PMID- 26606867 OWN - NLM STAT- MEDLINE DCOM- 20160714 LR - 20220317 IS - 1549-4713 (Electronic) IS - 0161-6420 (Print) IS - 0161-6420 (Linking) VI - 123 IP - 3 DP - 2016 Mar TI - Gene Therapy for Leber Hereditary Optic Neuropathy: Initial Results. PG - 558-70 LID - S0161-6420(15)01210-5 [pii] LID - 10.1016/j.ophtha.2015.10.025 [doi] AB - PURPOSE: Leber hereditary optic neuropathy (LHON) is a disorder characterized by severe and rapidly progressive visual loss when caused by a mutation in the mitochondrial gene encoding NADH:ubiquinone oxidoreductase subunit 4 (ND4). We have initiated a gene therapy trial to determine the safety and tolerability of escalated doses of an adeno-associated virus vector (AAV) expressing a normal ND4 complementary DNA in patients with a G to A mutation at nucleotide 11778 of the mitochondrial genome. DESIGN: In this prospective open-label trial (NCT02161380), the study drug (self-complementary AAV [scAAV]2(Y444,500,730F)-P1ND4v2) was intravitreally injected unilaterally into the eyes of 5 blind participants with G11778A LHON. Four participants with visual loss for more than 12 months were treated. The fifth participant had visual loss for less than 12 months. The first 3 participants were treated at the low dose of vector (5 x 10(9) vg), and the fourth participant was treated at the medium dose (2.46 x 10(10) vg). The fifth participant with visual loss for less than 12 months received the low dose. Treated participants were followed for 90 to 180 days and underwent ocular and systemic safety assessments along with visual structure and function examinations. PARTICIPANTS: Five legally blind patients with G11778A LHON. MAIN OUTCOME MEASURES: Loss of visual acuity. RESULTS: Visual acuity as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart remained unchanged from baseline to 3 months in the first 3 participants. For 2 participants with 90-day follow-up, acuity increased from hand movements to 7 letters in 1 and by 15 letters in 1, representing an improvement equivalent to 3 lines. No one lost vision, and no serious adverse events were observed. Minor adverse events included a transient increase of intraocular pressure (IOP), exposure keratitis, subconjunctival hemorrhage, a sore throat, and a transient increase in neutralizing antibodies (NAbs) against AAV2 in 1 participant. All blood samples were negative for vector DNA. CONCLUSIONS: No serious safety problems were observed in the first 5 participants enrolled in this phase I trial of virus-based gene transfer in this mitochondrial disorder. Additional study follow-up of these and additional participants planned for the next 4 years is needed to confirm these preliminary observations. CI - Copyright (c) 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. FAU - Feuer, William J AU - Feuer WJ AD - Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida. FAU - Schiffman, Joyce C AU - Schiffman JC AD - Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida. FAU - Davis, Janet L AU - Davis JL AD - Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida. FAU - Porciatti, Vittorio AU - Porciatti V AD - Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida. FAU - Gonzalez, Phillip AU - Gonzalez P AD - Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida. FAU - Koilkonda, Rajeshwari D AU - Koilkonda RD AD - Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida. FAU - Yuan, Huijun AU - Yuan H AD - Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida. FAU - Lalwani, Anil AU - Lalwani A AD - Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida. FAU - Lam, Byron L AU - Lam BL AD - Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida. FAU - Guy, John AU - Guy J AD - Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida. Electronic address: JGuy@med.miami.edu. LA - eng SI - ClinicalTrials.gov/NCT02161380 GR - U10 EY024247/EY/NEI NIH HHS/United States GR - P30 EY014801/EY/NEI NIH HHS/United States GR - R01 EY017141/EY/NEI NIH HHS/United States GR - 1U10EY024247-01/EY/NEI NIH HHS/United States GR - 1U10EY023558-01A1/EY/NEI NIH HHS/United States GR - U10 EY023558/EY/NEI NIH HHS/United States GR - R01 EY012355/EY/NEI NIH HHS/United States GR - P30EY014801/EY/NEI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20151119 PL - United States TA - Ophthalmology JT - Ophthalmology JID - 7802443 RN - 0 (DNA, Mitochondrial) RN - 0 (NADH dehydrogenase subunit 4) RN - EC 1.6.99.3 (NADH Dehydrogenase) SB - IM CIN - Ophthalmology. 2016 Jul;123(7):e44-5. PMID: 27342337 CIN - Ophthalmology. 2016 Jul;123(7):e45. PMID: 27342339 CIN - Ophthalmology. 2017 Mar;124(3):e22-e23. PMID: 28219503 CIN - Ophthalmology. 2017 Mar;124(3):e22. PMID: 28219504 MH - Adult MH - DNA, Mitochondrial/*genetics MH - Dependovirus/*genetics MH - Electroretinography MH - Female MH - *Genetic Therapy MH - *Genetic Vectors MH - Humans MH - Intravitreal Injections MH - Male MH - Middle Aged MH - NADH Dehydrogenase/*genetics MH - Optic Atrophy, Hereditary, Leber/genetics/physiopathology/*therapy MH - Polymerase Chain Reaction MH - Polymorphism, Single Nucleotide MH - Prospective Studies MH - Tomography, Optical Coherence MH - Visual Acuity/physiology MH - Visual Field Tests MH - Visual Fields PMC - PMC5287094 MID - NIHMS732233 EDAT- 2015/11/27 06:00 MHDA- 2016/07/15 06:00 PMCR- 2017/03/01 CRDT- 2015/11/27 06:00 PHST- 2015/08/07 00:00 [received] PHST- 2015/10/13 00:00 [revised] PHST- 2015/10/13 00:00 [accepted] PHST- 2017/03/01 00:00 [pmc-release] PHST- 2015/11/27 06:00 [entrez] PHST- 2015/11/27 06:00 [pubmed] PHST- 2016/07/15 06:00 [medline] AID - S0161-6420(15)01210-5 [pii] AID - 10.1016/j.ophtha.2015.10.025 [doi] PST - ppublish SO - Ophthalmology. 2016 Mar;123(3):558-70. doi: 10.1016/j.ophtha.2015.10.025. Epub 2015 Nov 19.