Scientists have reported that a combinatorial therapy of antisense oligonucleotide (ASO) mediated therapy and low dose SMN with the protective modifier Chp1 is unable to significantly decrease the key pathological features of spinal muscular atrophy (SMA), as published in the Neurobiology of Disease.

SMA is a progressive neurodegenerative disorder that often results in early death. Ever since the genetics underpinning the disease were discovered, scientists have been pursuing various therapeutic strategies to ameliorate the disease. For example, some have proposed that the downregulation of Chp1 can ameliorate features of SMA. This is because CHP1 levels are higher in the brain and spinal cord of mouse models with severe SMA.

“Furthermore, crossing heterozygous Chp1 deficient mice . . . with the severely-affected SMA mouse model in addition to a systemic low-dose SMN-ASO administration immediately after birth, ameliorated disease hallmarks such as electrophysiology markers, neuromuscular junction size and maturity and reduced number of proprioceptive synapses per [motoneuron] soma,” the authors of the study wrote.

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They aimed to further investigate the therapeutic potential of downregulating Chp1 via the injection of Chp1-ASO in the central nervous system of presymptomatic SMA mice, together with the systemic administration of a suboptimal dose of SMN-ASO. Chp1 has a narrow therapeutic window in which it exerts its protective effects, causing difficulties in the development of combinatorial therapy.

The main finding of this study is that the combinatorial therapy using Chp1-ASO4 and low-dose SMN-ASO failed the ameliorate disease pathology in adult SMA mice in the long term. This stands in contrast with previous studies that suggest that this combinatorial therapy can relieve SMA pathology.

“Nonetheless, genetic modifiers represent promising therapeutic targets when successfully modulated and help researchers to decipher molecular mechanisms altered in SMA,” the authors concluded.


Muinos-Bühl A, Rombo R, Janzen E, et al. Combinatorial ASO-mediated therapy with low dose SMN and the protective modifier Chp1 is not sufficient to ameliorate SMA pathology hallmarksNeurobiol Dis. 2022;171:105795. doi:10.1016/j.nbd.2022.105795