Retinal AAV8-RS1 Gene Therapy for X-Linked Retinoschisis: Initial Findings from a Phase I/IIa Trial by Intravitreal Delivery
| Autor: | Sten Kjellstrom, Paul A. Sieving, Lisa L. Wei, Camasamudram Vijayasarathy, Yong Zeng, H. Nida Sen, Zhijian Wu, Henry E. Wiley, Brett G. Jeffrey, Peter Colosi, J. Fraser Wright, Suja Hiriyanna, Ronald A. Bush, Catherine A Cukras, Amy Turriff, Tae Kwon Park, Dario Marangoni, Lucia Ziccardi |
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| Přispěvatelé: | Cukras, C, Wiley, He, Jeffrey, Bg, Sen, Hn, Turriff, A, Zeng, Y, Vijayasarathy, C, Marangoni, D, Ziccardi, L, Kjellstrom, S, Park, Tk, Hiriyanna, S, Wright, Jf, Colosi, P, Wu, Z, Bush, Ra, Wei, Ll, Sieving, Pa. |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Technology genetic structures Genetic enhancement Retinoschisin Protein Retinoschisis Eye Medical and Health Sciences chemistry.chemical_compound 0302 clinical medicine Drug Discovery Retinal detachment clinical trial Middle Aged Biological Sciences gene therapy AAV vector medicine.anatomical_structure Tolerability 6.1 Pharmaceuticals Intravitreal Injections Molecular Medicine Female X-linked retinoschisis Biotechnology Adult medicine.medical_specialty Clinical Trials and Supportive Activities X-linked retinoschisi Retina ocular disease retinal disease Young Adult 03 medical and health sciences Clinical Research Ophthalmology Genetics medicine Humans Eye Proteins Eye Disease and Disorders of Vision Molecular Biology Aged Pharmacology business.industry Neurosciences Evaluation of treatments and therapeutic interventions Retinal Genetic Therapy medicine.disease eye diseases Clinical trial 030104 developmental biology chemistry Mutation 030221 ophthalmology & optometry business |
| Zdroj: | Molecular therapy : the journal of the American Society of Gene Therapy, vol 26, iss 9 |
| Popis: | This study evaluated the safety and tolerability of ocular RS1 adeno-associated virus (AAV8-RS1) gene augmentation therapy to the retina of participants with X-linked retinoschisis (XLRS). XLRS is a monogenic trait affecting only males, caused by mutations in the RS1 gene. Retinoschisin protein is secreted principally in the outer retina, and its absence results in retinal cavities, synaptic dysfunction, reduced visual acuity, and susceptibility to retinal detachment. This phase I/IIa single-center, prospective, open-label, three-dose-escalation clinical trial administered vector to nine participants with pathogenic RS1 mutations. The eye of each participant with worse acuity (≤63 letters; Snellen 20/63) received the AAV8-RS1 gene vector by intravitreal injection. Three participants were assigned to each of three dosage groups: 1e9 vector genomes (vg)/eye, 1e10 vg/eye, and 1e11 vg/eye. The investigational product was generally well tolerated in all but one individual. Ocular events included dose-related inflammation that resolved with topical and oral corticosteroids. Systemic antibodies against AAV8 increased in a dose-related fashion, but no antibodies against RS1 were observed. Retinal cavities closed transiently in one participant. Additional doses and immunosuppressive regimens are being explored to pursue evidence of safety and efficacy (ClinicalTrials.gov: NCT02317887). |
| Databáze: | OpenAIRE |
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