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Prognostic factors for visual acuity in patients with Leber's hereditary optic neuropathy after rAAV2-ND4 gene therapy.

ABSTRACT: IMPORTANCE:Factors affecting visual acuity prognosis after gene therapy in Leber's hereditary optic neuropathy (LHON) patients with mutation at site 11?778 are unknown. BACKGROUND:To analyse correlations between visual acuity prognosis and baseline characteristics of LHON after rAAV2-ND4 gene therapy. DESIGN:Retrospective study. PARTICIPANTS:Fifty-three LHON patients with a mutation at site 11?778. METHODS:Single-eye intravitreal injection of rAAV2-ND4. MAIN OUTCOME MEASURES:Sex, onset age, duration of disease, best-corrected visual acuity (BCVA), visual field index (VFI) and mean deviation (MD) were recorded for all patients at baseline. BCVA was recorded at 1- and 3-month follow-up visits after gene therapy. Correlations between BCVA prognosis and baseline characteristics were analysed by univariate analysis. Logistic regression analysis was performed on independent factors affecting BCVA prognosis. RESULTS:Univariate analysis showed significant differences in the VFI and MD of the injected eye between BCVA improvement and non-improvement groups after 3 months of treatment, with greater VFI and smaller absolute MD in the BCVA improvement group. Logistic regression showed that VFI and baseline BCVA were independent prognostic factors for visual acuity. The correlation between VFI and MD was statistically significant. CONCLUSIONS AND RELEVANCE:VFI and baseline BCVA were correlated with the visual acuity prognosis of LHON patients receiving gene therapy, with greater baseline VFI and better baseline BCVA predicting better visual acuity prognosis. MD was strongly correlated with VFI and might be correlated with gene therapy prognosis. This finding may form a basis for predicting the efficacy of gene therapy in these patients and guiding subsequent treatment.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC6767190 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Prognostic factors for visual acuity in patients with Leber's hereditary optic neuropathy after rAAV2-ND4 gene therapy.

Zhang Yong Y Li Xin X Yuan Jiajia J Tian Zhen Z Liu Hongli H Wang Dan D Li Bin B

Clinical & experimental ophthalmology 20190508 6

<h4>Importance</h4>Factors affecting visual acuity prognosis after gene therapy in Leber's hereditary optic neuropathy (LHON) patients with mutation at site 11 778 are unknown.<h4>Background</h4>To analyse correlations between visual acuity prognosis and baseline characteristics of LHON after rAAV2-ND4 gene therapy.<h4>Design</h4>Retrospective study.<h4>Participants</h4>Fifty-three LHON patients with a mutation at site 11 778.<h4>Methods</h4>Single-eye intravitreal injection of rAAV2-ND4.<h4>Mai ...[more]

PMID: 30968497

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Project description:PurposeTo investigate the role of mitochondrial haplotypes in the development of Leber's hereditary optic neuropathy (LHON) associated with the ND4 G11778A mutation in Chinese families.DesignEight Han Chinese families with maternally transmitted LHON were studied using clinical, genetic, and molecular evaluations.ParticipantsOne hundred sixty-seven subjects from 8 Chinese families with a wide age range and severity of visual impairment.MethodsAll subjects underwent the clinical and genetic evaluation, as well as molecular analysis of mitochondrial DNA (mtDNA).Main outcome measuresThe ophthalmologic examinations included visual acuity, visual field examination, visual evoked potentials, and fundus photography. Mitochondrial DNA analysis included the polymerase chain reaction amplification of the entire mtDNA and subsequent sequence determination.ResultsEight families exhibited extremely low penetrance of visual impairment, with the average of 13%. In particular, 14 (12 males and 2 females) of 119 matrilineal relatives in these families exhibited the variable severity and age at onset in visual dysfunction. The average age of onset of vision loss was 17 years. Molecular analysis of mtDNA identified the homoplasimic ND4 G11778A mutation and distinct sets of variants belonging to the Asian haplogroups M8a2, D4g2, B4a1c, B5b, N9a1, D4b2b, C, and M7b1. However, there was an absence of secondary LHON-associated mtDNA mutations in these 8 Chinese families.ConclusionsThe extremely low penetrance of vision loss in these 8 Chinese pedigrees strongly indicates that the G11778A mutation was itself insufficient to produce a clinical phenotype. The absence of secondary LHON mtDNA mutations suggest that these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the G11778A mutation in those Chinese families with very low penentrace of vision loss. However, nuclear backgrounds and environmental factors seem to be modifying factors for the phenotypic manifestation of the G11778A mutation in these Chinese families.

Project description:Leber's hereditary optic neuropathy (LHON, MIM#535000) is the most common form of inherited optic neuropathies and mitochondrial DNA-related diseases. The pathogenicity of mutations in genes encoding components of mitochondrial Complex I is well established, but the underlying pathomechanisms of the disease are still unclear. Hypothesizing that oxidative stress related to Complex I deficiency may increase protein S-glutathionylation, we investigated the proteome-wide S-glutathionylation profiles in LHON (n = 11) and control (n = 7) fibroblasts, using the GluICAT platform that we recently developed. Glutathionylation was also studied in healthy fibroblasts (n = 6) after experimental Complex I inhibition. The significantly increased reactive oxygen species (ROS) production in the LHON group by Complex I was shown experimentally. Among the 540 proteins which were globally identified as glutathionylated, 79 showed a significantly increased glutathionylation (p < 0.05) in LHON and 94 in Complex I-inhibited fibroblasts. Approximately 42% (33/79) of the altered proteins were shared by the two groups, suggesting that Complex I deficiency was the main cause of increased glutathionylation. Among the 79 affected proteins in LHON fibroblasts, 23% (18/79) were involved in energetic metabolism, 31% (24/79) exhibited catalytic activity, 73% (58/79) showed various non-mitochondrial localizations, and 38% (30/79) affected the cell protein quality control. Integrated proteo-metabolomic analysis using our previous metabolomic study of LHON fibroblasts also revealed similar alterations of protein metabolism and, in particular, of aminoacyl-tRNA synthetases. S-glutathionylation is mainly known to be responsible for protein loss of function, and molecular dynamics simulations and 3D structure predictions confirmed such deleterious impacts on adenine nucleotide translocator 2 (ANT2), by weakening its affinity to ATP/ADP. Our study reveals a broad impact throughout the cell of Complex I-related LHON pathogenesis, involving a generalized protein stress response, and provides a therapeutic rationale for targeting S-glutathionylation by antioxidative strategies.

Dataset Information

Prognostic factors for visual acuity in patients with Leber's hereditary optic neuropathy after rAAV2-ND4 gene therapy.

Publications

Prognostic factors for visual acuity in patients with Leber's hereditary optic neuropathy after rAAV2-ND4 gene therapy.

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