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Dr Dogra on LCA, Gene Therapy & India
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Dr Dogra on LCA, Gene Therapy & India

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Dr Dogra on LCA, Gene Therapy & India Dr Dogra on LCA, Gene Therapy & India Presentation Transcript

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