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NCT Number: NCT06582537

LAMA2 Genetic Correction

Merosin-deficient congenital muscle dystrophy type 1a (MDC1a), or LAMA2 muscular dystrophy (LAMA2-MD) is a severe autosomal recessive form of muscular dystrophy that is caused by homozygous or compound heterozygous mutations in the laminin alpha 2 (LAMA-2) gene. Many different LAMA-2 mutations have been reported. In most cases, MDC1a is diagnosed within the first year of life, and is characterized by hypotonia, delayed motor development and white matter abnormalities. Currently, no efficient treatment is available for this patient group. Generally, MDC1a patients with mutations causing a premature stop codon are most severely affected (early onset LAMA2-MD) and patients with missense mutations are generally affected more mild affected and more late-onset (late onset LAMA2-MD). However, large variation in disease severity and clinical course is observed, even between individuals with the same mutation, e.g. the LAMA2 c.5562+5G>C mutation, which is frequently observed in Dutch MDC1a patients. This study aims to isolate and culture fibroblasts and myogenic stem cells called mesoangioblasts from the skin and muscle biopsies of adult LAMA2 mutation carriers to explore if genetic correction of LAMA2 mutations using CRISPR-Cas9 can be achieved and subsequently assess the effect in vitro, as a first step towards therapy development.

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Key information

Conditions

MDC1A Congenital, Hereditary, and Neonatal Diseases and Abnormalities Genetic Diseases, Inborn Muscular Diseases Muscular Disorders, Atrophic Muscular Dystrophies Musculoskeletal Diseases Nervous System Diseases Neuromuscular Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Observational

Primary location

Academisch Ziekenhuis Maastricht

Maastricht, Limburg, 6229HX, Netherlands

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • LAMA2 mutation carriers:
  • Age >18 years
  • Heterozygous or homozygous LAMA2 c.5562+5G>C mutation
  • Written informed consent

Controls:

  • Written informed consent
  • Age >18 years
  • No muscular dystrophy or other disease known to affect muscle morphology or function

Exclusion criteria

  • MDC1a patients and controls:
  • No informed consent
  • Use of anti-coagulants, anti-thrombotics and other medication influencing coagulation
  • Have a weekly alcohol intake of ≥ 35 units (men) or ≥ 24 units (women)
  • Current history of drug abuse
  • A history of strokes
  • Significant concurrent illness
  • Ongoing participation in other clinical trials
  • Major surgery within 4 weeks of the visit
  • Pregnant or lactating women
  • Patients unable and/or unwilling to comply with treatment and study instructions
  • Any other factor that in the opinion of the investigator excludes the patient from the study

Treatment and study plan

Participants sample collection

Procedure

A skeletal muscle biopsy and a venous blood sample will be collected. The skin biopsy will be obtained during the incision needed for the muscle biopsy.

Primary outcomes

  1. Compare RNA transcription of corrected and not corrected DNA

    Time frame: 1 day

    qPCR

  2. Assess effect LAMA2 mutations on muscle protein quantity (amount of LAMA2)

    Time frame: 1 day

    LAMA2 immunostaining

  3. Assess effect LAMA2 mutations on muscle protein quality (localization of LAMA2)

    Time frame: 1 day

    LAMA2 immunostaining

  4. Assess effect LAMA2 mutations on muscle protein quantity (LAMA2 overall levels)

    Time frame: 1 day

    LAMA2 western blot

  5. Assess effect LAMA2 mutations on muscle protein quality (fibrosis)

    Time frame: 1 day

    LAMA2 HE staining

Secondary outcomes

  1. Verification of the LAMA2 mutations or exclusion of LAMA2 mutations in controls

    Time frame: 1 day

    DNA analysis

  2. Blood markers to assess level of muscle inflammation, damage and regeneration in MDC1a patients: CK

    Time frame: 1 day

    ELISA assay

  3. Blood markers to assess level of muscle inflammation, damage and regeneration in MDC1a patients: TNFa

    Time frame: 1 day

    ELISA assay

  4. Blood markers to assess level of muscle inflammation, damage and regeneration in MDC1a patients: IL-6

    Time frame: 1 day

    ELISA assay

  5. Blood markers to assess level of muscle inflammation, damage and regeneration in MDC1a patients: SDF1

    Time frame: 1 day

    ELISA assay

Sponsors and collaborators

Lead sponsor

Maastricht University

Other

Registry information

Official study title

Ex Vivo Genetic Correction of LAMA2 Mutation(s) in Myogenic Stem Cells of Patients with Merosin-deficient Congenital Muscle Dystrophy Type 1a (MDC1a)

Important dates

Study start
2020
Primary completion
2024
Study completion
2024
First posted
Sep 3, 2024
Registry last updated
Sep 3, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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