Outside of survival motor neuron (SMN) treatment, there are several alternatives used in cases where SMN approaches are not appropriate for treating spinal muscular atrophy (SMA).
Although survival motor neuron (SMN) approaches like nusinersen and onasemnogene abeparvovec have become a cornerstone of spinal muscular atrophy (SMA) treatment, there are cases in which the approaches are not viable, resulting in a need for alternative treatment strategies.
Outside of SMN, there are several alternatives used in cases where SMN approaches are not appropriate, including when patients, particularly at a later symptomatic stage, cannot receive the therapy in the ideal time window, resulting in insufficient recovery and remaining or progressing symptoms. There are also cases in which non-SMN approaches can complement SMN approaches when presymptomatic patients do not respond adequately to SMN-based treatment.
Findings were published in Neurological Research and Practice.
Alternative approaches include those that target the neuromuscular endplate, such as R-Roscovitine and GV-58, both calcium channel openers that have shown potential, in murine models, for improving motoneuron survival and life span, counteracting the degeneration of neuromuscular endplates, and benefitting neuromuscular transmission and muscle strength.
“Neuromuscular endplates are severely affected in SMA. Not only reduced acetylcholine release, but also altered signaling mechanisms between motoneuron and muscle contribute to a degenerative process that ultimately results in muscle atrophy,” explained the researchers. “Counteracting such signaling defects depends on (1) proper initial development of the neuromuscular endplates, including the presynaptic structures for controlled vesicle release, and (2) homeostatic mechanisms that maintain axons and presynaptic terminals in motoneurons.”
Another non-SMN approach has focused on neuroprotection, as neurotrophic factor contributes to motoneuron survival. The researchers outlined several neuroprotection approaches, including the application of brain-derived neurotrophic factor, ciliary neurotrophic factor, and/or glial derived neurotrophic factor to isolated primary motoneurons. The application of these factors, say the researchers, promotes the survival of the motoneurons, upregulates cholinergic differentiation and transmitter production, and results in an increased release of acetylcholine in quantal packets.
Muscle-directed strategies have also been promoted, as it’s been suggested that muscle-autonomous disease mechanisms may contribute to the course of SMA, particularly for patients with SMA type 2 or 3.
“In order to prevent loss of muscle mass, myostatin inhibition has been proposed as an option since this secreted growth/differentiation factor acts as a negative regulator of skeletal muscle fiber growth and size,” commented the researchers. “Myostatin activity is normally inhibited by follistatin and myostatin pro-peptide.”
In initial studies of myostatin inhibition, there were no significant effects in severe cases of disease. Instead, the effects were more pronounced in murine models of more mild cases of disease. According to the researchers, in later stages of SMA, the approach appears to show benefit for motor function and survival in addition to muscle and bone atrophy.
Research has also investigated troponin activator Reldesemtiv (CK-2127107), another modulator of muscle atrophy and diminished muscle strength. In a double-blind, randomized, placebo-controlled phase 2 study, oral use of Reldesemtiv was well tolerated, although it is not yet clear if the approach also improves motor function.
Jablonka S, Hennlein L, Sendtner M. Therapy development for spinal muscular atrophy: perspectives for muscular dystrophies and neurodegenerative disorders. Neurol Res Pract. Published online January 4, 2022. doi:10.1186/s42466-021-00162-9