Gene Therapy in

Irene H Maumenee Columbia University Therapy in Ophthalmology

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Gene Therapy in Ophthalmology • Dec 19, 1917 the FDA issued an approval letter for Luxturna • Luxturna is used in adeno-associated virus vector-based (AAV) gene therapy of RPE65, a subtype of Leber congenital amaurosis • Manufacturer: Spark Therapeutics, Inc. Gene Therapy in Ophthalmology • Indication: Treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. Patients had to have evidence of viable retinal cells as determined by the treating physician(s). RPE 65 Phenotype

• Early severe disorder • Retinal pigmentary mottling, atrophy • Gradual improvement followed by progressive loss • Presence of nightblindness • Refractive status, hypermetropia,

RPE65

Gene Therapy in Ophthalmology Gene Therapy in Ophthalmology • Drug is injected into the subretinal space • Immediate post-op decline of acuity • Positive effect is seen within months of injection • Measured after one year in a mobility test, where obstacles are placed in a maze to be navigated in different light conditions Gene Therapy in Ophthalmology • Cost of the drug: $875,000 for both eyes (500,000 for one eye) • Unknown how long the positive effect will last • Animal model: Briard dog • Effect lasted throughout the dog’s life span of 10-12 years Briard Dog Gene Therapy in Ophthalmology Search for: •Treatment hypotheses for additional ocular diseases •other modes of gene therapy •other approaches to drug delivery •animal models Gene Therapy in Ophthalmology Led to immediate use of AAV or CRISPR technology in other retinal dystrophies, which now are undergoing clinical trials: •: CNGB3; CNGA3; BCM •Best disease: BEST1 •: CHM •Leber congenital amaurosis: GUCY2D; CEP290 •Rp4: RHO •: ABCA4 •X-linked Rp: RPGR •X-linked : XLRS Achromatopsia

• Lifelong, stable poor acuity • • • Normal functioning in mesopic conditions • Diagnosis confirmed on • Give patients red tinted glasses • Red contacts may be well tolerated for years Achromatopsia Achromatopsia Achromatopsia Achromatopsia

• CNGB3 • CNGA3 • Cone transducin GNAT2 • Cone Phosphodiesterase deficiency PDE6C • Incomplete achromatopsia – Blue Cone – X-linked Achromatopsia

• 1148delC in CNGB3 is the most common mutation leading to achromatopsia • It originated in Aland, Finland and has spread around the world X-linked Incomplete Achromatopsia

• • Caused by deletions of the promoter region of the red-green near the terminal end of the X-chromosome X-linked Incomplete Achromatopsia

• is poor in first five years of life • Nystagmus; photophobia • Slow improvement is seen up to 20/60 acuity • Recurring decline of acuity in late teens down to 2-3/200

Progress in Leber Congenital Amaurosis Leber congenital amaurosis presents in infancy with: – Profound loss of vision – Nystagmus – Sluggish pupillary responses – Markedly reduced to abolished ERG

Progress in Leber Congenital Amaurosis

Incidence

• 1- 2 in 100,000 • 5% of all inherited retinal dystrophies Progress in Leber Congenital Amaurosis This disease is separated from pigmentosa because of its congenital onset and more significant impact on vision. That separation is arbitrary LCA is among the important groups of diseases to be understood in order to develop methods of treatment and prevention Progress in Leber Congenital amaurosis • Identification of new loci • Identification of new genes in chromosomal regions of positive linkage • Mutation analysis • Screening and sequencing of known genes ($2,500) • Whole exome sequencing ($6,000) • Whole genome sequencing ($2,500) Leber Congenital Amaurosis LCA1 GUCY2D LCA11 IMPDH1 LCA2 RPE65 LCA12 CEP290 LCA3 SPATA7 LCA13 RD3 LCA4 CRX LCA14 TULP1 LCA5 LEBERCILIN LCA15 NPHN5 LCA6 AIPL1 LCA16 IQCB1 LCA7 RPGRIP1 LCA17 LCA8 CRB1 LCA18 OTX2 LCA9 NMNAT1 LCA19 CABP4 LCA10 RDH12 LCA20 DTHT1 Progress in Leber congenital amaurosis

• GUCY2D cGMP levels in photoreceptors • RPE65 Vitamin A metabolism • SPATA7 Protein transport • CRX PR development, maintenance • Lebercilin Protein transport • AIPL1 PR development, protein folding • RPGRIP1 Protein transport Progress in Leber Congenital Amaurosis • GUCY2D Regulation of cyclic GMP levels • CRB1 Mueller cell – photoreceptor interaction (rods and cones) • NMNAT1 Neuroprotection • RDH12 PR retinol dehydrogenase • IMPDH1 Guanine synthesis • CEP290 Centrosomal protein • LCA5 Protein transport Gene Therapy in Ophthalmology Biotech Companies: •Spark •Abeona •AGTC •Biogen •Novartis

Gene Therapy in Ophthalmology

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