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.
FKRP LGMD – GNT 0006
| Preclinical | Phase I/II | Pivotal Phase | Approval |
Genethon developed a gene therapy product, demonstrated its efficacy in animals and carried out the pre-clinical development of the product.
It was licensed to Atamyo for clinical development.
Gamma sarco-glycanopathy – GNT 0007
| Preclinical | Phase I/II | Pivotal Phase | Approval |
Genethon developed a gene therapy product and performed much of the pre-clinical development.
This product was licensed to Atamyo for clinical development and a clinical trial application is expected to be filed shortly.
Calpaïnopathy – GNT 0008
| Preclinical | Phase I/II | Pivotal Phase | Approval |
Genethon developed a gene therapy product that was licensed to Atamyo, which is responsible for the pre-clinical development initiated by Genethon.
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?
The natural history study launched by Genethon in 2019 in three countries (Denmark, France and Great Britain) has now been completed. Ongoing analysis of the data collected during this study will enable us to have a better understanding of the disease.
The gene therapy product has been licensed to Atamyo, a Genethon spin-off, which is responsible for clinical development in collaboration with Genethon. To date, the trial is underway with the inclusion and treatment of several patients in France, Denmark and, shortly, the UK.
Encouraging clinical results from the first cohort were presented by Atamyo at the ASGCT 2023 congress: https://www.genethon.com/first-clinical-results-of-a-gene-therapy-for-the-treatment-of-limb-girdle-muscular-dystrophy-presented-at-esgct-congress/ and Myology in 2024.
The gene therapy treatment has also received approval from the US regulatory agency (FDA) to start a clinical trial in the USA.
Find out more
Publications
- 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 (2010-201, 9 patients included).
One month after intramuscular injection of AAV vector carrying a normal copy of the gene, the first trial showed good tolerance and the presence of the product in patients treated at the highest dose but in limited quantity.
Benefiting from recent developments in gene transfer technologies, this program demonstrated the possibility of restoring expression of the defective gene in animal models, as well as physiological parameters.
The gene therapy product has been licensed to Atamyo, a Genethon spin-off, which is responsible for its clinical development.
Gamma-sarcoglycanopathy: what’s happening today?
In March 2024, this program obtained authorization to start a phase I/II clinical trial with the new product GNT0007 in France and Italy.
In March 2024, this program also obtained authorization to start a natural history study in France and Tunisia, to better understand the disease and facilitate the design of future clinical trials.
Find out more
Publications
- 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.
Press releases
- Atamyo Therapeutics Obtains Regulatory Authorization in Europe to Initiate a Clinical Trial for ATA-200, its Gene Therapy to Treat Limb-Girdle Muscular Dystrophy Type 2C/R5 Press Releases – Atamyo Therapeutics
- Towards a clinical trial for gamma-sarcoglycanopathy, limb-girdle muscular dystrophy. (2019/05/24)
ClinicalTrials links
Clinical Trial: Study Details | ATA-200 Dose-escalation Gene Therapy Trial in Patients With LGMDR5 | ClinicalTrials.gov
Natural study : Study Details | Natural History Study in Patients With LGMDR5/2c | ClinicalTrials.gov
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 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. 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?
The gene therapy product has been licensed to Atamyo, a Genethon spin-off company, which is developing it in collaboration with Genethon.
This program has demonstrated the possibility of restoring deficient gene expression in animal models using an innovative statistical analysis approach combined with artificial intelligence.
The teams are currently preparing a clinical trial.
Find out more
Publications
- 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
Poster
- Oral presentation and poster at the 28th Annual Congress of World Muscle Society (WMS) in October 2023:
P282 Evaluation of gene transfer efficiency in a mild model of dystrophic muscle disorder performed by machine learning and linear discriminant analysis. Brureau A, Roudaut C, Faivre M, Stockholm D, Richard I - Poster at the American Society of Gene and Cell Therapy Congress (ASGCT), in May 2023:
Evaluation of gene transfer efficiency in a mild model of dystropic muscle disorder performed by machine learning and linear discriminant analysis”. Brureau A, Roudaut C, Faivre M, Stockholm D, Richard I
