Ophthalmology Gene Therapy in - nysgeneticstaskforce.org · Ophthalmology •Dec 19, 1917 the FDA issued an approval letter for Luxturna •Luxturna is used in adeno-associated virus

Gene Therapy in OphthalmologyIrene H MaumeneeColumbia University

Gene 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, myopia

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:

•Achromatopsia: CNGB3; CNGA3; BCM •Best disease: BEST1•Choroideremia: CHM•Leber congenital amaurosis: GUCY2D; CEP290•Rp4: RHO•Stargardt disease: ABCA4•X-linked Rp: RPGR•X-linked retinoschisis: XLRS

Achromatopsia

• Lifelong, stable poor acuity• Photophobia• Nystagmus• Normal functioning in mesopic conditions• Diagnosis confirmed on electroretinography• 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

Monochromacy – 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

• Blue cone monochromacy• Caused by deletions of the promoter

region of the red-green genes near the terminal end of the X-chromosome

X-linked Incomplete Achromatopsia

• Visual acuity 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 retinitis pigmentosa because of its congenital onset and more significant impact on vision. That separation is arbitrary

LCA is among the important groups of human 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 AmaurosisLCA1 GUCY2D LCA2 RPE65LCA3 SPATA7LCA4 CRXLCA5 LEBERCILINLCA6 AIPL1LCA7 RPGRIP1 LCA8 CRB1 LCA9 NMNAT1LCA10 RDH12

LCA11 IMPDH1LCA12 CEP290LCA13 RD3LCA14 TULP1LCA15 NPHN5LCA16 IQCB1LCA17 LCA18 OTX2 LCA19 CABP4LCA20 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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