Evidence map›Paper›PMID 41665410›Full record

Trial reportThe New England journal of medicine2026

AAV9 Gene Therapy in Type II GM1 Gangliosidosis - A Phase 1-2 Trial.

Connor J Lewis, Precilla D'Souza, Jean M Johnston, Maria T Acosta, Cristan Farmer, Eva H Baker, Anna Crowell, Yoliann Mojica, Sumaiya Ashraf, Lisa Joseph and 21 more

Registry-linked trialAbstract readClinical Trial, Phase IClinical Trial, Phase II
PubMed Full text at PMC Publisher
In one paragraph

Trial report in The New England journal of medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03952637 (A Phase 1/2 Study of Intravenous Gene Transfer With an AAV9 Vector Expressing Human Beta-galactosidase in Type I and Type II GM1 Gangliosidosis), which is not on this map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT03952637 phase1 / phase2recruitingnot on this map

A Phase 1/2 Study of Intravenous Gene Transfer With an AAV9 Vector Expressing Human Beta-galactosidase in Type I and Type II GM1 Gangliosidosis

TypeinterventionalSponsorNational Human Genome Research Institute (NHGRI)Ran2019 to 2028Enrolled54ConditionsLysosomal Diseases, Gangliosidosis, GM1ArmsAAV9-GLB1, Abdominal ultrasound, Rituximab, Sirolimus, Methylprednisolone
3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Article
  2. Article
  3. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

31 authors.

Connor J LewisOffice of the Clinical Director, National Human Genome Research Institute, Bethesda, MD.ORCID 0000-0002-8204-5848
Precilla D'SouzaOffice of the Clinical Director, National Human Genome Research Institute, Bethesda, MD.
Jean M JohnstonOffice of the Clinical Director, National Human Genome Research Institute, Bethesda, MD.
Maria T AcostaOffice of the Clinical Director, National Human Genome Research Institute, Bethesda, MD.
Cristan FarmerNeurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, Bethesda, MD.
Eva H BakerDepartment of Diagnostic Radiology, National Institutes of Health Clinical Center, Bethesda, MD.
Anna CrowellOffice of the Clinical Director, National Human Genome Research Institute, Bethesda, MD.
Yoliann MojicaOffice of the Clinical Director, National Human Genome Research Institute, Bethesda, MD.
Sumaiya AshrafMedical Genetics Branch, National Human Genome Research Institute, Bethesda, MD.
Lisa JosephNeurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, Bethesda, MD.
Gilbert VézinaDivision of Diagnostic Imaging and Radiology, Children's National Hospital, Washington, DC.
Zenaide QuezadoDepartment of Perioperative Medicine, National Institutes of Health Clinical Center, Bethesda, MD.
Muhammad H YousefDepartment of Perioperative Medicine, National Institutes of Health Clinical Center, Bethesda, MD.
Zeynep VardarDepartment of Radiology, University of Massachusetts Chan Medical School, Worcester.
Mohammed Salman ShazeebDepartment of Radiology, University of Massachusetts Chan Medical School, Worcester.
Manuela CortiDepartment of Pediatrics, University of Florida, Gainesville.
Meghan BlackwoodHorae Gene Therapy Center and Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester.ORCID 0000-0002-3051-6548
Kirsten ColemanPowell Gene Therapy Center, University of Florida, Gainesville.ORCID 0000-0002-6289-4711
Rita BatistaHorae Gene Therapy Center and Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester.
Audrey ThurmNeurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, Bethesda, MD.
Erika De BoeverEDB Consulting, Haverford, PA.
William A GahlMedical Genetics Branch, National Human Genome Research Institute, Bethesda, MD.
Barry J ByrneDepartment of Pediatrics, University of Florida, Gainesville.
Terence R FlotteHorae Gene Therapy Center and Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester.ORCID 0000-0002-8255-0588
Xuntian JiangDepartment of Medicine, Washington University School of Medicine, St. Louis.
Amanda L GrossScott-Ritchey Research Center, Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL.
Allison M KeelerHorae Gene Therapy Center and Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester.
Heather Gray-EdwardsDepartment of Radiology, University of Massachusetts Chan Medical School, Worcester.
Douglas R MartinScott-Ritchey Research Center, Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL.
Miguel Sena-EstevesHorae Gene Therapy Center and Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester.
Cynthia J TifftOffice of the Clinical Director, National Human Genome Research Institute, Bethesda, MD.

Funding

Pathogenesis informs therapy in the GM1 and GM2 GangliosidosesZIAHG200409 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI TIFFT, CYNTHIA · 2020 to 2025
$4.1M
Validation of analytical methods for quantification of a pentasaccharide biomarker in efficacy assessment of AVV treatment for GM1 gangliosidosisU01NS114156 · NINDS · WASHINGTON UNIVERSITY · PI JIANG, XUNTIAN · 2021 to 2025
$1.9M
Auburn University R01HD060576Intramural NIH HHS ZIA HG200409National Tay-Sachs and Allied Diseases Association 59NHGRI NIH HHS Tifft ZIAHG200409NIMH NIH HHS Thurm ZICMH002961NINDS NIH HHS U01 NS114156University of Florida R01-HL139708-02University of Florida U01-NS116752-01A1University of Massachusetts Medical School R01HD060576Washington University School of Medicine in St. Louis U01NS114156
6 · The paper itself

Abstract

backgroundGM1 gangliosidosis, caused by biallelic variants in

methodsIn a phase 1-2, open-label, dose-escalation study, we assessed immunosuppression and a single intravenous infusion of adeno-associated virus serotype 9 (AAV9) encoding β-galactosidase in children with type II GM1 gangliosidosis with late-infantile or juvenile onset. The primary end point was safety. Secondary end points included changes from baseline in the cerebrospinal fluid (CSF) GM1 ganglioside concentration and β-galactosidase activity, clinical assessments (including the Clinical Global Impression-Improvement [CGI-I] score, assessed on a scale from 1 [very much improved] to 7 [very much worse]), and neuroimaging patterns.

resultsNine participants were enrolled. Over a 3-year period, 124 adverse events occurred, 30 of which (8 gastrointestinal events, 21 laboratory abnormalities associated with inflammation, and 1 tachycardia event) were deemed by the investigator as being possibly, probably, or definitely related to the gene therapy. Five serious adverse events occurred, including vomiting that led to hospitalization in one participant, which was attributed to the gene therapy. Serum aspartate and alanine aminotransferase levels increased in all participants and returned to baseline levels by 18 months. In all participants, the CSF β-galactosidase level increased and CSF GM1 ganglioside level decreased. Expressive communication and gross motor scores appeared stable, but fine motor and receptive communication scores decreased. The median CGI-I score was 3 (indicating minimal improvement) at 2 years and 4 (indicating no change) at 3 years; in historical controls, scores have been shown to increase (indicating worsening) over time. Neuroimaging showed patterns consistent with reduced rates of cerebral atrophy and favorable changes in myelination as compared with baseline.

conclusionsIn this study involving nine participants with type II GM1 gangliosidosis, a single infusion of AAV9 encoding β-galactosidase was associated with adverse events, including severe vomiting in one participant and elevated liver-enzyme levels in all participants. Secondary end-point results suggested improvements in biochemical markers and neuroimaging patterns and stable or reduced rates of developmental deterioration in some measures. (Funded by the National Human Genome Research Institute and others; ClinicalTrials.gov number, NCT03952637.).

Indexed as

beta-GalactosidaseGangliosidosis, GM1Genetic TherapyGenetic VectorsAlanine TransaminaseAspartate AminotransferasesBrainChildChild, PreschoolDependovirusFemaleFollow-Up StudiesG(M1) GangliosideHumansInfusions, IntravenousMaleAlanine TransaminaseAspartate Aminotransferasesbeta-GalactosidaseGLB1 protein, humanG(M1) Ganglioside

Identifiers

PMID41665410
PMCPMC13215599

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.