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Ocular Gene Therapies

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Albert and Jakobiec's Principles and Practice of Ophthalmology

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Abstract

Loss of vision is one of the most severe handicaps highly impacting the daily life of affected individuals. Until recently there has been no treatment available for patients suffering from inherited blinding disorders. During the past years research activities in the field of ocular gene therapy have been intensified and led to marketing authorization of voretigene neparvovec (Keeler and Flotte, Annu Rev Virol, 2019), the first-in-class gene therapy product for the treatment of Leber’s congenital amaurosis (LCA), a retinal dystrophy caused by mutations in the retinal pigment epithelium (RPE) expressed gene RPE65. Voretigene neparvovec is a one-time gene augmentation therapy which utilizes a recombinant adeno-associated virus (AAV)-based vector to express a healthy copy of the human RPE65 gene in the patient’s RPE cells. For other forms of inherited retinal dystrophies many promising approaches are in clinical and preclinical development. Most approaches use the principle of gene augmentation with AAV vectors designed to result in sustained expression of a therapeutic gene in specific target cells of the retina, for example, RPE, cone or rod photoreceptors. The goal of gene augmentation is to achieve long-term gene expression and, thus, to augment or endow the function which is impaired or missing due to the gene mutation. The success with gene augmentation therapy in monogenic disorders like RPE65-linked LCA helped to further develop gene therapy technologies and broaden the concept of gene supplementation also for nongenetic disorders, such as age-related macular degeneration (AMD). This chapter aims to introduce the most commonly used principles and technologies of gene therapy and provide an overview of current approaches and clinical trials. Moreover, limitations and risks of the existing technologies will be discussed followed by an outlook on next-generation technologies which could help to address the unmet needs in ocular gene therapy.

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Abbreviations

AAV:

adeno-associated virus

ACHM:

achromatopsia

Ad:

adenovirus

AMD:

age-related macular degeneration

AON:

antisense oligonucleotides

Cas:

CRISPR-associated nucleases

CHM:

choroideremia

ChR2:

channelrhodopsin-2

CRD:

cone-rod dystrophies

CRISPR:

clustered regularly interspaced short palindromic repeats

EIAV:

equine infectious anemia virus

ILM:

inner limiting membrane

IRD:

inherited retinal dystrophies

ITR:

inverted terminal repeat

IVT:

intravitreal

LCA:

Leber’s congenital amaurosis

LV:

lentivirus

NpHR:

halorhodopsin

PEDF:

epithelium derived factor

PR:

photoreceptors

rAAV:

recombinant adeno-associated virus

RP:

retinitis pigmentosa

RPE:

retinal pigment epithelium

STGD:

Stargardt disease

SR:

subretinal

VEGF:

vascular endothelial growth factor

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Authors and Affiliations

  1. Department of Ophthalmology, University Hospital LMU Munich, Munich, Germany

    Stylianos Michalakis, Maximilian-Joachim Gerhardt, Claudia Priglinger & Siegfried Priglinger

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  1. Stylianos Michalakis
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  2. Maximilian-Joachim Gerhardt
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  3. Claudia Priglinger
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  4. Siegfried Priglinger
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Correspondence to Stylianos Michalakis .

Editor information

Editors and Affiliations

  1. Department of Ophthalmology, Oregon Health & Science University Department of Ophthalmology, Portland, OR, USA

    Daniel Albert

  2. Massachusetts Eye and Ear, Boston, MA, USA

    Joan Miller

  3. Department of Ophthalmology, University of Illinois at Chicago Department of Ophthalmology, Chicago, IL, USA

    Dimitri Azar

  4. Department of Ophthalmology, Harvard Medical School, Boston, MA, USA

    Lucy H. Young

Section Editor information

  1. Massachusetts Eye and Ear, Boston, USA

    Jason Comander

  2. Massachusetts Eye and Ear, Boston, USA

    Luk Vandenberghe

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Michalakis, S., Gerhardt, MJ., Priglinger, C., Priglinger, S. (2021). Ocular Gene Therapies. In: Albert, D., Miller, J., Azar, D., Young, L.H. (eds) Albert and Jakobiec's Principles and Practice of Ophthalmology. Springer, Cham. https://doi.org/10.1007/978-3-319-90495-5_150-1

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  • DOI: https://doi.org/10.1007/978-3-319-90495-5_150-1

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