Gene Therapy for Leber Hereditary Optic Neuropathy: Low- and Medium-Dose Visual Results.

PURPOSE: To determine the effects of AAV2(Y444,500,730F)-P1ND4v2 in patients with Leber hereditary optic neuropathy (LHON). DESIGN: Prospective open-label, unilateral single-dose, intravitreal injection of AAV2(Y444,500,730F)-P1ND4v2 per participant. PARTICIPANTS: Fourteen patients with visual loss and mutated G11778A mitochondrial DNA. METHODS: Intravitreal injection with the gene therapy vector AAV2(Y444,500,730F)-P1ND4v2 into 1 eye. Six participants with chronic bilateral visual loss lasting more than 12 months (group 1), 6 participants with bilateral visual loss lasting less than 12 months (group 2), and 2 participants with unilateral visual loss (group 3) were treated. Nine patients had at least 12 months of follow-up. Clinical testing included visual acuity, visual fields, optical coherence tomography, pattern electroretinography, and neuro-ophthalmic examinations. Generalized estimating equation methods were used for longitudinal analyses. MAIN OUTCOME MEASURE: Loss of visual acuity. RESULTS: For groups 1 and 2, month 12 average acuity improvements with treatment relative to baseline were 0.24 logarithm of the minimum angle of resolution (logMAR). Fellow eyes had a 0.09-logMAR improvement. A post hoc comparison found that at month 12, the difference between study eye minus fellow eye improvement in group 2 patients of 0.53 logMAR was greater than that observed in our prior acute natural history patients of 0.21 logMAR (P = 0.053). At month 18, the difference between study eye minus fellow eye improvement in our acute group 2 gene therapy patients of 0.96 was more than that observed in our prior acute natural history patients (0.17 logMAR; P < 0.001). Two patients demonstrated asymptomatic uveitis that resolved without treatment. Optical coherence tomography of treated eyes showed an average temporal retinal nerve fiber layer thickness of 54 µm before injection and 55 µm at month 12. For fellow eyes before injection, it was 56 µm, decreasing to 50 µm at month 12 (P = 0.013). Generalized estimating equations suggested that PERG amplitudes worsened more in treated eyes than in fellow eyes by approximately 0.05 µV (P = 0.009 exchangeable). No difference between eyes in outcomes of other visual function measures was evident. CONCLUSIONS: Allotopic gene therapy for LHON at low and medium doses seems to be safe and does not damage the temporal retinal nerve fiber layer, opening the door next for testing of the high dose.

Gene Therapy for Leber Hereditary Optic Neuropathy: Initial Results.

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 × 10(9) vg), and the fourth participant was treated at the medium dose (2.46 × 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.

Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial.

IMPORTANCE: Whether culture-expanded mesenchymal stem cells or whole bone marrow mononuclear cells are safe and effective in chronic ischemic cardiomyopathy is controversial. OBJECTIVE: To demonstrate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy. DESIGN, SETTING, AND PATIENTS: A phase 1 and 2 randomized, blinded, placebo-controlled study involving 65 patients with ischemic cardiomyopathy and left ventricular (LV) ejection fraction less than 50% (September 1, 2009-July 12, 2013). The study compared injection of MSCs (n=19) with placebo (n = 11) and BMCs (n = 19) with placebo (n = 10), with 1 year of follow-up. INTERVENTIONS: Injections in 10 LV sites with an infusion catheter. MAIN OUTCOMES AND MEASURES: Treatment-emergent 30-day serious adverse event rate defined as a composite of death, myocardial infarction, stroke, hospitalization for worsening heart failure, perforation, tamponade, or sustained ventricular arrhythmias. RESULTS: No patient had a treatment-emergent serious adverse events at day 30. The 1-year incidence of serious adverse events was 31.6% (95% CI, 12.6% to 56.6%) for MSCs, 31.6% (95% CI, 12.6%-56.6%) for BMCs, and 38.1% (95% CI, 18.1%-61.6%) for placebo. Over 1 year, the Minnesota Living With Heart Failure score improved with MSCs (-6.3; 95% CI, -15.0 to 2.4; repeated measures of variance, P=.02) and with BMCs (-8.2; 95% CI, -17.4 to 0.97; P=.005) but not with placebo (0.4; 95% CI, -9.45 to 10.25; P=.38). The 6-minute walk distance increased with MSCs only (repeated measures model, P = .03). Infarct size as a percentage of LV mass was reduced by MSCs (-18.9%; 95% CI, -30.4 to -7.4; within-group, P = .004) but not by BMCs (-7.0%; 95% CI, -15.7% to 1.7%; within-group, P = .11) or placebo (-5.2%; 95% CI, -16.8% to 6.5%; within-group, P = .36). Regional myocardial function as peak Eulerian circumferential strain at the site of injection improved with MSCs (-4.9; 95% CI, -13.3 to 3.5; within-group repeated measures, P = .03) but not BMCs (-2.1; 95% CI, -5.5 to 1.3; P = .21) or placebo (-0.03; 95% CI, -1.9 to 1.9; P = .14). Left ventricular chamber volume and ejection fraction did not change. CONCLUSIONS AND RELEVANCE: Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00768066.