In a Special Issue of the journal Disease Models and Mechanisms Highlights, James J. Dowling et al describes pediatric neuromuscular diseases as mostly genetic and affecting areas of the peripheral nervous system. Specific examples are:
- Charcot-Marie-Tooth disease (peripheral nerve)
- Spinal muscular Atrophy (anterior horn cell)
- Congenital myasthenic syndrome (the neuromuscular junction)
- myopathies and muscular dystrophies (muscle)
Until recently, pediatric neuromuscular disorders were thought of in the context of dire prognoses with no possibilities of treatment.
Then corticosteroids were discovered for Duchenne muscular dystrophy. Treatments now in clinical trials have been shown to be effective. One such example is spinraza therapy for spinal muscular atrophy.
Several other therapies are now being investigated for a variety of conditions but to date there are no curative treatments available for NMDs.
About Treatment Options
NMDs are diverse, genetic (inherited) diseases involving muscle and peripheral nerves. Almost all NMD patients experience muscle weakness. Other NMD conditions may involve the musculoskeletal system and especially respiratory and cardiac functions.
Most of these disorders have been studied for decades resulting in vast amounts of data on their cause and effect.
Yet there are still very few treatment options. This can be attributed to the diverse nature and complexity of the disorders as well as the amount of muscle tissue needing treatment.
2020 Review of Muscular Dystrophy by Morgan and Partridge
Muscular dystrophy (MD) is caused by abnormal genes that interrupt the production of proteins that form healthy muscle.
There are many forms of the disease. Therefore, signs and symptoms will be evident in different muscle groups and the onset of the disease may occur at various ages. Most of the disorders involve loss of muscle mass and progressive weakness beginning in early childhood.
Yet available treatments cannot cure muscular dystrophy, only minimize symptoms and slow progression.
An article by Morgan and Partridge highlights defects in cell function causing MD. The authors also point out that better understanding of the processes that govern muscle regeneration and development can be valuable to researchers when tracking disease progression and treatment response.
Utilizing Animal Models
The use of animal models is extremely important for the continued execution of preclinical research. In addition to testing that leads up to the first phase of human studies, the animal models allow researchers to assess a compound’s safety and therapeutic effects.
An article by Demonbreun et al describes how they developed a dystrophic mouse model using CRISPR/Cas9. The exon 45 gene found in the human DMD gene was deleted in hDMD mice. The researchers used this model as a demonstration to prove the efficacy of the CRISPR/Cas9.
About Limb-girdle Muscular Dystrophy Type 2C (LGMD 2C)
Here, the authors Demonbreun et al. used CRISPR/Cas9 gene editing to create a mouse model for limb-girdle muscular dystrophy type 2C. They demonstrated that mice having two different versions of a gene (heterozygous) present with a muscle disease and low platelets (thrombocytopenia).
Muscles and neurons (nerves that supply muscle) work together as a unit. Therefore, if a disease affects both of these systems, the results are the wasting away of muscles and subsequent paralysis.
Autosomal recessive mutations refer to one gene inherited from each parent. These mutations occurring in the y-sarcoglycan gene are the underlying cause of Limb-girdle muscular dystrophy type 2C (LGMD 2C).
As in muscular dystrophy, at this time there is still no curative treatment for this particular type of LGMD other than therapy to provide cardiac and respiratory support.
Contributions by Other Authors
The skeletal muscle system is primarily affected in NMDs. However, some NMDs also may affect other organs.
- (Stay et al., 2019) Mutations in DMD gene lead to a deficit of brain-specific dystrophin isoforms (proteins). This protein complex strengthens and protects muscle fibers. Cognitive and behavioral changes result when these proteins are absent or non-functional.
- (Ardan et al., 2020; Baxa et al., 2020). A group led by Zdenka Ellederová described the cause and effect of the nerves and brains of the minipig model used to study Huntington’s disease.
- (Sui et al., 2018) re: Editorial by Dominic Wells explaining how the CRISPR/Cas9-generated DMD rabbit model conforms to the existing NMD animal models.
- Figueroa-Romero et al. re: mice models for amyotrophic lateral sclerosis (ALS)
- O’Brien et al. re: the effect of metabolism and diet on motor neuron health
Authors of the journal’s aforementioned Special Issue refer to the tendency of researchers to publish the most positive data. However, they point out that it is just as important to advise whether a drug candidate falls short of expectations. The authors point out that negative findings carry almost as much weight as confirming suitability of a drug or model system.
In conclusion, the Special Issue covers some very encouraging progress in the neuromuscular field.