Adeno-associated viral vector serotype 9-based gene replacement therapy for SURF1-related Leigh syndrome

Molecular Therapy: Methods & Clinical Development

Yuhui Hu¹  Steven J. Gray¹  Matthew Rioux¹  Qinglan Ling¹  MinJae Lee² 

[1] Department of Pediatrics, UTSW Medical Center, Dallas, TX 75390, USA;Department of Population and Data Science, UTSW Medical Center, Dallas, TX 75390, USA;

关键词: SURF1;    Leigh syndrome;    gene therapy;    adeno-associated virus;    AAV;   

DOI  :  

来源: DOAJ

【 摘 要 】

SURF1 (surfeit locus protein 1)-related Leigh syndrome is an early-onset neurodegenerative disorder, characterized by reduction in complex IV activity, resulting in disrupted mitochondrial function. Currently, there are no treatment options available. To test our hypothesis that adeno-associated viral vector serotype 9 (AAV9)/human SURF1 (hSURF1) gene replacement therapy can provide a potentially meaningful and long-term therapeutic benefit, we conducted preclinical efficacy studies using SURF1 knockout mice and safety evaluations with wild-type (WT) mice. Our data indicate that with a single intrathecal (i.t.) administration, our treatment partially and significantly rescued complex IV activity in all tissues tested, including liver, brain, and muscle. Accordingly, complex IV content (examined via MT-CO1 protein expression level) also increased with our treatment. In a separate group of mice, AAV9/hSURF1 mitigated the blood lactic acidosis induced by exhaustive exercise at 9 months post-dosing. A toxicity study in WT mice showed no adverse effects in either the in-life portion or after microscopic examination of major tissues up to a year following the same treatment regimen. Taken together, our data suggest a single dose, i.t. administration of AAV9/hSURF1 is safe and effective in improving biochemical abnormalities induced by SURF1 deficiency with potential applicability for SURF1-related Leigh syndrome patients.

【 授权许可】

Unknown