New Research on Gene Therapies for Limb-Girdle Muscular Dystrophy 2B

According to a recent article, Dr. Jyoti K. Jaiswal shared his research pertaining to gene therapies to be used to treat limb-girdle muscular dystrophy 2B (LGMD2B).

Limb-Girdle Muscular Dystrophy (LGMD)

Limb-girdle muscular dystrophy is a group of diseases that fall into the larger category of muscular dystrophy. It is characterized by progressive weakness and loss of muscle mass in the proximal muscles. The most commonly affected muscles are the shoulders, upper arms, pelvic area, and thighs. 

Severity, onset, and affected areas can vary greatly among individuals with this condition. It can be so different that people in the same family experience very different symptoms. 

It is estimated that about one in every 14,500 to 123,000 people are affected by this disease.

Symptoms:

The early stages of this disease see symptoms such as an abnormal gait and difficulty with running. Affected individuals may need to use their arm muscles to help them stand from a squatting or sitting position due to weak thigh muscles.

As the disease progresses, people may need a wheelchair. As muscles deteriorate, changes in posture may occur. Shoulder blades often stick out from the back, and scoliosis and lordosis may happen as well. Contractures and overgrowth of the calf muscles are other common symptoms in later stages of the disease. 

Cardiomyopathy is a less common effect of this disease, as is the weakening of the muscles needed to breathe. Other uncommon symptoms are intellectual disabilities and developmental delays.  

About Dr. Jyoti K. Jaiswal

Dr. Jyoti K. Jaiswal is the Associate Director of Academics and Senior Investigator at the Children’s National Research Institute. He is a cell biologist who tries to understand the way cells traffic their membranes and proteins and how these relate to certain disease, and he then uses that information to create novel therapies with his teams.

Currently, he is interested specifically in the defects in cellular and subcellular responses to muscle injury in patients with limb-girdle muscular dystrophy 2B, as there are no therapies to treat such defects.

Understanding the Defect

Recessive mutations in the dysferlin gene are the genetic defects that cause LGMDB2. These mutations cause the decrease or loss of the dysferlin protein, and are how patients with the disease are able to be diagnosed.

Dysferlin in the muscle cells is a protein that is needed to fix the skeletal muscle cell membranes when they are injured or experience some kind of trauma. Without this protein, the skeletal cell membranes are not able to be repaired, and therefore the muscles degenerate, causing them to become weak and dysfunctional.

A Lack of Therapies

There are no therapies to treat LGMB2B at this time. This is to due the fact that the gene is of a large size, and that is not ideal for restorative gene therapies. Furthermore, there are challenges with using vectors for muscle delivery.

There are trials being done on mouse models, but none have established clinical and safety efficacy as of yet.

Dr. Jyoti K. Jaiswal’s Mission to Overcome

Through his research, Dr. Jaiswal is aiming to take an unconventional approach towards creating a gene therapy to treat LGMB2B. He and his team decided to focus on the downstream defect (the release of the acid sphingomyelinase enzyme) that is a result of a lack of the dysferlin protein, rather than trying to just restore the missing protein.

In order for the acid sphingomyelinase enzyme (ASM) to be released outside of the muscle fibers, dysferlin is needed. Therefore, Dr. Jaiswal and his team tried substituting the dysferlin deficit by giving the enzyme to the muscles externally. The team produced ASM within the liver and then secreted it into the blood so that it would be able to reach the muscle. He and his team then tested the dose and its benefits as it pertains to relieving muscle weakness and degeneration.

Impact

The results of the testing showed the therapy was able to reduce muscle damage thus reducing the necessity of muscle regeneration. It reduced the muscle loss that was a result of muscle damage, and maintained the health and functionality of the muscle fibers. These results give hope that this therapy will be able to slow the progression of symptoms of LGMB2B and prolong a patient’s ability to have a healthy and functioning active life.

The team’s next steps are to establish the safety of the therapy long-term.

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