Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment

Abstract

BACKGROUND. Spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein. New SMN-enhancing therapeutics are associated with variable clinical benefits. Limited knowledge of baseline and druginduced SMN levels in disease-relevant tissues hinders efforts to optimize these treatments. METHODS. SMN mRNA and protein levels were quantified in human tissues isolated during expedited autopsies. RESULTS. SMN protein expression varied broadly among prenatal control spinal cord samples, but was restricted at relatively low levels in controls and SMA patients after 3 months of life. A 2.3-fold perinatal decrease in median SMN protein levels was not paralleled by comparable changes in SMN mRNA. In tissues isolated from nusinersen-treated SMA patients, antisense oligonucleotide (ASO) concentration and full-length (exon 7 including) SMN2 (SMN2-FL) mRNA level increases were highest in lumbar and thoracic spinal cord. An increased number of cells showed SMN immunolabeling in spinal cord of treated patients, but was not associated with an increase in whole-tissue SMN protein levels. CONCLUSIONS. A normally occurring perinatal decrease in whole-tissue SMN protein levels supports efforts to initiate SMN-inducing therapies as soon after birth as possible. Limited ASO distribution to rostral spinal and brain regions in some patients likely limits clinical response of motor units in these regions for those patients. These results have important implications for optimizing treatment of SMA patients and warrant further investigations to enhance bioavailability of intrathecally administered ASOs.

Pre-natal manifestation of systemic developmental abnormalities in spinal muscular atrophy

“…Combining μCT with these results, we present evidence suggesting that SMN depletion leads to a range of morphological and molecular developmental perturbations in SMA, manifesting in advance of the onset of degenerative neuromuscular symptoms commonly associated with the disease. It has long been known that SMN levels are higher prenatally than postnatally ( 8 , 39 ). Our findings therefore provide experimental support for the hypothesis that high levels of SMN during development highlight a strong requirement for the protein during prenatal stages of development and may help to explain, at least in part, some of the systemic alterations observed in SMA pathology ( 22 ).…”

Newborn Screening for SMA - Results After Two Years of a Large Pilot Project 

“…NBS avoided a diagnostic delay which otherwise still is the rule 25,26 . Since SMN expression is highest prenatally 5 , it is reasonable that motor neuron death already occurs to some extent before birth. Our electrophysiological data (Fig.…”

“…Reduced levels of SMN protein result in motor neuron death in the spinal cord. Expression of SMN protein in spinal cord samples is highest during early stages of development 5 . In humans there is a paralogous gene termed SMN2 that differs from SMN1 by only a few nucleotides.…”

The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration

“…Antisense oligonucleotides (ASOs) are chemically modified single-stranded nucleic acids of [16][17][18][19][20][21][22][23][24][25] nucleotides in length that bind complementary RNA via Watson-Crick hybridization and can modulate the expression of genes by harnessing a variety of mechanisms (1). To reduce the expression of genes, ASOs can be designed to harness the RNase H1 mechanism (referred to herein as gapmers) (2).…”

“…In clinical trials for Spinraza, a uniform MOE SMN splicing ASO developed for the treatment of SMA, intrathecal delivery resulted in the accumulation of the ASO in neurons and glial cells in the spinal cord and cortex obtained at autopsy. In addition, there was a robust increase in SMN2 mRNA and SMN protein levels in spinal cord and cortex (25). Spinraza showed substantial efficacy in clinical trials, improving motor function and prolonging survival of SMA infants (26), and became the first centrally administered ASO approved for human use (27).…”