekly schedule, or to a daily schedule. Schedules are not rigid and may be adjusted either for medical reasons or even for matters of convenience.

Orthokeratology style lenses/contact lenses:

Definition of Curve Widths

[0058] The modern Orthokeratology Lens typically has multiple zones. A Base Curve zone for optical properties, a Reverse Curve zone which provides the proper positioning of the Base Curve to the apex of the eye, an Alignment Curve zone which allows the lens to comfortably fit the eye, and a Peripheral Curve zone that provides edge lift and tear exchange.

Measure the cornea: Topographic Data (The "Best-Fit" Shape )

[0059] A topographic map that yields either elevation data or slope data from the apex of the cornea out to a distance no less than the outermost width of the Alignment Curve Zone is needed. Smaller samplings could be used, but the alignment curve would then be based on extrapolated data, similar to the Keratometer reading assumption below.

[0060] The data from the topographic map is used to construct a "Best- Fit" shape to be used as a reference model for calculating the concave surface of the contact lens. The "Best-Fit" shape can be an Ellipsoid or any other mathematically defined three-dimensional shape that is the closest match to the measured corneal surface. A rotationally symmetric contact lens can be designed to be fit onto any portion of the "Best-Fit" Shape.

Rotationally symmetric contact lenses are typically fit onto spherical corneas. A non-rotationally symmetric contact lens can be designed to be fit onto any portion of the "Best-Fit" Shape. Non-rotationally symmetric contact lenses are typically fit onto toric (astigmatic) corneas. Non-rotationally symmetric contact lenses are also fit on diseased corneas, such as Keratoconus, or on Post- Surgical corneas. If a "Best-Fit" shape cannot be mathematically determined, the Topographical Data will be used directly to design the contact lens.

[0061 ] The orthokeratology style lenses are preferably designed to maintain the shape and structure of corneal tissue to prevent development of myopia.

[0062] Individuals who are predisposed to develop myopia and so would benefit from treatment can be identified in several ways. As mentioned, Chinese and Japanese populations have high myopia prevalence rates of >50 to 70% and progression in Asian populations is twice that of Caucasians. Further, children with two myopic parents have a 32.9% chance of developing myopia, while 18.2% of children with one myopic parent develop myopia. Thus, subjects may be selected for treatment by the myope status of their parents. Additional selection criteria are described herein and can include ethnicity, additional components of one or both parent's family history, and twin status.

[0063] In addition, although no single genetic marker has as of yet been firmly identified that would permit screening of populations to identify those predisposed to develop myopia, associations exist with chromosomes 1 , 2, 3, 4, 5, 9, 12, 17, and X, and candidate loci include MYP1 on

chromosome Xq27.3 to 28, MYP2 on chromosome 18p1 1 .31 , MYP3 on chromosome 12q21 -23, MYP5 on chromosome 17q21-23, MYP9 on chromosome 4q 12, MYP12 on chromosome 2q37, MYP14 on chromosome 1 q36 and MYP15 on chromosome 1 q41. Further, family studies have identifies genes that may be used as markers for genetic testing of other members of that family. Accordingly, once a genetic marker or combination of markers are identified which will allow screening to detect those predisposed to develop myopia, the inventors envision utilizing genetic testing for appropriate markers to identify individuals for whom the disclosed therapies can be used to prevent the development of myopia. EXAMPLES

Example 1. Case History of Prevention of myopia in children

[0064] A female physician of Asian descent fitted her two mildly myopic children (-1 .5) with the Emerald orthokeratology contact lenses manufactured by Euclid Systems Corporation. Both patients are myopic and both of these children developed myopia by age 7. The physician reported that Emerald lens wear stopped myopia progression in the children. A third, younger child had not yet developed myopia and was also fitted with Emerald

orthokeratology contact lenses at age 6. This child has not yet developed myopia after several months.

Example 2. Prevention of Myopia by Orthokeratology type lens (prophetic)

[0065] Prevention of myopia is evaluated in children or adolescents aged 6 through 17 years of age from families where either both parents are myopic or only one parent is myopic. For example, two siblings are children of parents who are both myopic. The siblings have not yet been diagnosed with myopia. The older sibling is fitted with an orthokeratology style lens, such as the Emerald lens, and begins overnight wear. The younger sibling does not wear orthokeratologic lenses. Subjects are generally examined at various time intervals ranging from 1 week to 2 years. For example, examinations are conducted at 1 month, 3 months, and 6 months after the older sibling begins wearing the Emerald lens. At 6 months, the older sibling is not diagnosed with myopia. However, the younger sibling is diagnosed as a myope.

Example 3. Prevention of Myopia by Administration of Stabilizing

Molecules or Orthokeratology Type Lens Wear (prophetic)

[0066] Prevention of myopia is evaluated in children or adolescents aged 6 through 17 years of age from families where either both parents are myopic or only one parent is myopic. For example, three siblings are children of parents who are both myopic. The oldest sibling is diagnosed as a myope. The younger siblings are evaluated and are diagnosed as not having myopia. The sibling of intermediate age is treated with a stabilizing molecule without orthokeratology style lens wear. A solution of decorin, such as recombinant human decorin core protein (Catalent Pharma, 4.47mg/mL) in physiological buffer, is applied to the cornea either as eye drops following addition of a solution shown to enhance intrastromal penetration, such as tetracaine HCI or by direct injection into the corneal stroma. The biomechanical integrity of the cornea is measured using the Reichert Optical Response Analyzer. Results show an increase in corneal hysteresis following treatment, for example an increase of at least 1 unit. The youngest sibling is fitted with an

orthokeratology style lens, such as the Emerald lens, for overnight wear. Subjects are generally examined at intervals from 1 week to 2 years. In this case, the siblings are examined at 1 , 3, and 6 months following decorin administration and orthokeratology style lens wear. The sibling treated with decorin maintains the increased corneal hysteresis and is not diagnosed with myopia. The sibling wearing the Emerald orthokeratology lens alone is not diagnosed with myopia. The oldest sibling shows an increase in myopia. Example 4. Prevention of Myopia in Subjects Identified as Carrying a Myopia Susceptibility Gene (prophetic)

[0067] Prevention methods are conducted as described in any of the Examples. However, the children or adolescents in this case are identified on the basis of the presence of one or more genes linked to susceptibility to myopia or the absence of one or more genes associated with an absence of myopia.

[0068] Although the present invention has been described with reference to preferred embodiments, one skilled in the art can easily ascertain its essential characteristics and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention herein. Such equivalents are intended to be encompassed in the scope of the present invention.

[0069] All references, including patents, publications, and patent applications, mentioned in this specification are herein incorporated by reference in the same extent as if each independent publication, patent or patent application was specifically and individually indicated to be incorporated by reference.

REFERENCES

Diether S, et.al. Effects of intravitreally and intraperitoneal^ injected atropine on two types of experimental myopia in chicken. 2007. Exp. Eye Res. 84:266- 274

Fredrick, DR. Myopia. 2002. 324: 1 195-1 199

Foster, PJ. Myopia is Asia.2004 Br. J. Ophthalmol. 88:443-444

Genome Screening of Pathological Myopia Clinical Study. National Taiwan University Hospital

Goss, DA and Winkler, RL Progression of myopia in youths: age of cessation. Am. J. Optom. Physiol. Opt. 1983. 60:651 -680

Le QH, et.al. Effect of Pirenzepine ophthalmic solution on form-deprivation myopia in guinea pigs. 2005. Chin. Med. J. 1 18: 561 -566

Nallasamy, et.al. Genetic linkage study of high-grade myopia in a Hutterite population from South Dakota. Molecular Vision. 2007. 13:229-236

National Eye Institute. Correction of Myopia Evaluation Trial (COMET)

National Institute of Health. Family Myopia Study

P.-C. Wu and P.-C. Fang, Myopia Prevention With 0.025% Atropine Solution in Premyopia Children, ARVO 2008

Ruskiewicz, J. Ortho-K: An answer for Myopia Control. Review of Optometry, 2009. March Saw, SM, et.al., Epidemiology of myopia. Epidemiol. Rev. 1996. 18: 175-127

Wong, TY. Issues and Challenges for Myopia Research. 2004 Annals Academy of Medicine. 33: 1 -3

Yanovitch, T. et.al. Hepatocyte Growth Factor and Myopia: Genetic Association Analyses in a Caucasian Population. 2009. Molecular Vision. 15: 1028-1035

Young, TL. Molecular Genetics of Human Myopia: An Update. 2009. Optometry and Vision Science. 86: E8-E22

Claims

We Claim:

1. A method of preventing myopia in a subject identified as being predisposed to develop myopia but who has not yet developed myopia by fitting the cornea with an orthokeratology style lens.

2. A method of preventing myopia in a subject identified as being predisposed to develop myopia but who has not yet developed myopia by fitting the cornea with an orthokeratology style lens and administering at least one stabilizing agent that stabilizes corneal structure.

3. The method of claim 2, wherein the method comprises:

a second step comprising applying to the corneal tissues an agent to facilitate penetration of at least one stabilizing agent into the cornea stroma; a third step comprising administering the at least one stabilizing agent, optionally via an applicator to control distribution onto the cornea; and

a fourth step comprising rinsing the cornea with physiological buffers, or suitable eye washes.

4. A method of preventing myopia in a subject identified as being predisposed to develop myopia but who has not yet developed myopia by administering at least one stabilizing agent that stabilizes corneal structure; wherein the method comprises:

a first step comprising applying to the corneal tissues an agent to facilitate penetration of stabilizing molecules into the cornea stroma;

a second step comprising administering the stabilizing agent, optionally using an applicator to control distribution onto the cornea; and

a third step comprising rinsing the cornea with physiological buffers, or suitable eye washes; to thereby prevent the development of myopia.

5. The method of claim 2 or claim 4, wherein the at least one stabilizing agent is at least one SLRP chosen from decorin, recombinant human decorin, biglycan, keratocan, lumican, mimican, or fibromodulin.

6. The method of claim 2 or claim 4, wherein the at least one stabilizing agent is at least one FACIT chosen from Type VI, Type X, Type XII, or Type XIV collagen.

7. A method of preventing myopia in a subject who is predisposed to myopia but who has not yet developed myopia comprising:

obtaining a family history to establish that at least one parent is a myope;

fitting the subject with orthokeratology style lenses that are constructed so as to maintain the emmetropic shape of each cornea; and

providing the subject with the orthokeratology style lenses; to thereby prevent development of myopia.

8. The method of claim 7, wherein the method further comprises administering at least one stabilizing agent.

9. A method of preventing myopia in a subject who is predisposed to myopia but who has not yet developed myopia comprising:

obtaining a family history to establish that at least one parent is a myope;

administering at least one stabilizing agent; to thereby prevent development of myopia.

10. The method of claim 8 or claim 9, wherein the at least one stabilizing agent is recombinant human decorin.

1 1. The method of claim 8 or claim 9, further comprising obtaining a family history to establish that both parents are myopic.

12. The method of claim 1 1 , further comprising obtaining a family history to establish that both parents developed myopia before the age of 16.

13. The method of claim 8 or claim 9, further comprising establishing at least one other risk factor for development of myopia if the family history establishes that only one parent is a myopic.

14. The method of claim 13, wherein the additional risk factor is chosen from at least one of Chinese ethnicity, Japanese ethnicity, or the monozygotic twin of a myope.

15. A kit for preventing myopia in a subject who is predisposed to myopia but who has not yet developed myopia, comprising at least one orthokeratology style lens and at least one agent that stabilizes corneal structure.