medRxiv : the preprint server for health sciences · 2025
AAV9 Gene Therapy in GM1 Gangliosidosis Type II: A Phase 1/2 Trial.
СтатьяПрепринтНазвание и аннотация: Перевод в очереди
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Lewis Connor J, D'Souza Precilla, Johnston Jean M, Acosta Maria T, Farmer Cristan, Baker Eva H, Crowell Anna, Mojica Yoliann, Rahman Sumaiya, Joseph Lisa, Hartman Adam, Vézina Gilbert, Quezado Zenaide, Yousef Muhammad H, Luckett Amelia, Vardar Zeynep, Shazeeb Mohammad Salman, Corti Manuela, Blackwood Meghan, Coleman Kirsten, Thurm Audrey, De Boever Erika, Gahl William A, Byrne Barry J, Flotte Terence R, Jiang Xuntian, Gross Amanda L, Keeler Allison M, Gray-Edwards Heather, Martin Douglas R, Sena-Esteves Miguel, Tifft Cynthia J
Аннотация
BACKGROUND: GM1 gangliosidosis, caused by biallelic variants in GLB1, results from deficiency of lysosomal β-galactosidase, the enzyme primarily responsible for degradation of GM1 ganglioside. This progressive neurodegenerative disease is uniformly fatal with no approved therapies, but preclinical studies utilizing gene therapy have shown promising results.
METHODS: This phase 1-2 open label dose escalation study utilized a single intravenous administration of adeno-associated virus serotype 9 (AAV9) encoding β-galactosidase in the first nine enrolled Type II GM1 gangliosidosis participants. The primary endpoint was safety after 3 years; secondary and exploratory efficacy outcomes included cerebrospinal fluid (CSF) GM1 ganglioside and β-galactosidase, clinical assessments, and neuroimaging changes.
RESULTS: One serious adverse event was attributed to the vector, i.e., vomiting requiring rehospitalization for IV hydration. Serum aspartate and alanine aminotransferase levels increased following gene transfer but returned to baseline by 18 months. Per protocol analysis found stability in Vineland Expressive Communication and Gross Motor and significant declines in Fine Motor and Receptive Communication. Median CGI-Improvement scores at 2 and 3 years after gene transfer were "minimally improved" or "no change". CSF β-galactosidase increased and GM1 ganglioside decreased in all participants. MRI showed improved myelination by differential tractography and declines in cerebral atrophy. MRS showed reduced loss of N-acetylaspartate+N-acetylaspartyl glutamate (NAA) compared with historical controls.
CONCLUSIONS: A single IV infusion of AAV9 encoding β-galactosidase was well-tolerated among the first nine Type II GM1 gangliosidosis participants. Secondary and exploratory outcomes suggested improvements in biochemical markers and neuroimaging and stabilized or reduced rates of developmental deterioration (NCT03952637).
METHODS: This phase 1-2 open label dose escalation study utilized a single intravenous administration of adeno-associated virus serotype 9 (AAV9) encoding β-galactosidase in the first nine enrolled Type II GM1 gangliosidosis participants. The primary endpoint was safety after 3 years; secondary and exploratory efficacy outcomes included cerebrospinal fluid (CSF) GM1 ganglioside and β-galactosidase, clinical assessments, and neuroimaging changes.
RESULTS: One serious adverse event was attributed to the vector, i.e., vomiting requiring rehospitalization for IV hydration. Serum aspartate and alanine aminotransferase levels increased following gene transfer but returned to baseline by 18 months. Per protocol analysis found stability in Vineland Expressive Communication and Gross Motor and significant declines in Fine Motor and Receptive Communication. Median CGI-Improvement scores at 2 and 3 years after gene transfer were "minimally improved" or "no change". CSF β-galactosidase increased and GM1 ganglioside decreased in all participants. MRI showed improved myelination by differential tractography and declines in cerebral atrophy. MRS showed reduced loss of N-acetylaspartate+N-acetylaspartyl glutamate (NAA) compared with historical controls.
CONCLUSIONS: A single IV infusion of AAV9 encoding β-galactosidase was well-tolerated among the first nine Type II GM1 gangliosidosis participants. Secondary and exploratory outcomes suggested improvements in biochemical markers and neuroimaging and stabilized or reduced rates of developmental deterioration (NCT03952637).