@article{84ce891654c64027bae45b2f69d809df,
title = "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 drug-induced 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. FUNDING. SMA Foundation, SMART, NIH (R01-NS096770, R01-NS062869), Ionis Pharmaceuticals, and PTC Therapeutics. Biogen provided support for absolute real-time RT-PCR.",
author = "Ramos, {Daniel M.} and Constantin d{\textquoteright}Ydewalle and Vijayalakshmi Gabbeta and Amal Dakka and Klein, {Stephanie K.} and Norris, {Daniel A.} and John Matson and Taylor, {Shannon J.} and Zaworski, {Phillip G.} and Prior, {Thomas W.} and Snyder, {Pamela J.} and David Valdivia and Hatem, {Christine L.} and Ian Waters and Nikhil Gupte and Swoboda, {Kathryn J.} and Frank Rigo and {Frank Bennett}, C. and Nikolai Naryshkin and Sergey Paushkin and Crawford, {Thomas O.} and Sumner, {Charlotte J.}",
note = "Funding Information: We would like to express our profound gratitude for the generosity and altruism of donors and their families, whose gifts of organs and tissues serve an integral role in advancing medical research and education, as well as our colleagues who referred patients, including Kathryn J. Swoboda, John Brandsema, Gihan Tenne-koon, Samiah Al-Zaidy, Richard Shell, Nancy Kuntz, and Christine DiDonato, among others. We also thank the numerous pathologists with whom we have worked, including Jody Hooper, who leads the rapid autopsy program at Johns Hopkins, and Brian Harding at Children{\textquoteright}s Hospital of Philadelphia. Additionally, we would like to thank Kathleen Smart at Children{\textquoteright}s National Hospital for aid in program coordination. We also acknowledge the support of The Living Legacy Foundation of Maryland, the organization that works with donor families to honor their loved ones through the donation of organs and tissue for transplantation, education, and research. Some human tissues were received from the NIH Neu-roBioBank at the University of Maryland (Baltimore, Maryland, USA). This work was supported by funding to CJS from the SMA Foundation, SMART, the NIH (R01-NS096770, R01-NS062869), Ionis, and PTC Therapeutics. KJS receives grant support from the NIH. Biogen provided support for absolute SMN2 mRNA quantitation and absolute real-time RT-PCR. Funding Information: Conflict of interest: VG, AD, and NN are employees of PTC Therapeutics. SKK, DAN, JM, FR, and CFB are employees of Ionis Pharmaceuticals. CFB holds a patent covering nusinersen licensed to Biogen (8980853). KJS receives grant support from Biogen and Cure SMA. CJS served as a paid advisor, consultant, and/or speaker to the SMA Foundation, Biogen, Ionis Pharmaceuticals, PTC Therapeutics, Roche/Genentech, AveXis, Cytokinetics, and Pfizer and is an associate editor for the JCI. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Copyright: {\textcopyright} 2019, American Society for Clinical Investigation. Submitted: August 10, 2018; Accepted: August 7, 2019; Published: October 7, 2019. Reference information: J Clin Invest. 2019;129(11):4817–4831. https://doi.org/10.1172/JCI124120. Funding Information: We would like to express our profound gratitude for the generosity and altruism of donors and their families, whose gifts of organs and tissues serve an integral role in advancing medical research and education, as well as our colleagues who referred patients, including Kathryn J. Swoboda, John Brandsema, Gihan Tennekoon, Samiah Al-Zaidy, Richard Shell, Nancy Kuntz, and Christine DiDonato, among others. We also thank the numerous pathologists with whom we have worked, including Jody Hooper, who leads the rapid autopsy program at Johns Hopkins, and Brian Harding at Children?s Hospital of Philadelphia. Additionally, we would like to thank Kathleen Smart at Children?s National Hospital for aid in program coordination. We also acknowledge the support of The Living Legacy Foundation of Maryland, the organization that works with donor families to honor their loved ones through the donation of organs and tissue for transplantation, education, and research. Some human tissues were received from the NIH NeuroBioBank at the University of Maryland (Baltimore, Maryland, USA). This work was supported by funding to CJS from the SMA Foundation, SMART, the NIH (R01-NS096770, R01-NS062869), Ionis, and PTC Therapeutics. KJS receives grant support from the NIH. Biogen provided support for absolute SMN2mRNA quantitation and absolute real-time RT-PCR. Publisher Copyright: {\textcopyright} 2019, American Society for Clinical Investigation. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",
year = "2019",
month = nov,
day = "1",
doi = "10.1172/JCI124120",
language = "English (US)",
volume = "129",
pages = "4817--4831",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "11",
}