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

Inclusion Criteria

• •1. Male or female participants with genetically diagnosed TSD or SD mutations of either HEXA gene or HEXB gene
• •a. 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
• •2. 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:
• •1. 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.
• •2. 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'.
• •* 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. .
• •3. 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)
• •3. 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:
• •1. Head control - While supine, with head in midline turns head symmetrically (score of 3 on GMFM item 1)
• •2. Uses hands to support self while sitting
• •3. Reach for an object that is held out for them above their chest while supine
• •4. Transfer of object from hand to hand while supine
• •5. Eye tracking while supine
• •6. Looks at an object of interest for at least 3 continuous seconds
• •4. 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
• •5. 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
• •6. Ability to reliably travel to the study sites for study visits according to the Schedule of Assessments