Gene Therapy for IGHMBP2-Related Diseases

Study Overview
=================
Brief Summary
-----------------
Open-label, single intrathecal injection study of a AAV9 vector carrying the IGHMBP2 gene for IGHMBP2-related diseases.

Official Title
-----------------
Phase I/IIa Intrathecal Gene Delivery Clinical Trial for IGHMBP2-Related Diseases

Conditions
-----------------
SMARD1, CMT2S

Intervention / Treatment
-----------------
* Biological: Gene Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmation of two pathogenic variants in the IGHMBP2 gene from a CLIA-certified lab Pre-ambulant (not yet walking and less than 18 months) or ambulant (as defined by the ability to walk 10 meters without assistance) or non-ambulant (inability to walk more than 10 meters unassisted) Ability to cooperate with functional assessments as per PI's discretion Exclusion Criteria: Prior participation in a gene or cell therapy program for any kind. Immunizations of any kind in the month prior to the study. Active infection based on clinical observations Serological evidence of HIV infection, or Hepatitis B or C infection Diagnosis of (or ongoing treatment for) an autoimmune disease Persistent leukopenia or leukocytosis (WBC ≤ 3.5 10^3/μL or ≥ 20.0 10^3/μL) or an absolute neutrophil count < 1.5 10^3/μL Abnormal liver function as indicated by an elevated GGT (>2X normal if no other laboratory abnormalities), bilirubin and/or abnormal PT/INR Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer AAV9 binding antibody titers > 1:50 as determined by ELISA immunoassay performed by Athena Diagnostics Abnormal laboratory values in the clinically significant range, based upon normal values in the Nationwide Children's Hospital Laboratory Diagnosis of any other systemic illness that increases the risk of gene transfer per the PI's opinion; Has a medical condition or extenuating circumstance that, in the opinion of the PI, might compromise the subject's ability to comply with the protocol required testing or procedures or compromise the subject's well-being, safety, or clinical interpretability Any requirement for immune modulatory therapy and for which it would be unsafe for the subject to undergo an appropriate wash out period Contraindication for intrathecal injection A positive JCV antibody test of >0.40

Ages Eligible for Study
-----------------
Minimum Age: 2 Months
Maximum Age: 14 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Intrathecal Delivery<br> | Biological: Gene Therapy<br>* AAV9 carrying the IGHMBP2 gene.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Monitoring for the development of unacceptable toxicity. | Unacceptable toxicity is defined as the occurrence of two or more unexpected Grade III or higher treatment-related toxicities, as defined by CTCAE 5.0. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For pre-ambulant participants, ages less than 18 months, change in the Neuromuscular Gross Motor Outcome (GRO) from baseline |  | Days 90 and 180, Months 12, 18, 24 and 36 | 
| For ambulant participants, change in the 100-meter timed test from baseline |  | Days 90 and 180, Months 12, 18, 24 and 36 | 
| For non-ambulant participants, ages 18 months to 6 years, change in the Neuromuscular Gross Motor Outcome (GRO) from baseline |  | Days 90 and 180, Months 12, 18, 24 and 36 | 
| For non-ambulant participants, ages greater than 6 years, change in the revised upper limb module for SMA (RULM) from baseline |  | Days 90 and 180, Months 12, 18, 24 and 36 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
IGHMBP2