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

• Published in: The Journal of clinical investigation Vol. 129; no. 11; pp. 4817 - 4831
• Main Authors: Ramos, Daniel M, d'Ydewalle, Constantin, Gabbeta, Vijayalakshmi, Dakka, Amal, Klein, Stephanie K, Norris, Daniel A, Matson, John, Taylor, Shannon J, Zaworski, Phillip G, Prior, Thomas W, Snyder, Pamela J, Valdivia, David, Hatem, Christine L, Waters, Ian, Gupte, Nikhil, Swoboda, Kathryn J, Rigo, Frank, Bennett, C Frank, Naryshkin, Nikolai, Paushkin, Sergey, Crawford, Thomas O, Sumner, Charlotte J
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.11.2019
• Subjects: Age; Antisense oligonucleotides; Atrophy; Bioavailability; Biomedical research; Brain; Clinical Medicine; Disease; FDA approval; Genes; Medical screening; Messenger RNA; Motor units; mRNA; Muscular atrophy; Neuromuscular diseases; Neurons; Nusinersen; Patients; Pregnant women; Protein folding; Proteins; Retirement benefits; RNA; Scientific equipment industry; SMN protein; Spinal cord; Spinal muscular atrophy; Thorax; United States; Maryland; Argentina; Development; Neurodevelopment; Neuromuscular disease; Neuroscience; Neurodegeneration
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI124120

BACKGROUNDSpinal 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 drug-induced SMN levels in disease-relevant tissues hinders efforts to optimize these treatments.METHODSSMN mRNA and protein levels were quantified in human tissues isolated during expedited autopsies.RESULTSSMN 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.CONCLUSIONSA 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.FUNDINGSMA Foundation, SMART, NIH (R01-NS096770, R01-NS062869), Ionis Pharmaceuticals, and PTC Therapeutics. Biogen provided support for absolute real-time RT-PCR.