Phenotypic variation of FXN compound heterozygotes in a Friedreich ataxia cohort.

OBJECTIVE: Most individuals with Friedreich ataxia (FRDA) have homozygous GAA triplet repeat expansions in the FXN gene, correlating with a typical phenotype of ataxia and cardiomyopathy. A minority are compound heterozygotes carrying a GAA expansion on one allele and a mutation on the other. The study aim was to examine phenotypic variation among compound heterozygotes. METHODS: Data on FXN mutations were obtained from the Friedreich Ataxia Clinical Outcome Measures Study (FA-COMS). We compared clinical features in a single-site FA-COMS cohort of 51 compound heterozygous and 358 homozygous patients, including quantitative measures of cardiac, neurologic, and visual disease progression. RESULTS: Non-GAA repeat mutations were associated with reduced cardiac disease, and patients with minimal/no function mutations otherwise had a typical FRDA phenotype but with significantly more severe progression. The partial function mutation group was characterized by relative sparing of bulbar and upper limb function, as well as particularly low cardiac involvement. Other clinical features in this group, including optic atrophy and diabetes mellitus, varied widely depending on the specific type of partial function mutation. INTERPRETATION: These data support that the typical FRDA phenotype is driven by frataxin deficiency, especially severe in compound heterozygotes with minimal/no function mutations, whereas the heterogeneous presentations of those with partial function mutations may indicate other contributing factors to FRDA pathogenesis.

Combination of AIBP, apoA-I, and Aflibercept Overcomes Anti-VEGF Resistance in Neovascular AMD by Inhibiting Arteriolar Choroidal Neovascularization.

Purpose: Anti-VEGF resistance represents a major unmet clinical need in the management of choroidal neovascularization (CNV). We have previously reported that a combination of AIBP, apoA-I, and an anti-VEGF antibody overcomes anti-VEGF resistance in laser-induced CNV in old mice in prevention experiments. The purpose of this work is to conduct a more clinically relevant study to assess the efficacy of the combination of AIBP, apoA-I, and aflibercept in the treatment of anti-VEGF resistance of experimental CNV at different time points after laser photocoagulation. Methods: To understand the pathobiology of anti-VEGF resistance, we performed comprehensive examinations of the vascular morphology of laser-induced CNV in young mice that are highly responsive to anti-VEGF treatment, and in old mice that are resistant to anti-VEGF therapy by indocyanine green angiography (ICGA), fluorescein angiography (FA), optical coherence tomography (OCT), and Alexa 568 isolectin labeled choroid flatmounts. We examined the efficacy of the combination therapy of AIBP, apoA-I, and aflibercept intravitreally delivered at 2, 4, and 7 days after laser photocoagulation in the treatment of CNV in old mice. Results: Laser-induced CNV in young and old mice exhibited cardinal features of capillary and arteriolar CNV, respectively. The combination therapy and the aflibercept monotherapy were equally effective in treating capillary CNV in young mice. In old mice, the combination therapy was effective in treating anti-VEGF resistance by potently inhibiting arteriolar CNV, whereas aflibercept monotherapy was ineffective. Conclusions: Combination therapy of AIBP, apoA-I, and aflibercept overcomes anti-VEGF resistance in experimental CNV in old mice by inhibiting arteriolar CNV.