Characterization of SMA type II skeletal muscle from treated patients shows OXPHOS deficiency and denervation

or several muscle cell types, but not in MNs (11,12).This work strongly suggests that restoring SMN to the muscle is critical for optimal care.Several years ago, SMA treatment underwent a radical transformation, with the approval of 3 different SMN-dependent disease-modifying therapies (1), which revolutionized the life expectancy of patients.However, these treatments remain noncurative.Of these, the most efficacious is the gene therapy onasemnogene abeparvovec (ZOLGENSMA) (13), which is available as a treatment for infants with type I SMA, rendering this previous fatal disease survivable.For those patients who are not eligible for ZOLGENSMA treatment, either because of age of symptom onset, current age, or AAV immunoreactivity, 2 other treatments are available that act on the SMN2 (1) splicing mechanism, nusinersen (Spinraza) and risdiplam (Evrysdi).Both nusinersen and risdiplam are SMN-dependent therapies whose mechanism of action is based on inducing the inclusion of exon 7 in the remaining SMN2 copies (1, 14).While these treatments have been life changing for SMA patients, the road ahead contains challenges for patients and clinicians because the 3 treatments do not always lead to a full restoration or alteration of clinical symptoms, partially due to the need for early treatment, putatively before symptom onset, to fully restore all SMN-related deficiency problems (15,16).This may be partially because the levels of SMN are highest prenatally (17).However, in older children and adults with SMA, which collectively represent twothirds of the SMA population, early gene therapy treatment is not an option, and these patients may need additional SMN-independent therapies to restore function of muscle and other tissues.Type II SMA patients represent approximately 20% of all cases and have an onset of symptoms at between 6 and 18 months, with an unassisted life expectancy of 25 years, which has been vastly improved by the new therapies and supportive care.Most patients achieve sitting milestones, although sometimes with delay, and by clinical definition, these patients generally do not sit or walk independently.They display proximal predominant weakness, especially in the lower limbs, and most, if not all, have scoliosis (18).Due to the age of onset, clinical management includes treatment with risdiplam and nusinersen injections.However, posttreatment challenges remain, including muscle fatigue, limited mobility, and other skeletal problems, such as hip dysplasia and scoliosis (19).Due to the rarity of tissues, there are few molecular studies on the muscle of patients with SMA, especially in those with type II SMA.In this work, we performed a histopathological and molecular characterization of paravertebral muscle from the surgical discards in a small cohort of 8 treated SMA type II patients undergoing spinal surgery for scoliosis as well as 7 non-SMA control individuals.We used RNAseq to characterize their transcriptional profiles and correlate these with muscle histology.