Neuromuscular diseases: A pharmacological therapeutic approach for certain sarcoglycanopathies

A research team led by Dr Isabelle Richard (CNRS-FRE3087) from the Genethon laboratory financed by the AFM through Téléthon donations has just demonstrated the efficacy of a novel pharmacological strategy in the mouse for certain mutations of alpha-sarcoglycanopathy or LGMD2D, a recessive limb girdle dystrophy. This pharmacological strategy could be applied to other limb girdle muscular dystrophies characterised by the same type of genetic mutation. This work is published online in the review Human Molecular Genetics.

Limb girdle muscular dystrophies (LGMD) form a group of neuromuscular diseases characterised by progressive
muscular weakness which affects mainly the limb girdle scapular and pelvic muscles. At present the different subtypes
of LGMD are distinguished by protein and genetic analyses. Type 2D LGMD or alpha-sarcoglycanopathy is
inherited autosomal recessively and is caused by mutations of the Sgca gene located on chromosome 17 and
coding for alpha-sarcoglycan, a protein from the sarcoglycan complex. In normal conditions this complex – situated
in the muscle cell membrane – ensures the stability and mechanical resistance of the cell membrane during muscle
contractions. In case of mutation in one of the cells of this complex, as is the case in alpha-sarcoglycanopathy, the
repetition of contractions create microlesions in the muscle fibre membrane which eventually finish by destroying
the muscle tissues irreversibly and therefore lead to a loss of muscle strength. At the present time no treatment
exists to cure this disease.

It is known that one third of all alpha-sarcoglycanopathy patients are carriers of the same mutation (R77C), which is
the most frequent mutation in this disease. In partnership with the Luminy Immunology Centre at Marseille,
Généthon researchers produced a mouse model that reproduces this mutation and noted that it presented no
dystrophic signs. From these observations of cell and animal models, Généthon researchers were able to
demonstrate that the consequence of the R77C mutation was the production of a malformed protein which cannot
reach the membrane once it is synthesised, as it is eliminated by the “quality control” mechanism of proteins in the
endoplasmic reticulum. Therefore, the disease is not caused by a loss of protein function but by its premature
degradation which prevents it from reaching the cell membrane and integrating into the sarcoglycan complex.

Exploiting this discovery, the researchers used molecules capable of inhibiting alpha-mannosidase, one of the
elements of the quality control system. They administered one of these inhibiting molecules by intramuscular
injection to mice into which a gene coding for the mutated human protein (R77C) had already been injected and
showed that, using the product, the mutated alpha-sarcoglycan could be redirected in the cell membrane, thus
restoring functionality to the sarcoglycan complex. Also, the researchers noted a reduction of dystrophic damage in
the muscle fibres treated.

This work opens up prospects for a novel pharmacological therapeutic approach for the LGMD2D caused by this
type of mutation, but also for other sarcoglycanopathies due to the same type of mutation – that which disrupts the
transport of a fully-functional protein to the membrane.

The “Limb girdle muscular dystrophies” team at Généthon, led by Dr Isabelle Richard since 1999 illustrates
perfectly the amount of ground covered since the AFM set up the laboratory in 1991, financed by Téléthon
donations. In fact, this team has identified many genes and mechanisms at the origin of limb girdle muscle
dystrophies. At present it is working on the development of innovative therapies for these diseases and – in
particular – preparing a gene therapy trial for calpainopathies.