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Tay-Sachs DiseasePhase 1NCT04669535

A Dose-escalation and Safety & Efficacy Study of AXO-AAV-GM2 in Tay-Sachs or Sandhoff Disease

A Phase 1 study testing AXO-AAV-GM2 Starting Dose, AXO-AAV-GM2 Low Dose and AXO-AAV-GM2 Middle Dose in people with Tay-Sachs Disease and Sandhoff Disease, run by Terence Flotte at 2 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

The AXO-GM2-001 study is an open-label, two-stage clinical trial designed to evaluate safety and dose-escalation (Stage 1) and safety and efficacy (Stage 2) of a bilateral thalamic and intracisternal/intrathecal infusion of AXO-AAV-GM2 in pediatric participants with GM2 Gangliosidosis (also known as Tay-Sachs or… Read more about this study

Who is it for?
Ages 6 months to 12 years
Conditions the study is for
Tay-Sachs Disease, Sandhoff Disease
What is being tested?
AXO-AAV-GM2 Starting Dose, AXO-AAV-GM2 Low Dose and AXO-AAV-GM2 Middle Dose
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
9 participants
Where
2 sitesUnited States
Study dates
15 Jan 2021to 16 Dec 2024
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 6 months to 12 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • Male or female participants with genetically diagnosed TSD or SD mutations of either HEXA gene or HEXB gene
  • Stage 1 juvenile-onset participants must be ≥ 2 years old and ≤ 12 years old at time of gene transfer i. Diagnosis consistent with juvenile-onset TSD or SD b. Stage 1 infantile-onset participants must be between 6-20 months of age at the time of gene transfer i. Diagnosis consistent with infantile-onset TSD or SD
  • Juvenile onset participants must demonstrate a minimum of 2 of the following age-appropriate clinical features/abilities, confirmed by the site examiner at the time of screening and reaffirmed prior to the initiation of immunosuppression:
  • A Gross Motor Function Classification-MLD (GMFC-MLD) score of 0, 1 or 2. The minimum gross motor function (GMFC-MLD level 2) is the 'ability to walk with support and walking without support is not possible (fewer than 5 steps)'. (Participants aged 2-12 years) Note: Any form of support is permitted; however, the participant must initiate each step and complete it for a total of 5 steps.
  • Fine Motor Function
  • For Participants aged 4-12 years: A Manual Ability Classification System (MACS) score of I, II, III, or IV. The minimum level of manual ability (level IV) corresponds to 'Handles a limited selection of easily managed objects in adapted situations'.
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  • For participants aged 2-4 years: attainment of fine motor function/coordination abilities and milestones with normal or a reduced quality of performance. That is, the ability to coordinate fingers and both hands to play, such as swinging a bat or opening a container (pathways.org) OR the ability to use fingertips to pick up small objects, i.e., the child uses pad of his/her thumb and any fingertip to grasp a pellet or small object as described in BSID III Fine Motor Sub-test Item #26. .
  • Speech:
  • For participants aged 4-12 years, a speech disturbance score of 0, 1, 2 or 3 on the speech disturbance subset of the Scale for Assessment and Rating of Ataxia (SARA). The minimum speech requirement is a speech disturbance in which most words can be understood, with occasional words difficult to understand secondary to dysarthria.
  • Participants aged 2-4 years who have attained the communication milestone of ability to consistently use 2-3 word phrases may be assessed in line with this criterion using the speech disturbance subset of the SARA.
  • For participants aged 2-4 years who have not yet attained the above communication milestone, the minimum requirement is the ability to imitate at least one word, even if the imitation consists of vowels only (BSID III, expressive communication subtest, item #16)
  • Infantile onset participants must demonstrate current* or historical† ability to sit without support for at least 5 seconds
  • As assessed in item 22 of the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) Gross Motor Scale or documented medical records
  • † Documented within available medical records
  • In addition, infantile onset participants must demonstrate a minimum of 3 of the following developmental skills confirmed by the site examiner at the time of screening and reaffirmed prior to the initiation of immunosuppression:
  • Head control - While supine, with head in midline turns head symmetrically (score of 3 on GMFM item 1)
  • Uses hands to support self while sitting
  • Reach for an object that is held out for them above their chest while supine
  • Transfer of object from hand to hand while supine
  • Eye tracking while supine
  • Looks at an object of interest for at least 3 continuous seconds
  • Surgical readiness for gene transfer by the routes of administration confirmed by the study neurosurgeon*, based on examination and MRI findings
  • The following findings will disallow the performance of the BiTh procedure thereby excluding the participant from participation:
  • Any scalp and skull related lesion (e.g., vascular, infectious) over the surgical entry area
  • Any intracranial lesion (e.g., vascular, cystic, other mass lesions), significant immaturity or deformity of the brain anatomy that would make the intended surgical trajectory high risk
  • The following findings will disallow the performance of the ICM/IT procedure thereby excluding the participant from participation:
  • Any skin related lesion (e.g., vascular, infectious) over the lumbar puncture site
  • Any intraspinal or intracranial lesion in posterior fossa (e.g., vascular, cystic, other mass lesions) or significantly deformed, distorted brain, spinal and cisternal anatomy that make the intended intrathecal trajectory high risk or not feasible * Participants otherwise eligible for study participation but deemed not currently fit for neurosurgery may be re-screened at the discretion of the investigator
  • Participants receiving off-label Zavesca® (miglustat) and/or Tanganil® (acetyl-leucine) must be willing to discontinue these therapies 30 days prior to the start of screening
  • Ability to reliably travel to the study sites for study visits according to the Schedule of Assessments

Who cannot join

  • Presence of G269S or W474C mutation in HEXA
  • Evidence of lower respiratory tract aspiration not easily manageable with thickening of feedings or substitution of a modified bottle nipple, as judged on a multi-texture contrast swallow.
  • History of multiple aspiration pneumonias occurring in the past twelve months.
  • Respiratory support in the form of ventilation (invasive or non-invasive).
  • History of drug-resistant seizures or status epilepticus
  • History and/or findings of spinal cord disease that would preclude the lumbar puncture and ICM/IT infusion procedures including:
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  • Infectious process involving the spinal canal which may cause adhesions or septations in the spinal and/or subarachnoid space
  • Previous spinal surgeries
  • History of trauma, bleeding in the spinal canal
  • Vascular or cystic lesions, or any other mass lesion
  • Congenital deformities and malformations involving the spinal canal
  • Posterior fossa findings (low lying cerebellar tonsils, crowded foramen magnum, small or absent cisterna manga)
  • The participant's parent(s) or legal guardian(s) is unable to understand the nature, scope, and possible consequences of the study, or does not agree to comply with the protocol-defined schedule of assessments
  • Any prior participation in a study in which a gene therapy vector or stem cell transplantation was administered
  • Immunizations of any kind in the month prior to screening
  • Cardiomyopathy or other cardiac disease based on echocardiogram and/or electrocardiogram, (ECG) that in the opinion of the Investigator would deem the participant unsafe to undergo surgical gene transfer
  • Indwelling ferromagnetic devices that would preclude MRI//MRS/DTI imaging
  • Ongoing medical condition that is deemed by the Investigator to interfere with the conduct or assessments of the study
  • Current clinically significant infections including any requiring systemic treatment including but not limited to human immunodeficiency virus (HIV), Hepatitis A, B, or C
  • History of or current chemotherapy, radiotherapy or other immunosuppressive therapy within the past 30 days. Corticosteroid treatment may be permitted at the discretion of the PI
  • Clinically significant laboratory abnormalities:
  • Based on age-specific reference range and determined by the investigator:
  • Total WBC count
  • Hemoglobin
  • Creatinine
  • Pancreatic enzymes
  • Based on the following thresholds:
  • Platelet count (< 150,000/μL)
  • Prothrombin (PT), partial thromboplastin time (PTT) >2X normal
  • Liver transaminases (Hy's Law: > 3x elevations above the ULN of ALT or AST and serum total bilirubin > 2xULN)
  • Participants for whom any of the proposed study procedures or medications (i.e., sirolimus, trimethoprim/sulfamethoxazole) would be contraindicated
  • Failure to thrive, defined as falling 20 percentiles (20/100) in body weight in the 3 months preceding Screening/Baseline
  • Participant is not suitable for participation in the study in the opinion of the Principal Investigator

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Massachusetts General Hospital, Center for Rare Neurological Diseases

    Boston, Massachusetts, 02114

  • University of Massachusetts Medical Health Center

    Worcester, Massachusetts, 01655

Other trials in United States

About this study

Official title: A Two-Stage, Dose-Escalation and Safety & Efficacy Study of Bilateral Intraparenchymal Thalamic and Intracisternal/Intrathecal Administration of AXO-AAV-GM2 in Tay-Sachs or Sandhoff Disease

The AXO-GM2-001 study is an open-label, two-stage clinical trial designed to evaluate safety and dose-escalation (Stage 1) and safety and efficacy (Stage 2) of a bilateral thalamic and intracisternal/intrathecal infusion of AXO-AAV-GM2 in pediatric participants with GM2 Gangliosidosis (also known as Tay-Sachs or Sandhoff Diseases), a set of rare and fatal pediatric neurodegenerative genetic disorders caused by defects in the HEXA (leading to Tay-Sachs disease) or HEXB (leading to Sandhoff disease) genes that encode the two subunits of the β-hexosaminidase A (HexA) enzyme. AXO-AAV-GM2 is an investigational gene therapy that aims to restore HexA function by introducing a functional copy of the HEXA and HEXB genes via co-administration of two vectors utilizing the neurotropic adeno-associated virus recombinant human 8 serotype (AAVrh.8) capsid carrying the human HEXA or HEXB cDNA.

The trial is expected to enroll pediatric participants with Tay-Sachs or Sandhoff Diseases, where infantile-onset participants will range from 6 months to 20 months old, and juvenile-onset participants will range from 2 years to 12 years old.

Being tested
AXO-AAV-GM2 Starting Dose, AXO-AAV-GM2 Low Dose, AXO-AAV-GM2 Middle Dose, AXO-AAV-GM2 High Dose
Keywords
GM2 Gangliosidosis, Hexosaminidase A Deficiency, HexA Deficiency, TSD, SD, Lysosomal Storage Disorders, Tay-Sachs Disease, Sandhoff Disease
Medical subject headings
Tay-Sachs Disease, Sandhoff Disease, Gangliosidoses, GM2, Lysosomal Storage Diseases

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AXO-AAV-GM2 Starting DoseBiological

    Also called AAVrh8-HEXA and AAVrh8-HEXB

    1:1 ratio of AAVrh8-HEXA and AAVrh8-HEXB, administered via bilateral thalamic (BiTh) and dual intracisterna magna (ICM)/intrathecal (IT) administration into the cerebrospinal fluid (CSF).

  • AXO-AAV-GM2 Low DoseBiological

    Also called AAVrh8-HEXA and AAVrh8-HEXB

    1:1 ratio of AAVrh8-HEXA and AAVrh8-HEXB, administered via bilateral thalamic (BiTh) and dual intracisterna magna (ICM)/intrathecal (IT) administration into the cerebrospinal fluid (CSF).

  • AXO-AAV-GM2 Middle DoseBiological

    Also called AAVrh8-HEXA and AAVrh8-HEXB

    1:1 ratio of AAVrh8-HEXA and AAVrh8-HEXB, administered via bilateral thalamic (BiTh) and dual intracisterna magna (ICM)/intrathecal (IT) administration into the cerebrospinal fluid (CSF).

  • AXO-AAV-GM2 High DoseBiological

    Also called AAVrh8-HEXA and AAVrh8-HEXB

    1:1 ratio of AAVrh8-HEXA and AAVrh8-HEXB, administered via bilateral thalamic (BiTh) and dual intracisterna magna (ICM)/intrathecal (IT) administration into the cerebrospinal fluid (CSF).

Study groups in NCT04669535
Study groupRoleWhat they receive
AXO-AAV-GM2ExperimentalAXO-AAV-GM2 infusion
Receives: Biological: AXO-AAV-GM2 Starting Dose; Biological: AXO-AAV-GM2 Low Dose; Biological: AXO-AAV-GM2 Middle Dose; Biological: AXO-AAV-GM2 High Dose

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Incidence, Severity, Seriousness and Relatedness to Treatment of Treatment Emergent Adverse Events

    The measure of total numbers of total treatment emergent adverse events (TEAEs), serious adverse events (SAEs) after treatment with the vector whether related or unrelated to treatment as well as the number of adverse events (AEs) related to AXO-AAV-GM2 vector and neurosurgical procedures.

    Measured: At least through 24 weeks post-treatment (infantile-onset participants) to 48 weeks post-treatment (juvenile-onset participants). All AEs are reported through the transition of the study to long-term follow-up.

Secondary outcomes (4)

  1. Number of Participants With Clinically Significant Abnormal Vital Signs Per Investigator Assessment

    Any abnormal vital signs that the investigator determined was clinically significant was recorded as an adverse event.

    Measured: 24 weeks (infantile-onset participants) to 48 weeks (juvenile-onset participants)

  2. Number of Participants With Clinically Significant Abnormal Physical Exam Per Investigator Assessment

    Physical exam findings that the investigator determined to be clinically significant and related to the treatment with AXO-AAV-GM2, surgical procedure or immune suppression.

    Measured: 24 weeks (infantile-onset participants) to 48 weeks (juvenile-onset participants)

  3. Number of Participants With Clinically Significant Abnormal Clinical Safety Laboratory Tests on Blood/Urine/CSF

    Abnormal laboratory findings in subjects treated with AXO-AAV-GM2 that were felt to be clinically significant and reported as adverse events.

    Measured: 24 weeks (infantile-onset participants) to 48 weeks (juvenile-onset participants)

  4. Serum Cellular and Antibody Immune Response to Vector Capsid/Transgene

    Subjects with clinically significant serum cellular and antibody immune response to vector capsid/transgene that were reported as adverse events and treated with an increase in steroids.

    Measured: 24 weeks (infantile-onset participants) to 48 weeks (juvenile-onset participants)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Dec 2020
  2. Study start15 Jan 2021
  3. Primary completion23 May 2024
  4. Study completion16 Dec 2024

Why it stopped: Sponsor withdrew from the study and there was a lack of funding to complete stage 2 of the designed study.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
9 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04669535
Sponsor's protocol ID
AXO-GM2-001
Status last verified
Aug 2025
First submitted
23 Nov 2020
Last updated
2 Sep 2025
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Eichler F, Cataltepe OI, Daci R, Puri AS, Taghian T, Jiang X, Shazeeb MS, Kuhn A, Hader A, Celik H, Vardar Z, Lewis CJ, Artinian R, Nagy A, Vachha B, Thompson R, Gallagher T, Bateman S, Parzych J, Spanakis SG, Vaughn TA, Pier K, De Boever E, Abbott MA, D Ambrosio E, Kokoski D, Blackwood M, Drummond E, Ratai EM, Townsend EL, McLaughlin H, Tifft CJ, Keeler AM, Sena-Esteves M, Gray-Edwards HL, Flotte TR. Dual-vector rAAVrh8 gene therapy for GM2 gangliosidosis: a phase 1/2 trial. Nat Med. 2025 Sep;31(9):2927-2935. doi: 10.1038/s41591-025-03822-4. Epub 2025 Aug 15.

    PubMed 40817303

  • De BP, Rosenberg JB, Selvan N, Wilson I, Yusufzai N, Greco A, Kaminsky SM, Heier LA, Ricart Arbona RJ, Miranda IC, Monette S, Nair A, Khanna R, Crystal RG, Sondhi D. Assessment of Safety and Biodistribution of AAVrh.10hCLN2 Following Intracisternal Administration in Nonhuman Primates for the Treatment of CLN2 Batten Disease. Hum Gene Ther. 2023 Sep;34(17-18):905-916. doi: 10.1089/hum.2023.067.

    PubMed 37624739

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing AXO-AAV-GM2 Starting Dose, AXO-AAV-GM2 Low Dose and AXO-AAV-GM2 Middle Dose in people with Tay-Sachs Disease and Sandhoff Disease, run by Terence Flotte at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 30 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 2 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 22 May 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence, Severity, Seriousness and Relatedness to Treatment of Treatment Emergent Adverse Events (time frame: At least through 24 weeks post-treatment (infantile-onset participants) to 48 weeks post-treatment (juvenile-onset participants). All AEs are reported through the transition of the study to long-term follow-up.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04669535, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Sep 2025.

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