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Adeno-Associated Viral Gene Therapy for Inherited Retinal Disease

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Abstract

Inherited retinal diseases (IRDs) are a group of rare, heterogenous eye disorders caused by gene mutations that result in degeneration of the retina. There are currently limited treatment options for IRDs; however, retinal gene therapy holds great promise for the treatment of different forms of inherited blindness. One such IRD for which gene therapy has shown positive initial results is choroideremia, a rare, X-linked degenerative disorder of the retina and choroid. Mutation of the CHM gene leads to an absence of functional Rab escort protein 1 (REP1), which causes retinal pigment epithelium cell death and photoreceptor degeneration. The condition presents in childhood as night blindness, followed by progressive constriction of visual fields, generally leading to vision loss in early adulthood and total blindness thereafter. A recently developed adeno-associated virus-2 (AAV2) vector construct encoding REP1 (AAV2-REP1) has been shown to deliver a functional version of the CHM gene into the retinal pigment epithelium and photoreceptor cells. Phase 1 and 2 studies of AAV2-REP1 in patients with choroideremia have produced encouraging results, suggesting that it is possible not only to slow or stop the decline in vision following treatment with AAV2-REP1, but also to improve visual acuity in some patients.

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Abbreviations

AAV:

Adeno-associated virus

adRP:

Autosomal dominant retinitis pigmentosa

arRP:

Autosomal recessive retinitis pigmentosa

BCVA:

Best-corrected visual acuity

BSS:

Balanced salt solution

CAG:

CMV enhancer-CBA promoter-rabbit β-globin splice acceptor site

CBA:

Chicken β-actin

CRISPR:

Clustered Regularly Interspersed Short Palindromic Repeats

DNA:

Deoxyribonucleic acid

ER:

Endoplasmic reticulum

ETDRS:

Early Treatment Diabetic Retinopathy Study

GA:

Golgi apparatus

GG:

Geranylgeranyl

GGTase:

Geranylgeranyltransferase

hCHM:

Wild-type human CHM cDNA

IRDs:

Inherited retinal diseases

MOI:

Multiplicity of infection

OCT:

Optical coherence tomography

ORF15:

Open reading frame 15

R:

Ribosome

Rab:

Ras-associated binding

REP1:

Rab escort protein 1

REP2:

Rab escort protein 2

RP:

Retinitis pigmentosa

RPE:

Retinal pigment epithelium

RPE65:

Retinal pigment epithelial 65-kDa protein

RPGR:

Retinitis pigmentosa guanosine triphosphate hydrolase regulator

RPGRIP:

RPGR-interacting protein

SE:

Standard error

VA:

Visual acuity

WPRE:

Woodchuck hepatitis virus posttranscriptional regulatory element

WT:

Wild-type

XLRP:

X-linked retinitis pigmentosa

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Acknowledgments and Disclosures

Figure 1 images courtesy of DGB. Editorial support was provided by Rebecca Franklin of Fishawack Communications Ltd. and funded by Nightstar Therapeutics. Tuyen Ong is an employee and equity holder of Nightstar Therapeutics. Mark E. Pennesi is a consultant for AGTC, Astellas, Biogen, Editas, FFB, Gensight, Horama, Ionis, Nacuity, Nightstar Therapeutics, Ophthotech, ProQR Therapeutics, RegenexBio, Sanofi, and Spark Therapeutics, and has received clinical trial support from AGTC and Nightstar Therapeutics. His institution has received support through grant P30 EY010572 from the National Institutes of Health (Bethesda, MD), and by unrestricted departmental funding from Research to Prevent Blindness (New York, NY). David G. Birch is a consultant for Acucela, AGTC, Editas, Genentech, Ionis, Nacuity, and Nightstar Therapeutics, and has received clinical trial support from AGTC, Nightstar, Ionis, and 4D Therapeutics, and grant support through EY09076 from the National Institutes of Health (Bethesda, MD, USA) and from the Foundation Fighting Blindness. Byron L. Lam declares he has no conflict of interest. Stephen H. Tsang declares he has no conflict of interest.

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Authors and Affiliations

  1. Nightstar Therapeutics, 203 Crescent Street, Suite 303, Waltham, Massachusetts, 02453, USA

    Tuyen Ong

  2. Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA

    Mark E. Pennesi

  3. Retina Foundation of the Southwest, Dallas, Texas, USA

    David G. Birch

  4. Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA

    Byron L. Lam

  5. Department of Ophthalmology and of Pathology and Cell Biology, Columbia University, New York, New York, USA

    Stephen H. Tsang

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  1. Tuyen Ong
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  2. Mark E. Pennesi
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  3. David G. Birch
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  4. Byron L. Lam
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  5. Stephen H. Tsang
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Correspondence to Tuyen Ong.

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Guest Editors: Hovhannes J Gukasyan, Shumet Hailu, and Thomas Karami

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Ong, T., Pennesi, M.E., Birch, D.G. et al. Adeno-Associated Viral Gene Therapy for Inherited Retinal Disease. Pharm Res 36, 34 (2019). https://doi.org/10.1007/s11095-018-2564-5

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