Gene therapy for inherited retinal and optic nerve degenerations

ABSTRACT

Introduction: The eye is a target for investigational gene therapy due to the monogenic nature of many inherited retinal and optic nerve degenerations (IRD), its accessibility, tight blood-ocular barrier, the ability to non-invasively monitor for functional and anatomic outcomes, as well as its relative immune privileged state.Vectors currently used in IRD clinical trials include adeno-associated virus (AAV), small single-stranded DNA viruses, and lentivirus, RNA viruses of the retrovirus family. Both can transduce non-dividing cells, but AAV are non-integrating, while lentivirus integrate into the host cell genome, and have a larger transgene capacity.

Areas covered: This review covers Leber’s congenital amaurosis, choroideremia, retinitis pigmentosa, Usher syndrome, Stargardt disease, Leber’s hereditary optic neuropathy, Achromatopsia, and X-linked retinoschisis.

Expert opinion: Despite great potential, gene therapy for IRD raises many questions, including the potential for less invasive intravitreal versus subretinal delivery, efficacy, safety, and longevity of response, as well as acceptance of novel study endpoints by regulatory bodies, patients, clinicians, and payers. Also, ultimate adoption of gene therapy for IRD will require widespread genetic screening to identify and diagnose patients based on genotype instead of phenotype.

KEYWORDS:

• Gene therapy
• adeno-associated virus
• inherited retinal disease
• Leber’s Congenital Amaurosis
• retinitis pigmentosa
• choroideremia
• Stargardt Disease

Article highlights

• Gene therapy has a promising future in the treatment of degenerative retinal diseases.

• A variety of viral vectors and surgical delivery techniques are being investigated in clinical trials to identify the safest and most effective method for targeting pertinent retinal cellular structures.

• Local tolerability of vector therapy for IRDs has been demonstrated in numerous small studies and no serious systemic complications have been reported.

• Continued advancements in the understanding of the pathophysiology of IRDs will allow for improved, more targeted, genetic therapy.

• The monogenic nature of IRDs and lack of effective treatment to date makes gene therapy a compelling approach and continued investigation is warranted.

This box summarizes key points contained in the article.

Declaration of Interest

Dr. Ciulla had an employment relationship with, and equity ownership in, Ophthotech corporation during manuscript preparation and submission. He had an employment relationship with, and equity ownership in, Spark therapeutics after submission. This work was undertaken in his role as Volunteer Clinical Professor at Indiana University School of Medicine, and does not reflect the views or opinions of these corporations or management. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This manuscript has not been funded.