New gene therapy approach offers a potential long-term treatment for limb-girdle muscular dystrophy 2B
Researchers developed the first non-muscle targeted gene therapy that
enhances diseased muscle fiber repair and improves muscle function

Date:
January 4, 2022
Source:
Children's National Hospital
Summary:
Medical experts have developed a new pre-clinical gene therapy for
a rare disorder, known as limb-girdle muscular dystrophy (LGMD)
2B, that addresses the primary cellular deficit associated with
this disease.

Using a single injection of a low dose gene therapy vector,
researchers restored the ability of injured muscle fibers to
repair in a way that reduced muscle degeneration and enhanced
the functioning of the diseased muscle. The treatment was safe,
attenuated fibro-fatty muscle degeneration, and restored myofiber
size and muscle strength, according to a new study.



FULL STORY ========================================================================== Children's National Hospital experts developed a new pre-clinical gene
therapy for a rare disorder, known as limb-girdle muscular dystrophy
(LGMD) 2B, that addresses the primary cellular deficit associated with
this disease. Using a single injection of a low dose gene therapy vector, researchers restored the ability of injured muscle fibers to repair in
a way that reduced muscle degeneration and enhanced the functioning of
the diseased muscle. The treatment was safe, attenuated fibro-fatty
muscle degeneration, and restored myofiber size and muscle strength,
according to the study published in the Journal of Clinical Investigation.


==========================================================================
With an incidence of less than 1 in 100,000, LGMD2B is a rare disorder
caused by a genetic mutation in a large gene called dysferlin. This
faulty gene leads to muscle weakness in the arms, legs, shoulder and
pelvic girdle. Affected children and adults face trouble walking,
climbing stairs, and getting out of chairs. Individuals typically lose
the ability to walk within years after the onset of symptoms, and often
need assistance with everyday tasks such as showering, dressing and transferring.

This study described a new approach that avoids the need for packaging
a large gene, like dysferlin, or giving a large vector dose to target
the muscles, which are bottlenecks faced in ongoing gene therapy efforts
aimed at muscular dystrophies.

"Currently, patients with LGMD2B have no gene or drug-based therapies
available to them, and we are amongst the few centers developing
therapeutic approaches for this disease," said Jyoti K. Jaiswal,
M.Sc. Ph.D., senior investigator of the Center for Genetic Medicine
Research at Children's National. "We are working to further enhance the efficacy of this approach and perform a longer- term safety and efficacy
study to enable the clinical translation of this therapy." The genetic
defect in dysferlin that is associated with LGMD2B causes the encoded
protein to be truncated or degraded. This hinders the muscle fiber's
ability to heal, which is required for healthy muscles. In recessive
genetic disorders, like LGMD2B, common pre-clinical gene therapy
approaches usually target the mutated gene in the muscle, making them
capable of producing the missing proteins.

"The large size of the gene mutated in this disease, and impediments in
body- wide delivery of gene therapy vectors to reach all the muscles,
pose significant challenges for developing gene therapies to treat this disease," said Jaiswal.

To overcome these challenges, the researchers found another way to slow
down the disease's progression. The authors built upon their previous
discovery that acid sphingomyelinase (hASM) protein is required to
repair injured muscle cells. In this current work, the research team administered a single in vivo dose of an Adeno-associated virus (AAV)
vector that produces a secreted version of hASM in the liver, which then
was delivered to the muscles via blood circulation at a level determined
to be efficacious in repairing LGMD2B patient's injured muscle cells.

"Increased muscle degeneration necessitates greater muscle regeneration,
and we found that improved repair of dysferlin-deficient myofibers by
hASM-AAV reduces the need for regeneration, causing a 2-fold decrease
in the number of regenerated myofibers," said Daniel Bittel, D.P.T.,
PhD., research postdoctoral fellow of the Center for Genetic Medicine
Research at Children's National and a lead author of this study.

Sreetama Sen Chandra, Ph.D., who was a research postdoctoral fellow
at Children's National at the time of this study and served as co-lead
author, also added that "these findings are also of interest to patients
with Niemann- Pick disease type A since the pre-clinical model for this
disease also manifests poor sarcolemma repair." Children's National researchers of the Center for Genetic Medicine Research and the Rare
Disease Institute (RDI) are constantly pursuing high-impact opportunities
in pediatric genomic and precision medicine. Both centers combine
its strengths with public and private partners, including industry, universities, federal agencies, start-up companies and academic medical centers. They also serve as an international referral site for rare
disorders.

========================================================================== Story Source: Materials provided by Children's_National_Hospital. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Daniel C. Bittel, Sen Chandra Sreetama, Goutam Chandra, Robin
Ziegler,
Kanneboyina Nagaraju, Jack H. Van der Meulen, Jyoti
K. Jaiswal. Secreted acid sphingomyelinase as a potential gene
therapy for limb girdle muscular dystrophy 2B. Journal of Clinical
Investigation, 2022; 132 (1) DOI: 10.1172/JCI141295 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220104120616.htm
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