Limb girdle muscular dystrophies
Limb Girdle Muscular Dystrophies (LGMD) cover a set of pathologies that are characterized by progressive degeneration of the pelvic muscles (pelvic girdle) and the shoulder muscles (shoulder girdle), leading to loss of motor skills in the upper and lower limbs. There are over 30 types of limb girdle muscular dystrophy related to genetic mutations. Today, several of these dystrophies are being studied in Isabelle Richard’s laboratory, and this work has enabled the design of therapy approaches currently in development.
Limb girdle muscular dystrophy with FKRP deficiency (LGMDR9 or formerly LGMD2I)
What is limb girdle muscular dystrophy with FKRP deficiency?
Limb girdle muscular dystrophy with FKRP deficiency (LGMDR9 or 2i) is a disease caused by anomalies in the gene coding FKRP (Fukutin-Related Protein), located on chromosome 19. The FKRP protein contributes to the stability and resistance of the muscle tissue. It acts on one of the key elements of the link between the muscle cells and their environment, alpha dystroglycan.
The age of onset of this dystrophy varies between early childhood and early adulthood and is characterized by a rapid deterioration and loss of mobility in adolescence, or later in adulthood. It may be accompanied by respiratory distress and/or cardiac symptoms.
Limb girdle muscular dystrophy with FKRP deficiency is particularly common in Northern Europe, but it is universal and is one of the most common limb girdle muscular dystrophies (ORPHA:34515).
There is currently no specific treatment for this disease.
FKRP Limb girdle muscular dystrophies: Genethon’s role
Genethon’s laboratory is the leader in research on FKRP limb girdle muscular dystrophy. Several scientific works from Isabelle Richard’s team have achieved proof of principle showing that a gene therapy treatment is liable to halt development of the disease in animal models. The results of this work have been essential to developing a product to treat patients suffering from this disease.
FKRP Limb girdle muscular dystrophies: what’s happening today?
In 2019, Genethon initiated a natural history study in three countries: Denmark, France and Great Britain. This study is in the active recruitment phase (with 60 patients among 3 centers).
The GNT 0006 product is currently in preclinical development with a view to entering human trials.
Find out more
- Gicquel, E. et al. (2017) AAV-mediated transfer of FKRP shows therapeutic efficacy in a murine model but requires control of gene expression. Human Molecular Genetics, 26(10), 1952-1965.
Gamma-sarcoglycanopathy (LGMDR5 or formerly LGMD2C)
What is Gamma-sarcoglycanopathy?
Gamma-sarcoglycanopathy (or LGMDR5, formerly named LGMD2C) is a limb girdle muscular dystrophy caused by mutations in the gamma-sarcoglycan gene.
It manifests in progressive weakness of the pelvic muscles and the shoulder muscles, which generally begins before the age of 10, with loss of the ability to walk at puberty. The heart muscle can also be affected and breathing difficulties can occur as the disease evolves, worsening the prognosis and sometimes leading to premature death.
Gamma-sarcoglycanopathy: Genethon’s role
Genethon has been a pioneer in research in this field, and has been sponsor of a phase-I clinical trial for gamma-sarcoglycanopathy (2010-2011). This trial involved intramuscular administration of an AAV vector carrying a normal copy of the gene. Nine patients were included in total. This first trial showed good tolerance of the product and presence of the therapeutic gene in patients treated at the highest dose but in limited quantity.
Gamma-sarcoglycanopathy: what’s happening today?
With the benefit of recent developments in gene transfer technologies, this program has demonstrated the possibility of restoring expression of the defective gene in animal models, and of physiological parameters.
Researchers are working on preparing a clinical trial.
Find out more
- David Israeli, Jérémie Cosette, Guillaume Corre, Fatima Amor, Jérôme Poupiot, Daniel Stockholm, Marie Montus, Bernard Gjata, Isabelle Richard. An AAV-SGCG Dose-Response Study in a γ-Sarcoglycanopathy Mouse Model in the Context of Mechanical Stress. Molecular Therapy – Methods & Clinical Development, Volume 13, 2019, Pages 494-502, ISSN 2329-0501, https://doi.org/10.1016/j.omtm.2019.04.007.
- Towards a clinical trial for gamma-sarcoglycanopathy (05/23/2019)
- The results were published in January 2012 in the Brain scientific journal (01/12/2012). Read the press release.
Calpainopathy (LGMDR1 or formerly LGMD2A)
What is Calpainopathy?
Calpainopathy is a form of limb girdle muscular dystrophy caused by mutations in the calpain 3 gene. It is the most common form of LGMD worldwide.
It manifests in progressive weakness of the muscles of the torso and upper leg, generally beginning between the ages of 8 and 15, with loss of the ability to walk 10 to 20 years later.
Calpainopathy: progress at Genethon
Genethon has been one of the pioneers in this field, from identification of the gene responsible for the pathology to the early gene therapy approaches.
Several studies demonstrating the effectiveness of the gene transfer approach for treating Calpainopathy have been published by its teams in recent years. Genethon has also coordinated a natural history study comprising 85 patients on 3 sites (Paris, Saint Pierre – Réunion Island, and San Sebastián in Spain) to find out more about the disease and facilitate the design of future clinical studies. (Richard et al., 2016).
Calpainopathy: what’s happening today?
R&D efforts are underway to prepare an effective and safe gene therapy clinical trial for treatment of calpainopathy.
Find out more
- Bartoli M et al., Safety and efficacy of AAV-mediated calpain 3 gene transfer in a mouse model of limb-girdle muscular dystrophy type 2A. Mol Ther. 2006;13(2):250-9
- Roudaut C et al., Restriction of calpain3 expression to the skeletal muscle prevents cardiac toxicity and corrects pathology in a murine model of limb-girdle muscular dystrophy. Circulation. 2013;128(10):1094-104
- Richard I et al., Natural history of LGMD2A for delineating outcome measures in clinical trials. Ann Clin Transl Neurol. 2016 Mar 4;3(4):248-65