Successfully reported this slideshow.
Leber Congenital Amaurosis: Gene Therapy & India <ul><li>Dr Mangat R Dogra </li></ul><ul><li>Advanced Eye Centre </li></ul...
Financial Disclosure <ul><li>None </li></ul>
Gene therapy <ul><li>Treatment for previously   incurable hereditary retinal degenerations are emerging.   </li></ul><ul><...
Gene therapy <ul><li>Suitable for autosomal recessive diseases where there is no normal protein production </li></ul><ul><...
Gene therapy <ul><li>Gene therapy is delivery system for bioactive substances </li></ul><ul><li>Diseases that produce gene...
Gene therapy <ul><li>Gene replacement – LCA </li></ul><ul><li>RNA interference – AMD, RP and Retinal Neovascularisation </...
Obstacles in gene therapy <ul><li>Immune barriers to vector delivery </li></ul><ul><li>Toxicity of vectors </li></ul><ul><...
Ongoing gene therapy trials <ul><li>Leber congenital amaurosis  Stargardts disease </li></ul><ul><li>Juvenile retinoschisi...
Leber congenital amaurosis(LCA) <ul><li>Heterogenous group of diseases </li></ul><ul><li>Mostly bilateral, symmetrical and...
Leber congenital amaurosis(LCA) <ul><li>Group of disorders accounting for 5% of all retinal dystrophies </li></ul><ul><li>...
Leber congenital amaurosis <ul><li>Autosomal recessive inheritance </li></ul><ul><li>Characterised by moderate visual impa...
Leber congenital amaurosis <ul><li>Mild pigmentation to frank atrophic retinal changes which are progressive </li></ul><ul...
15, M, Night blindness : Early age Visual Acuity R/E : 6/60, L/E : 6/60, FH+ nystagmus ERG : No wave formation
13, M, Night blindness : Early age, FH + Visual Acuity R/E : 6/36 L/E : 6/36 n Nystagmus High myopia Scotopic ERG : No wav...
16, M, Night blindness : early age,FH- nystagmus Visual Acuity R/E : 6/60  L/E : HM ERG : No wave formation
Differential diagnosis <ul><li>Congenital stationary night blindness </li></ul><ul><li>Retinitis pigmentosa </li></ul><ul>...
48, M, Night blindness :  25 yrs, FH + Visual Acuity R/E : HM  L/E : HM ERG : No wave formation
Retinitis pigmentosa
Leber congenital amaurosis <ul><li>There are at least 12 mutations known in LCA, RPE65 is one of them. </li></ul><ul><li>H...
LCA caused by RPE65 mutation <ul><li>RPE65 is required for production of 11-cis- retinal in retinal visual cycle </li></ul...
Gene therapy for LCA caused by RPE65 mutation <ul><li>Early results of 3 human trials were reported in 2008 </li></ul><ul>...
Gene Therapy for Leber Congenital Amaurosis Caused by  RPE65  Mutations <ul><li>Safety and Efficacy in 15 Children and Adu...
Gene therapy in LCA <ul><li>Open – label ,dose –escalation phase 1 study of 15 patients (11-30 yrs) of LCA </li></ul><ul><...
Gene therapy for LCA caused by RPE65 mutation  <ul><li>Gene therapy for LCA caused by RPE 65 mutations is sufficiently saf...
Conclusions <ul><li>LCA may occur in isolation or as a part of  multisystem syndrome </li></ul><ul><li>Characterised by mo...
Thank You
Upcoming SlideShare
Loading in …5
×

Dr Dogra on LCA, Gene Therapy & India

2,015 views

Published on

Published in: Health & Medicine, Technology
  • Be the first to comment

  • Be the first to like this

Dr Dogra on LCA, Gene Therapy & India

  1. 1. Leber Congenital Amaurosis: Gene Therapy & India <ul><li>Dr Mangat R Dogra </li></ul><ul><li>Advanced Eye Centre </li></ul><ul><li>PGIMER, Chandigarh </li></ul>
  2. 2. Financial Disclosure <ul><li>None </li></ul>
  3. 3. Gene therapy <ul><li>Treatment for previously incurable hereditary retinal degenerations are emerging. </li></ul><ul><li>Gene therapy for inherited retinal disease has the potential to become a future part of clinical practice. </li></ul>
  4. 4. Gene therapy <ul><li>Suitable for autosomal recessive diseases where there is no normal protein production </li></ul><ul><li>Not for autosomal dominant diseases as there is defective copy that produces protein </li></ul>
  5. 5. Gene therapy <ul><li>Gene therapy is delivery system for bioactive substances </li></ul><ul><li>Diseases that produce genetically engineered protein, peptides, RNA or RNA fragment </li></ul><ul><li>Proof has been established in animal models for a variety of genetic and non genetic retinal diseases </li></ul>
  6. 6. Gene therapy <ul><li>Gene replacement – LCA </li></ul><ul><li>RNA interference – AMD, RP and Retinal Neovascularisation </li></ul><ul><li>DNA using nanoparticles - RP </li></ul>
  7. 7. Obstacles in gene therapy <ul><li>Immune barriers to vector delivery </li></ul><ul><li>Toxicity of vectors </li></ul><ul><li>Lack of sustained therapeutic gene expression </li></ul>
  8. 8. Ongoing gene therapy trials <ul><li>Leber congenital amaurosis Stargardts disease </li></ul><ul><li>Juvenile retinoschisis </li></ul><ul><li>Usher syndrome </li></ul><ul><li>Exudative macular degeneration </li></ul>
  9. 9. Leber congenital amaurosis(LCA) <ul><li>Heterogenous group of diseases </li></ul><ul><li>Mostly bilateral, symmetrical and inherited disorders </li></ul><ul><li>Progressive photoreceptor and RPE dystrophy </li></ul>
  10. 10. Leber congenital amaurosis(LCA) <ul><li>Group of disorders accounting for 5% of all retinal dystrophies </li></ul><ul><li>Account for 10% to 18% of congenital blindness </li></ul><ul><li>LCA with ophthalmic findings only </li></ul><ul><li>LCA with systemic associations like deafness, mental retardation, cardiomyopathy, hepatic dysfunction and skeletal abnormalities </li></ul>
  11. 11. Leber congenital amaurosis <ul><li>Autosomal recessive inheritance </li></ul><ul><li>Characterised by moderate visual impairment to blindness from infancy </li></ul><ul><li>Present with nystagmus and eye rubbing (oculo digital sign ) </li></ul><ul><li>May have associated hyperopia and Keratoconus </li></ul>
  12. 12. Leber congenital amaurosis <ul><li>Mild pigmentation to frank atrophic retinal changes which are progressive </li></ul><ul><li>Mild attenuation of vessels with waxy disc pallor </li></ul><ul><li>Macular coloboma in late stages </li></ul><ul><li>ERG is markedly reduced </li></ul>
  13. 13. 15, M, Night blindness : Early age Visual Acuity R/E : 6/60, L/E : 6/60, FH+ nystagmus ERG : No wave formation
  14. 14. 13, M, Night blindness : Early age, FH + Visual Acuity R/E : 6/36 L/E : 6/36 n Nystagmus High myopia Scotopic ERG : No wave formation
  15. 15. 16, M, Night blindness : early age,FH- nystagmus Visual Acuity R/E : 6/60 L/E : HM ERG : No wave formation
  16. 16. Differential diagnosis <ul><li>Congenital stationary night blindness </li></ul><ul><li>Retinitis pigmentosa </li></ul><ul><li>Achromatosia </li></ul><ul><li>Infantile neuronal ceroid lipofucinosis </li></ul><ul><li>Renal retinal syndromes </li></ul>
  17. 17. 48, M, Night blindness : 25 yrs, FH + Visual Acuity R/E : HM L/E : HM ERG : No wave formation
  18. 18. Retinitis pigmentosa
  19. 19. Leber congenital amaurosis <ul><li>There are at least 12 mutations known in LCA, RPE65 is one of them. </li></ul><ul><li>Half of these are also implicated in RP </li></ul><ul><li>LCA caused by RPE65 mutations has been included for initial gene therapy clinical trials </li></ul>
  20. 20. LCA caused by RPE65 mutation <ul><li>RPE65 is required for production of 11-cis- retinal in retinal visual cycle </li></ul><ul><li>Night blindness, usually VA (6/60 to 6/30) </li></ul><ul><li>Low hyperopia or sometimes myopia </li></ul><ul><li>Yellow white outer retinal dots with vascular attenuation and optic atrophy </li></ul><ul><li>Concentrically constricted visual field </li></ul>
  21. 21. Gene therapy for LCA caused by RPE65 mutation <ul><li>Early results of 3 human trials were reported in 2008 </li></ul><ul><li>These preliminary results showed safety and modest efficacy after subretinal injections of adeno-associated virus 2 (AAV2)carrying RPE65 </li></ul><ul><li>N Engl J Med . 2008;358(21):2231-2239. </li></ul><ul><li>N Engl J Med . 2008;358(21):2240-2248. </li></ul><ul><li>Hum Gene Ther .2008;19(10):979-990. </li></ul>
  22. 22. Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations <ul><li>Safety and Efficacy in 15 Children and Adults Followed Up to 3 Years </li></ul>Jacobson SM et al Arch Ophthalmol. 2012;130(1):9-24 . CLINICAL TRIAL
  23. 23. Gene therapy in LCA <ul><li>Open – label ,dose –escalation phase 1 study of 15 patients (11-30 yrs) of LCA </li></ul><ul><li>Subetinal injection of rAAV2-RPE65 vector into worse-functioning eye </li></ul><ul><li>No systemic toxicity was detected </li></ul>
  24. 24. Gene therapy for LCA caused by RPE65 mutation <ul><li>Gene therapy for LCA caused by RPE 65 mutations is sufficiently safe and substantially efficatious in the extrafoveal retina </li></ul><ul><li>There is no benefit and some risk in treating the fovea </li></ul><ul><li>Patients with better foveal structure lost retinal thickness and acuity after subfoveal injections </li></ul>Jacobson SM et al Arch Ophthalmol. 2012;130(1):9-24
  25. 25. Conclusions <ul><li>LCA may occur in isolation or as a part of multisystem syndrome </li></ul><ul><li>Characterised by moderate visual impairment to blindness from infancy </li></ul><ul><li>Findings are nystagmus, RPE changes, attenuated arterioles and waxy pallor of disc </li></ul><ul><li>Gene therapy for LCA caused by RPE65 mutations is sufficiently safe and substantially efficatious. </li></ul>
  26. 26. Thank You

×