Therapeutic regimens and methods for improving visual function in visual disorders associated with an endogenous retinoid deficiency

Abstract

Therapeutic regimes for improving visual function in a subject having a deficiency in endogenously produced 11-cis retinal comprising administering the synthetic retinal derivative as a divided dose over 2-7 days then providing a resting period of 7-28 days after which the second dose of the synthetic retinal derivative is administered. Preferred synthetic retinal derivatives are 9-or 11-cis-retinyl esters. Disorders associated with deficiency in endogenously produced 11-cis retinal include retinitis pigmentosa and Leber congenital amaurosis

1 - 190 . (canceled) 
     
     
         191 . A method of improving visual function in a subject having an endogenous retinoid deficiency comprising:
 a. administering a first therapeutic dose of a synthetic retinal derivative to a subject in need thereof, wherein the first therapeutic dose is administered as a divided dose over a period of from about 2 to about 7 days;   b. providing a resting period of from about 7 to about 28 days; and   c. administering a second therapeutic dose of the synthetic retinal derivative to said subject following the end of the resting period,   wherein said subject demonstrates a decline in visual function prior to administration of the second therapeutic dose.   
     
     
         192 . The method of  claim 191 , wherein the subject has retinitis pigmentosa (RP). 
     
     
         193 . The method of  claim 192 , wherein the subject has moderate to severe RP. 
     
     
         194 . The method of  claim 192 , wherein the subject has mild RP. 
     
     
         195 . The method of  claim 192 , wherein the subject has early onset or juvenile RP. 
     
     
         196 . The method of  claim 191 , wherein the subject has Leber congenital amaurosis (LCA). 
     
     
         197 . The method of  claim 191 , wherein the subject has an LRAT gene mutation. 
     
     
         198 . The method of  claim 191 , wherein the subject has an RPE65 gene mutation. 
     
     
         199 . The method of  claim 191 , wherein the synthetic retinal derivative provides replacement of endogenously produced 11-cis-retinal. 
     
     
         200 . The method of  claim 191 , wherein the method further comprises repeating steps b and c one or more times. 
     
     
         201 . The method of  claim 191 , wherein the first therapeutic dose is administered as a divided dose over a period of 7 days. 
     
     
         202 . The method of  claim 191 , wherein the resting period is from about 7 days to about 21 days. 
     
     
         203 . The method of  claim 202 , wherein the resting period is about 21 days. 
     
     
         204 . The method of  claim 202 , wherein the resting period is about 14 days. 
     
     
         205 . The method of  claim 202 , wherein the resting period is about 7 days. 
     
     
         206 . The method of  claim 191 , wherein the subject is a human subject. 
     
     
         207 . The method of  claim 191 , wherein the first therapeutic dose is administered as a divided dose over a period of 6 days, 5 days, 4 days, 3 days, or 2 days. 
     
     
         208 . The method of  claim 192 , wherein said RP subject is 15 years or older, 20 years or older, 30 years or older, 40 years or older, 50 years or older, 60 years or older, about 20 years or less, about 30 years or less, about 40 years or less, or about 50 years or less, when the first therapeutic dose is administered. 
     
     
         209 . The method of  claim 191 , wherein the synthetic retinal derivative is a 9-cis-retinyl ester or an 11-cis-retinyl ester. 
     
     
         210 . The method of  claim 209 , wherein the synthetic retinal derivative is 11-cis-retinyl acetate. 
     
     
         211 . The method of  claim 209 , wherein the synthetic retinal derivative is 9-cis-retinyl acetate. 
     
     
         212 . The method of  claim 191 , wherein the first therapeutic dose:
 a) is from about 280 mg/m 2  to about 420 mg/m 2 ;   b) is about 280 mg/m 2 ;   c) is about 420 mg/m 2 ;   d) is about 10 mg/m 2  per day;   e) is about 20 mg/m 2  per day;   f) is about 40 mg/m 2  per day; or   g) is about 60 mg/m 2  per day.   
     
     
         213 . The method of  claim 191 , wherein the therapeutic doses are administered orally. 
     
     
         214 . The method of  claim 191 , wherein the second therapeutic dose is administered for substantially the same period and in substantially the same amount as the first therapeutic dose. 
     
     
         215 . The method of  claim 191 , wherein the dose in step c) is:
 i) lower than the amount of the first therapeutic dose;   ii) the same as the amount of the first therapeutic dose; or   iii) higher than the amount of the first therapeutic dose.   
     
     
         216 . The method of  claim 191 , wherein said improving visual function comprises an improvement in the subject's visual acuity or visual field. 
     
     
         217 . The method of  claim 216 , wherein said subject has very low visual acuity (light perception or hand waving, zero letters) at baseline. 
     
     
         218 . The method of  claim 217 , wherein said visual acuity is determined by Early Treatment of Diabetic Retinopathy Study (ETDRS) and wherein said improvement comprises an increase of any letters above baseline. 
     
     
         219 . The method of  claim 191 , wherein said improving visual function comprises increasing visual field in an eye by at least 20% from baseline as measured by Goldmann Visual Field (GVF) analysis, or increasing visual acuity in an eye by greater than or equal to 5 letters from baseline as measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart, or both. 
     
     
         220 . The method of  claim 191 , wherein the subject is a human subject having inherited mutations in RPE65 or LRAT genes associated with Leber congenital amaurosis or Retinitis Pigmentosa. 
     
     
         221 . The method of  claim 220 , wherein the human subject has Retinitis Pigmentosa (RP). 
     
     
         222 . The method of  claim 221 , wherein the human subject has moderate to severe RP. 
     
     
         223 . The method of  claim 221 , wherein the human subject has mild RP. 
     
     
         224 . The method of  claim 221 , wherein the human subject has early onset or juvenile RP. 
     
     
         225 . The method of  claim 220 , wherein the human subject has Leber congenital amaurosis (LCA). 
     
     
         226 . The method of  claim 220 , wherein the synthetic retinal derivative provides replacement of endogenously produced 11-cis-retinal. 
     
     
         227 . The method of  claim 220 , wherein the method further comprises repeating steps b and c one or more times. 
     
     
         228 . The method of  claim 220 , wherein the first therapeutic dose is administered as a divided dose over a period of 7 days. 
     
     
         229 . The method of  claim 220 , wherein the first therapeutic dose is administered as a divided dose over a period of 6 days, 5 days, 4 days, 3 days, or 2 days. 
     
     
         230 . The method of  claim 220 , wherein the resting period is from about 7 days to about 21 days. 
     
     
         231 . The method of  claim 230 , wherein the resting period is about 21 days, about 14 days, or about 7 days. 
     
     
         232 . The method of  claim 221 , wherein said RP human subject is 15 years or older, 20 years or older, 30 years or older, 40 years or older, 50 years or older, 60 years or older, about 20 years or less, about 30 years or less, about 40 years or less, or about 50 years or less, when the first therapeutic dose is administered. 
     
     
         233 . The method of  claim 220 , wherein the synthetic retinal derivative is a 9-cis-retinyl ester or an 11-cis-retinyl ester. 
     
     
         234 . The method of  claim 233 , wherein the synthetic retinal derivative is 11-cis-retinyl acetate. 
     
     
         235 . The method of  claim 233 , wherein the synthetic retinal derivative is 9-cis-retinyl acetate. 
     
     
         236 . The method of  claim 220 , wherein the first therapeutic dose:
 a) is from about 280 mg/m 2  to about 420 mg/m 2 ;   b) is about 280 mg/m 2 ;   c) is about 420 mg/m 2 ;   d) is about 10 mg/m 2  per day;   e) is about 20 mg/m 2  per day;   f) is about 40 mg/m 2  per day; or   g) is about 60 mg/m 2  per day.   
     
     
         237 . The method of  claim 220 , wherein the therapeutic doses are administered orally. 
     
     
         238 . The method of  claim 220 , wherein the second therapeutic dose is administered for substantially the same period and in substantially the same amount as the first therapeutic dose. 
     
     
         239 . The method of  claim 220 , wherein the dose in step c) is:
 i) lower than the amount of the first therapeutic dose;   ii) the same as the amount of the first therapeutic dose; or   iii) higher than the amount of the first therapeutic dose.   
     
     
         240 . The method of  claim 220 , wherein said improving visual function comprises an improvement in the subject's visual acuity or visual field. 
     
     
         241 . The method of  claim 240 , wherein said subject has very low visual acuity (light perception or hand waving, zero letters) at baseline. 
     
     
         242 . The method of  claim 241 , wherein said visual acuity is determined by Early Treatment of Diabetic Retinopathy Study (ETDRS) and wherein said improvement comprises an increase of any letters above baseline. 
     
     
         243 . The method of  claim 220 , wherein said improving visual function comprises increasing visual field in an eye by at least 20% from baseline as measured by Goldmann Visual Field (GVF) analysis, or increasing visual acuity in an eye by greater than or equal to 5 letters from baseline as measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart, or both. 
     
     
         244 . The method of  claim 191 , wherein the subject is deficient in endogenously produced 11-cis retinal. 
     
     
         245 . A kit for improving visual function in a subject having an endogenous retinoid deficiency, the kit comprising,
 a. at least a first therapeutic dose of a synthetic retinal derivative; and,   b. instructions for use that direct that the first therapeutic dose is administered as a divided dose over a period of from about 2 to about 7 days and that provides a resting period between the first therapeutic dose and a second therapeutic dose, wherein the resting period is from about 7 to about 28 days,   wherein said subject demonstrates a decline in visual function prior to administration of the second therapeutic dose.   
     
     
         246 . A dosing regimen for improving visual function of a subject having an endogenous retinoid deficiency, wherein the dosing regimen comprises at least, a first therapeutic dose, a second therapeutic dose and a resting period between the first therapeutic dose and the second therapeutic dose, the regimen comprising:
 a. administering a first therapeutic dose of a synthetic retinal derivative as a divided dose over a period of from about 2 to about 7 days to a subject in need thereof;   b. providing a resting period of from about 7 to about 28 days between the first therapeutic dose and the second therapeutic dose; and   c. administering the second therapeutic dose of the synthetic retinal derivative following the end of the resting period to the subject in need thereof,   wherein said subject demonstrates a decline in visual function prior to administration of the second therapeutic dose.