nusinersen and Nervous-System-Diseases

The last few decades have seen an explosion in identification of genes that cause monogenetic neurological diseases, as well as advances in gene-targeting therapeutics. Neurological conditions that were once considered incurable are now increasingly tractable. At the forefront is the motor neuron disease spinal muscular atrophy (SMA), historically the leading inherited cause of infant mortality. In the last 5 years, three SMA treatments have been approved by the US Food and Drug Administration (FDA): intrathecally delivered splice-switching antisense oligonucleotide (nusinersen), systemically delivered AAV9-based gene replacement therapy (onasemnogene abeparvovec), and an orally bioavailable, small-molecule, splice-switching drug (risdiplam). Despite this remarkable progress, clinical outcomes in patients are variable. Therapeutic optimization will require improved understanding of drug pharmacokinetics and target engagement in neurons, potential toxicities, and long-term effects. We review current progress in SMA therapeutics, clinical trials, shortcomings of current treatments, and implications for the treatment of other neurogenetic diseases.

Topics: Genetic Therapy; Humans; Muscular Atrophy, Spinal; Nervous System Diseases; Oligonucleotides

Gene regulation is the term used to describe the mechanisms by which a cell increases or decreases the amount of a gene product (RNA or protein). In complex organs such as the brain, gene regulation is of the utmost importance; aberrations in the regulation of specific genes can lead to neurological disorders. Understanding these mechanisms can create new strategies for targeting these disorders and progress is being made. Two drugs that function at the RNA level (nusinersen and eteplirsen) have now been approved by the FDA for the treatment of Spinomuscular atrophy and Duchenne muscular dystrophy, respectively; several other compounds for neurological disease are currently being investigated in preclinical studies and clinical trials. Areas covered: We highlight how gene regulation at the level of RNA molecules can be used as a therapeutic strategy to treat neurological disorders. We provide examples of how such an approach is being studied or used and discuss the current hurdles. Expert opinion: Targeting gene expression at the RNA level is a promising strategy to treat genetic neurological disorders. Safe administration, long-term efficacy, and potential side effects, however, still need careful evaluation before RNA therapeutics can be applied on a larger scale.

Topics: Animals; Drug Development; Gene Expression Regulation; Humans; Morpholinos; Nervous System Diseases; Oligonucleotides; RNA

Spinal muscular atrophy type 0 is the most severe phenotype of the disease, with patients presenting with contractures, weakness, and respiratory failure at birth, and is typically fatal within weeks. We describe the case of a patient with spinal muscular atrophy type 0 who was treated with both nusinersen and onasemnogene abeparvovec. She has made modest motor improvements since treatment initiation with a 30-point improvement in CHOP-INTEND score, and continues to make motor gains at age 13 months without regression of function, although she remains profoundly weak. Although she has had motor improvements, she has also had continued systemic complications from her spinal muscular atrophy, including chronic respiratory failure, dysphagia, congenital heart malformation, digit necrosis, and diffuse macular rash. This case highlights the challenges in treating those with more severe disease phenotypes and raises questions of how some systemic complications may respond to current SMN replacement therapies.

Topics: Biological Products; Female; Heart Diseases; Humans; Infant, Newborn; Nervous System Diseases; Nutritional Support; Oligonucleotides; Osteomyelitis; Recombinant Fusion Proteins; Respiration Disorders; Skin Diseases; Spinal Muscular Atrophies of Childhood; Treatment Outcome