LAMA2 Genetic Correction

NCT06582537 | Completed

• 1 other identifier: MABS03
• Study Type: observational
• Target: 7
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

MDC1A

Keywords

MDC1A; LAMA2; Muscular Dystrophy; Mesoangioblasts

Outcome Measures

Primary Outcomes (5)

• Compare RNA transcription of corrected and not corrected DNA

  qPCR

  1 day

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

  LAMA2 immunostaining

  1 day

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

  LAMA2 immunostaining

  1 day

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

  LAMA2 western blot

  1 day

• Assess effect LAMA2 mutations on muscle protein quality (fibrosis)

  LAMA2 HE staining

  1 day

Secondary Outcomes (5)

• Verification of the LAMA2 mutations or exclusion of LAMA2 mutations in controls

  1 day

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

  1 day

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

  1 day

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

  1 day

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

  1 day

Study Arms (2)

Adult carriers of the LAMA2 c.5562+5G>C mutation

Procedure: Participants sample collection

Healthy controls

Procedure: Participants sample collection

Interventions

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.

Adult carriers of the LAMA2 c.5562+5G>C mutation; Healthy controls

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The study will only include patients/controls living in The Netherlands

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Maastricht University: lead

Study Sites (1)

Academisch Ziekenhuis Maastricht

Maastricht, Limburg, 6229HX, Netherlands

Location

MeSH Terms

Conditions

Muscular Dystrophies

Condition Hierarchy (Ancestors)

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

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 11, 2022
• First Posted: September 3, 2024
• Study Start: July 1, 2020
• Primary Completion: July 18, 2024
• Study Completion: July 18, 2024
• Last Updated: September 3, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)