Emerging Gene Therapy Approaches Under Clinical Investigation for Retinal Degenerative Diseases
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 outcom
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Emerging Gene Therapy Approaches Under Clinical Investigation for Retinal Degenerative Diseases Benjamin Bakall, Kendra Klein, and Katrina Mears
Contents 1 Adeno-Associated Viral (AAV) Vectors for Retinal Gene Therapy 2 Gene Therapy Approaches Under Clinical Investigation to Treat Inherited Retinal Dystrophies 2.1 Retinitis Pigmentosa 2.2 Leber Congenital Amaurosis 10 (LCA10) 2.3 Stargardt Disease 2.4 Usher Syndrome Type I 2.5 Achromatopsia 2.6 Choroideremia 2.7 X-Linked Retinoschisis 3 Non-gene Therapy Approaches for Inherited Retinal Dystrophies 3.1 Clinical Trials Investigating Therapeutic Approaches Toward the Treatment of Stargardt Disease 3.2 N-Acetylcysteine Clinical Trials Investigating a Therapeutic Approach Toward the Treatment of Retinitis Pigmentosa References
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 B. Bakall (*) and K. Klein Department of Ophthalmology, University of Arizona College of Medicine Phoenix, Phoenix, AZ, USA e-mail: [email protected] K. Mears National Ophthalmic Research Institute, Fort Myers, FL, USA
B. Bakall et al.
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. Keywords ABCA4, CEP290, CHM, Choroideremia, CNGA3, CNGB3, Gene therapy, Leber congenital amaurosis, MERTK, MYO7A, Neurturin, Optogenetics, RALB1, Retinitis pigmentosa, Retinoschisis, Rhodopsin, RPE65, Stargardt disease, USH2A
Abbreviations A2E AAV ABCA4 AMD ASO Cas9 CEP290 CHM ChR CMV CNG CRISPR EIAV EMA ERG FDA FST IRDs LCA MERTK MYO7A NAC NEI ORF RALBP1 RBP4 RetGC1 RHO
N-retinylidene-N-retinylethanolamine Adeno-associated virus ATP-binding cassette subfamily A member 4 Age-related macular degeneration Antisense oligonucleotide CRISPR-associated protein 9 Centrosomal protein of 290 kDa Choroideremia Channelrhodopsin Cytomegalovirus Cyclic nucleotide-
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