Neuromuscular diseases: a revolution in therapies thanks to research and precision medicine

Over the past five years, research and precision medicine have revolutionised therapies for neuromuscular diseases, a heterogeneous group of pathologies that affect around 4 million people in Italia and involve the peripheral nervous system and muscles causing different levels of severity and impairment. They include, among others, Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), Myasthenia Gravis, Duchenne Muscular Dystrophy and other types of Myopathies and Peripheral Neuropathies, including those associated with chronic diseases such as diabetes. They can be of genetic or acquired origin and in 90% of cases they are rare forms with consequent criticalities in terms of diagnostic timeliness, uniform access to treatment and continuity of care.

The point on new treatment options was the main focus of the 9th Neuromuscular Diseases Day, scheduled on 21 March in 19 Italian cities with the involvement of 30 specialist centres operating as multidisciplinary clinical and care reference points for the diagnosis, therapy and follow-up of these diseases. The initiative is promoted by the Associazione Italiana Sistema Nervoso Periferico (ASNP), the Associazione Italiana Miologia (AIM) and the Società Italiana di Neurologia (SIN). What patients and their families can count on is a real paradigm shift. The hope of being able to treat a disease and stop or slow down its course has become a reality in many cases, and has produced an epoch-making transformation in paediatric and adult neurology. Diseases once considered incurable now benefit from therapies that act directly on the 'factory defect' in the DNA or immune system. "We are no longer dealing with drugs that only attempt to alleviate symptoms, but with 'disease-modifying' therapies. The ability to intervene in DNA or RNA makes it possible to transform some once fatal diseases into manageable or chronic conditions. Updating the scientific community, health institutions, patient associations, family doctors and paediatricians, specialists in various areas and patients themselves on developments in this field is one of the objectives of this year's Neuromuscular Disease Day," emphasise Professor Angelo Schenone and Professor Antonio Toscano, scientific leaders of Neuromuscular Disease Day.

An emblematic example is motor neuron disease. In particular, SMA, in which antisense oligonucleotides (ASOs) are enabling children born with this disease to survive first and reach previously unthinkable motor milestones. In this case, neonatal screening is crucial for early detection of the disease. ASOs function like little 'genetic patches' that instruct cells to ignore an error in the DNA. Even ALS, which in its sporadic form is still orphaned by therapy, has become a treatable disease with therapies based on ASOs for a specific group of patients carrying a mutation in the SOD1 gene (about 2-3% of cases).

In this area, there are also innovations for Duchenne Dystrophy. There are drugs that use the exon skipping technique to 'skip' the damaged part of the gene and produce a protein, dystrophin, without which the muscles become progressively weaker. The disease does not disappear completely, but changes from a severe form to a milder and slower-moving one. Thanks to RNA and gene therapies, not only the message is corrected, but also the root cause or toxic genes are silenced. SMA is once again prototypical for gene replacement therapies. The treatment is extremely expensive, but revolutionary: a single infusion replaces the defective gene. In Italia it is already reimbursed by the National Health Service. A drug has also been introduced for SMA, which already exists in a syrup formulation, in tablet form, with which 26,000 patients have been treated to date. The therapy was developed to increase and support the production of the SMN protein throughout the central nervous system (CNS) and peripheral tissues. The tablet version, which is more practical and portable because it does not require refrigeration, is suitable for people two years of age or older, who weigh 20 kg or more and are able to swallow without the use of a feeding tube. Research can also 'switch off' the production of toxic proteins in rare neuropathies. In this area, there are promising results with RNA for sarcoglycanopathies, which affect the pelvic and scapular girdle muscles, with infantile-adolescent onset, progressive weakness and possible respiratory and cardiac involvement.

For diseases such as Myasthenia Gravis or immune-mediated neuropathies, the problem is the immune system attacking the body. The latest generation of monoclonal antibody drugs act like precision switches: they block inflammation or eliminate 'crazed' antibodies without weakening the entire immune system as the old cortisone drugs did. "Neuromuscular diseases represent a complex clinical and organisational challenge. The effectiveness of such advanced drugs is strictly dependent on the quality of care. The therapeutic revolution only makes sense if it is accompanied by early diagnosis, as in neonatal screening, since many of these drugs perform best when administered before muscle damage is irreversible. Furthermore, a multidisciplinary approach is essential. These therapies require management involving neurologists, physiatrists, psychologists and specialist nurses, to ensure that the patient receives not only the drug, but a full course of treatment, including rehabilitation,' conclude Schenone and Toscano.