Gene Therapy for IGHMBP2-Related Diseases

NCT05152823 | Enrolling By Invitation Phase 1 DMC FDA Drug

• 1 other identifier: STUDY00002143
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

SMARD1; CMT2S

Keywords

IGHMBP2

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• 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

Study Arms (1)

Single Intrathecal Delivery

EXPERIMENTAL

Biological: Gene Therapy

Interventions

Gene Therapy BIOLOGICAL

AAV9 carrying the IGHMBP2 gene.

Single Intrathecal Delivery

Eligibility Criteria

• Age: 2 Months - 14 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Megan Waldrop: lead

Study Sites (1)

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Related Publications (7)

• Grohmann K, Schuelke M, Diers A, Hoffmann K, Lucke B, Adams C, Bertini E, Leonhardt-Horti H, Muntoni F, Ouvrier R, Pfeufer A, Rossi R, Van Maldergem L, Wilmshurst JM, Wienker TF, Sendtner M, Rudnik-Schoneborn S, Zerres K, Hubner C. Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1. Nat Genet. 2001 Sep;29(1):75-7. doi: 10.1038/ng703.

  PMID: 11528396 BACKGROUND

• Saladini M, Nizzardo M, Govoni A, Taiana M, Bresolin N, Comi GP, Corti S. Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights. J Cell Mol Med. 2020 Jan;24(2):1169-1178. doi: 10.1111/jcmm.14874. Epub 2019 Dec 4.

  PMID: 31802621 BACKGROUND

• Guenther UP, Handoko L, Varon R, Stephani U, Tsao CY, Mendell JR, Lutzkendorf S, Hubner C, von Au K, Jablonka S, Dittmar G, Heinemann U, Schuetz A, Schuelke M. Clinical variability in distal spinal muscular atrophy type 1 (DSMA1): determination of steady-state IGHMBP2 protein levels in five patients with infantile and juvenile disease. J Mol Med (Berl). 2009 Jan;87(1):31-41. doi: 10.1007/s00109-008-0402-7. Epub 2008 Sep 18.

  PMID: 18802676 BACKGROUND

• Viguier A, Lauwers-Cances V, Cintas P, Manel V, Peudenier S, Desguerre I, Quijano-Roy S, Vanhulle C, Fradin M, Isapof A, Jokic M, Mathieu-Dramard M, Dieterich K, Petit F, Magdelaine C, Giuliano F, Gras D, Haye D, Nizon M, Magen M, Bieth E, Cances C. Spinal muscular atrophy with respiratory distress type 1: A multicenter retrospective study. Neuromuscul Disord. 2019 Feb;29(2):114-126. doi: 10.1016/j.nmd.2018.10.002. Epub 2018 Oct 31.

  PMID: 30598237 BACKGROUND

• Tomaselli PJ, Horga A, Rossor AM, Jaunmuktane Z, Cortese A, Blake JC, Zarate-Lopez N, Houlden H, Reilly MM. IGHMBP2 mutation associated with organ-specific autonomic dysfunction. Neuromuscul Disord. 2018 Dec;28(12):1012-1015. doi: 10.1016/j.nmd.2018.08.010. Epub 2018 Aug 29.

  PMID: 30385095 BACKGROUND

• Eckart M, Guenther UP, Idkowiak J, Varon R, Grolle B, Boffi P, Van Maldergem L, Hubner C, Schuelke M, von Au K. The natural course of infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). Pediatrics. 2012 Jan;129(1):e148-56. doi: 10.1542/peds.2011-0544. Epub 2011 Dec 12.

  PMID: 22157136 BACKGROUND

• Cottenie E, Kochanski A, Jordanova A, Bansagi B, Zimon M, Horga A, Jaunmuktane Z, Saveri P, Rasic VM, Baets J, Bartsakoulia M, Ploski R, Teterycz P, Nikolic M, Quinlivan R, Laura M, Sweeney MG, Taroni F, Lunn MP, Moroni I, Gonzalez M, Hanna MG, Bettencourt C, Chabrol E, Franke A, von Au K, Schilhabel M, Kabzinska D, Hausmanowa-Petrusewicz I, Brandner S, Lim SC, Song H, Choi BO, Horvath R, Chung KW, Zuchner S, Pareyson D, Harms M, Reilly MM, Houlden H. Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2. Am J Hum Genet. 2014 Nov 6;95(5):590-601. doi: 10.1016/j.ajhg.2014.10.002. Epub 2014 Oct 30.

  PMID: 25439726 BACKGROUND

MeSH Terms

Conditions

Spinal muscular atrophy with respiratory distress 1

Interventions

Genetic Therapy

Intervention Hierarchy (Ancestors)

Biological Therapy; Therapeutics; Genetic Engineering; Genetic Techniques; Investigative Techniques

Study Officials

• Megan Waldrop, MD

  Nationwide Children's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Neurology

Study Record Dates

• First Submitted: November 25, 2021
• First Posted: December 10, 2021
• Study Start: November 4, 2021
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2030
• Last Updated: September 30, 2025

Record last verified: 2025-09

Locations

US (1)