| Eligibility |
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
Exclusion Criteria:
1. Presence of G269S or W474C mutation in HEXA
2. 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.
3. History of multiple aspiration pneumonias occurring in the past twelve months.
4. Respiratory support in the form of ventilation (invasive or non-invasive).
5. History of drug-resistant seizures or status epilepticus
6. History and/or findings of spinal cord disease that would preclude the lumbar puncture
and ICM/IT infusion procedures including:
- 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)
7. 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
8. Any prior participation in a study in which a gene therapy vector or stem cell
transplantation was administered
9. Immunizations of any kind in the month prior to screening
10. 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
11. Indwelling ferromagnetic devices that would preclude MRI//MRS/DTI imaging
12. Ongoing medical condition that is deemed by the Investigator to interfere with the
conduct or assessments of the study
13. Current clinically significant infections including any requiring systemic treatment
including but not limited to human immunodeficiency virus (HIV), Hepatitis A, B, or C
14. 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
15. 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)
16. Participants for whom any of the proposed study procedures or medications (i.e.,
sirolimus, trimethoprim/sulfamethoxazole) would be contraindicated
17. Failure to thrive, defined as falling 20 percentiles (20/100) in body weight in the 3
months preceding Screening/Baseline
18. Participant is not suitable for participation in the study in the opinion of the
Principal Investigator
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