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

• Main Authors: Qinglan Ling, Matthew Rioux, Yuhui Hu, MinJae Lee, Steven J. Gray
• Format: Article
• Language: English
• Published: Elsevier 2021-12-01
• Series: Molecular Therapy: Methods & Clinical Development
• Subjects: SURF1; Leigh syndrome; gene therapy; adeno-associated virus; AAV
• Online Access: http://www.sciencedirect.com/science/article/pii/S2329050121001364

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.