This new era is characterized by a paradigm shift from symptomatic management to targeted disease-modifying therapies. With the emergence of gene replacement strategies, antisense oligonucleotides and RNA modulating agents, we can now intervene at the molecular level to alter the natural history of diseases such as spinal muscular atrophy, Duchenne muscular dystrophy and certain genetic forms of amyotrophic lateral sclerosis...
This new era is characterized by a paradigm shift from symptomatic management to targeted disease-modifying therapies. With the emergence of gene replacement strategies, antisense oligonucleotides and RNA modulating agents, we can now intervene at the molecular level to alter the natural history of diseases such as spinal muscular atrophy, Duchenne muscular dystrophy and certain genetic forms of amyotrophic lateral sclerosis. This approach aims to either restore gene function or silence pathogenic variants. In SMA the introduction of gene therapy with onasemnogene abeparvovec, a one-time systemic delivery of SMN1 via AAV vector has been really transformative, particularly in presymptomatic infants. Nusinersen, that is an intrathecal ASO that promotes exon 7 inclusion in SMN2 transcripts, was the first disease-modifying treatment approved and remains widely used today. For DMD, exon skipping ASOs like eteplirsen or viltolarsen have demonstrated dystrophin restoration in muscle biopsy. So long-term functional benefit is still under evaluation to date. In ALS, for example, tofersen targets SOD1 mutations and has shown promise in slowing neurofilament light chain elevation, a potential biomarker for disease progression. So many drugs are in this moment in use for some of our neuromuscular diseases. The impact is very significant, especially when therapy is started early. For instance, SMA patients treated in infancy sometimes can reach motor milestones that were previously impossible to reach, like sitting or even walking. In the DMD, while therapies don’t cure the disease to date, they can slow muscle degeneration and delay the loss of ambulation. In ALS, new therapies targeting specific gene mutations are showing early signs of slowing disease progression.
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