September 30th is Limb Girdle Muscular Dystrophy Awareness Day!
Limb Girdle Muscular Dystrophy Awareness Day is an annual collaborative effort to globally raise awareness of individuals living with limb girdle muscular dystrophy (LGMD). The tenth annual global “LGMD Awareness Day” will be held on 30 September, 2024.
Limb girdle muscular dystrophy (LGMD) is a group of genetically inherited neuromuscular conditions that cause muscle weakness and wasting, especially around the shoulders, upper arms, pelvic area, hips and thighs.
There are more than 30 identified sub-types of LGMD, with new forms being discovered each year.
The degree to which an individual’s muscle ability is affected can vary from person to person and even between those whose condition is part of the same sub-type or biological family.
The heart muscle and / or respiratory muscles are weakened in some LGMD sub-types.
Symptoms of LGMD can be present early in life or develop later in life.
Individuals with LGMD carry mutations in genes that provide faulty instructions for making proteins involved in muscle maintenance and repair. As there are many sub-types of LGMD there are also many different genetic mutations that underlie these conditions.
LGMD types were previously labelled with numbers (e.g., LGMD 2A, 2B). They are now classified with the letter "R" to reflect a more standardised and clear classification system. This change was made to help distinguish between different forms of LGMD based on their genetic causes. In this new system, for example, LGMD 2A, which was caused by mutations in the CAPN3 gene, is now called LGMD R1. The letter ‘R’ indicates it is a recessive form, and the number helps specify the exact genetic subtype.
LGMD research news
Gene therapy
Sarepta Therapeutics and Atamyo Therapeutics are leading the way in gene therapy drug discoveries for LGMD.
Sarepta Therapeutics have three gene therapies at clinical trials phases. These are targeting LGMD2E/R4, LGMD2D/R3 and LGMD2B/R2. They also have three studies at pre-clinical stages for LGMD2C/R5, LGMD2L/R12 and LGMD2A/R1.
Atamyo Therapeutics’ pipeline is focused on developing novel treatments for different forms of limbgirdle muscular dystrophy. This includes, LGMD2i/R9, LGMD2C/R5, LGMD2A/R1, LGMD2B/R2 and LGMD2D/R3. A phase 1-2 study for LGMD2i/R9 started in 2022 and a phase 1b study for LGMD2C/R5 is due to start recruitment the end of 2024. The other studies are at preclinical stage.
Preclinical research is the stage of research before testing in humans. It is lab-based, using cell and animal models to assess safety, efficacy and effect of the drug at a biological level.
Sarepta Therapeutics - SRP-9003 gene therapy in LGMD2E
LGMD2E, also known as LGMDR4, is caused by mutations in the SGCB gene, which limit the production of beta-sarcoglycan. This leads to muscle weakness and wasting, mainly in the hips and shoulders.
The gene therapy SRP-9003 (bidridistrogene xeboparvovec) is designed to deliver a healthy SGCB gene to increase beta-sarcoglycan levels in muscles, especially the heart, because of the increased risk of cardiac and pulmonary complications in LGMD2E patients.
A Phase 1/2 trial was completed and enrolled six children with LGMD2E. SRP-9003 was administered in a single intravenous dose. Early results highlighted substantial increased protein expression up to two years after treatment and functional benefits, including enhanced mobility and quality of life. A concern in gene therapies is the potential for waning effects over time, therefore longer-term studies are needed. The patients in this Phase 1/2 study will continue to be followed, with a final analysis planned at 5 years post-therapy.
The Phase 3 clinical trial, called EMERGENE, will build on results from the phase 1/2 trial and will involve 15 patients aged 4 and older. This study will also include a six-month natural history study to observe disease progression without treatment. The aim of this trial is to measure the activity of the therapeutic gene (beta-sarcoglycan), 60 days after dosing. Functional and safety parameters will also be evaluated.
Atamyo Therapeutics - ATA-200 gene therapy in LGMD2C or LGMDR5
LGMD Type 2C/R5 is a subtype of LGMD caused by mutations in the SGCG gene. Mutations in the SBCB are thought to prevent the sarcoglycan complex from stabilising dystrophin. Dystrophin is one of the proteins that protect muscle fibres from damage during contraction and relaxation. Symptoms typically appear in early childhood, leading to progressive muscle weakness and loss of walking ability by adulthood. About half of people with LGMD 2C/R5 also develop dilated cardiomyopathy.
ATA-200 is a gene therapy designed to deliver a functional SGCG gene to restore sarcoglycan complex function and stabilise dystrophin. In animal models, a single dose was well tolerated and improved symptoms. A Phase 1b trial will enrol six children aged 6-11 with LGMD-2C/R5, testing two doses of ATA-200 to assess safety and efficacy.
The primary goal of the trial is to assess the safety of ATA-200 by monitoring adverse events for six months post-dosing, with participants followed for an additional 4.5 years. Researchers will also evaluate the therapy's efficacy, effects on the body, and potential immune response. The trial is due to commence before the end of this year.