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Emerging Gene Therapy Approaches Under Clinical Investigation for Retinal Degenerative Diseases

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Drug Delivery Challenges and Novel Therapeutic Approaches for Retinal Diseases

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 35))

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Abstract

Inherited retinal diseases (IRDs) have until recently not had prospects of effective treatment options. Preclinical studies have been very promising, but the number of clinical gene therapy trials has been very limited. The improved visual function outcomes in individuals affected by retinal dystrophy caused by biallelic variants in the RPE65 gene after gene therapy treatment contributed to the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval of the first gene therapy for any human inherited disease. This milestone in treatment for IRDs has greatly enhanced the development of new treatment trials. There are currently several active clinical trials for IRDs including retinitis pigmentosa, Leber congenital amaurosis, Stargardt disease, choroideremia, and achromatopsia. The area of optogenetics is an alternative approach where the remaining retinal neurons are converted into photosensitive cells. The majority of the current trials utilize a viral vector delivered into the subretinal space or into the vitreous cavity in order to express a specific gene. Other treatment options are targeting the mechanism of the retinal degeneration. This chapter is a review of the current gene therapy treatment clinical trials for IRDs, which may finally contribute to powerful treatment options for these progressive retinal dystrophies.

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Abbreviations

A2E:

N-retinylidene-N-retinylethanolamine

AAV:

Adeno-associated virus

ABCA4:

ATP-binding cassette subfamily A member 4

AMD:

Age-related macular degeneration

ASO:

Antisense oligonucleotide

Cas9:

CRISPR-associated protein 9

CEP290:

Centrosomal protein of 290 kDa

CHM:

Choroideremia

ChR:

Channelrhodopsin

CMV:

Cytomegalovirus

CNG:

Cyclic nucleotide-gated

CRISPR:

Clusters of regularly interspaced short palindromic repeats

EIAV:

Equine infectious anemia virus

EMA:

European Medicines Agency

ERG:

Electroretinogram

FDA:

Food and Drug Administration

FST:

Full-field sensitivity threshold

IRDs:

Inherited retinal diseases

LCA:

Leber congenital amaurosis

MERTK:

MER proto-oncogene tyrosine kinase

MYO7A:

Myosin 7A

NAC:

N-Acetylcysteine

NEI:

National Eye Institute

ORF:

Open reading frame

RALBP1:

RalA-binding protein 1

RBP4:

Retinol-binding protein 4

RetGC1:

Retinal guanylate cyclase-1

RHO:

Rhodopsin

RP:

Retinitis pigmentosa

RPE:

Retinal pigment epithelium

RPGR:

Retinitis pigmentosa GTPase regulator

RS1:

Retinoschisin 1

USH2A:

Usher syndrome type 2A

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Authors and Affiliations

  1. Department of Ophthalmology, University of Arizona College of Medicine Phoenix, Phoenix, AZ, USA

    Benjamin Bakall & Kendra Klein

  2. National Ophthalmic Research Institute, Fort Myers, FL, USA

    Katrina Mears

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  1. Benjamin Bakall
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  2. Kendra Klein
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Correspondence to Benjamin Bakall .

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Editors and Affiliations

  1. Departments of Basic and Clinical Sciences and Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY, USA

    Christopher L. Cioffi

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This manuscript is a review of previously published accounts; as such, no animal or human studies were performed.

Conflict of Interest

BB is a consultant for Biogen and Spark (honoraria), and is an investigator for clinical trials sponsored by Biogen and Alkeus, and is a member of the data and safety monitoring committee for the Allergan RST-001 trial.

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Bakall, B., Klein, K., Mears, K. (2020). Emerging Gene Therapy Approaches Under Clinical Investigation for Retinal Degenerative Diseases. In: Cioffi, C.L. (eds) Drug Delivery Challenges and Novel Therapeutic Approaches for Retinal Diseases. Topics in Medicinal Chemistry, vol 35. Springer, Cham. https://doi.org/10.1007/7355_2020_102

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