Dual-vector rAAVrh8 gene therapy for GM2 gangliosidosis: a phase 1/2 trial

The dual rAAVrh8-HEXA and rAAVrh8-HEXB vector can restore central nervous system hexosaminidase (Hex) enzyme activity, decrease GM2 levels in cerebrospinal fluid and rescue phenotypic consequences of GM2 gangliosidosis, Tay-Sachs and Sandhoff diseases in animal models following simultaneous bi-thalamic (BiT) injections. Following up on an n = 2 expanded access trial, we initiated a phase 1/2, single-dose, dose-escalation of combined BiT, intra-cisterna magna and intrathecal infusion in children with Tay-Sachs and Sandhoff diseases (six infantile, three juvenile). The BiT injection volume and vector dose were doubled between four cohorts, with the lowest dose matching the earlier expanded access trial. Cerebrospinal fluid HexA enzyme activity, serum total Hex activity and GM2 levels showed a dose-dependent biochemical correction of the disease. Serum Hex activity surpassed 40 nmol h<sup>-1</sup> ml<sup>-1</sup>, two times the lower limit of normal, and neuroimaging demonstrated increased fiber tracts. Correction was greatest at 12 weeks, but in decline by 24 weeks postdosing. Infantile patients experienced global clinical stabilization and prolonged oral feeding without aspiration until 3-3.5 years. Seizures had a later onset, were less frequent, less severe and more responsive to anti-convulsant medication. Adverse events were rare in infantile patients, but worsening dystonia was observed in juvenile patients, who were excluded from ongoing enrollment. ClinicalTrials.gov registration: NCT04669535 and NCT06614569 .

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Publication Details

Journal
Nature Medicine
Published
2025-08-15
DOI
https://doi.org/10.1038/s41591-025-03822-4
Citations
3
Primary Topic
Lysosomal Storage Disorders Research
Type
article
Field-Weighted Citation Impact
3.49

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article

Dual-vector rAAVrh8 gene therapy for GM2 gangliosidosis: a phase 1/2 trial

T. F. Gallagher, Terence R. Flotte, Ajit S Puri, Allison M. Keeler et al.
3 citations
Nature Medicine
Lysosomal Storage Disorders Research
3.49
article

Dual-vector rAAVrh8 gene therapy for GM2 gangliosidosis: a phase 1/2 trial

T. F. Gallagher, Terence R. Flotte, Ajit S Puri, Allison M. Keeler, Mohammed Salman Shazeeb, Meghan Blackwood, Asma Hader, Florian Eichler, Erika De Boever, Heather M. McLaughlin, Emma Drummond, Oğuz Çataltepe, Cynthia J. Tifft, Behroze Vachha, Anna Luisa Kühn, Elise L. Townsend, Miguel Sena‐Esteves, Amanda Nagy, Spiro G. Spanakis, Scot T. Bateman, Robert W. Thompson, Mary‐Alice Abbott, Julia Parzych, Rrita Daci, Connor Lewis, Eva‐Maria Ratai, Heather Gray‐Edwards, Toloo Taghian, Zeynep Vardar, Toby Vaughn, Xuntian Jiang, Danielle Kokoski, Rebecca Artinian, Eliane Papa Ambrosio, Hakki Celik, Kirsten Pier
article en
3 citations

Abstract

The dual rAAVrh8-HEXA and rAAVrh8-HEXB vector can restore central nervous system hexosaminidase (Hex) enzyme activity, decrease GM2 levels in cerebrospinal fluid and rescue phenotypic consequences of GM2 gangliosidosis, Tay-Sachs and Sandhoff diseases in animal models following simultaneous bi-thalamic (BiT) injections. Following up on an n = 2 expanded access trial, we initiated a phase 1/2, single-dose, dose-escalation of combined BiT, intra-cisterna magna and intrathecal infusion in children with Tay-Sachs and Sandhoff diseases (six infantile, three juvenile). The BiT injection volume and vector dose were doubled between four cohorts, with the lowest dose matching the earlier expanded access trial. Cerebrospinal fluid HexA enzyme activity, serum total Hex activity and GM2 levels showed a dose-dependent biochemical correction of the disease. Serum Hex activity surpassed 40 nmol h<sup>-1</sup> ml<sup>-1</sup>, two times the lower limit of normal, and neuroimaging demonstrated increased fiber tracts. Correction was greatest at 12 weeks, but in decline by 24 weeks postdosing. Infantile patients experienced global clinical stabilization and prolonged oral feeding without aspiration until 3-3.5 years. Seizures had a later onset, were less frequent, less severe and more responsive to anti-convulsant medication. Adverse events were rare in infantile patients, but worsening dystonia was observed in juvenile patients, who were excluded from ongoing enrollment. ClinicalTrials.gov registration: NCT04669535 and NCT06614569 .

Nature MedicineVol. 31(9)
National Institutes of Health (US), Baystate Medical Center (US), Harvard University (US), Haverford College (US), MGH Institute of Health Professions (US), University of Massachusetts Chan Medical School (US), Washington University in St. Louis (US), Empire Technical Development (United States) (US), Massachusetts General Hospital (US), National Human Genome Research Institute (US), Office of the Director (US), Jnana Therapeutics (United States) (US), Baystate Health (US), Athinoula A. Martinos Center for Biomedical Imaging (US), Neurological Surgery (US), NeuroNexus (United States) (US)
National Tay-Sachs and Allied Diseases Association
Good health and well-being
Openalex Percentile: Top 7%
Lysosomal Storage Disorders Research
3.49
DOIOpen Access PDFOpenAlex
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