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

Daniel M. Ramos, Constantin d’Ydewalle, Vijayalakshmi Gabbeta, Amal Dakka, Stephanie K. Klein, Daniel A. Norris, John Matson, Shannon J. Taylor, Phillip G. Zaworski, Thomas W. Prior, Pamela J. Snyder, David Valdivia, Christine L. Hatem, Ian Waters, Nikhil Gupte, Kathryn J. Swoboda, Frank Rigo, C. Frank Bennett, Nikolai Naryshkin, Sergey PaushkinThomas O. Crawford, Charlotte J. Sumner

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)4817-4831
Number of pages15
JournalJournal of Clinical Investigation
Volume129
Issue number11
DOIs
StatePublished - Nov 1 2019

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Spinal Muscular Atrophy
Motor Neurons
Therapeutics
Tissue Survival
Spinal Cord
Proteins
Antisense Oligonucleotides
Messenger RNA
Factor IX
Pharmaceutical Preparations
Biological Availability
Real-Time Polymerase Chain Reaction
Autopsy
Exons
Cell Survival
Thorax
Parturition

ASJC Scopus subject areas

  • Medicine(all)

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Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment. / 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; Frank Bennett, C.; Naryshkin, Nikolai; Paushkin, Sergey; Crawford, Thomas O.; Sumner, Charlotte J.

In: Journal of Clinical Investigation, Vol. 129, No. 11, 01.11.2019, p. 4817-4831.

Research output: Contribution to journalArticle

Ramos, DM, d’Ydewalle, C, Gabbeta, V, Dakka, A, Klein, SK, Norris, DA, Matson, J, Taylor, SJ, Zaworski, PG, Prior, TW, Snyder, PJ, Valdivia, D, Hatem, CL, Waters, I, Gupte, N, Swoboda, KJ, Rigo, F, Frank Bennett, C, Naryshkin, N, Paushkin, S, Crawford, TO & Sumner, CJ 2019, 'Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment', Journal of Clinical Investigation, vol. 129, no. 11, pp. 4817-4831. https://doi.org/10.1172/JCI124120
Ramos DM, d’Ydewalle C, Gabbeta V, Dakka A, Klein SK, Norris DA et al. Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment. Journal of Clinical Investigation. 2019 Nov 1;129(11):4817-4831. https://doi.org/10.1172/JCI124120
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 ; Frank Bennett, C. ; Naryshkin, Nikolai ; Paushkin, Sergey ; Crawford, Thomas O. ; Sumner, Charlotte J. / Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 11. pp. 4817-4831.
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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.",
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T1 - Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment

AU - Ramos, Daniel M.

AU - d’Ydewalle, Constantin

AU - Gabbeta, Vijayalakshmi

AU - Dakka, Amal

AU - Klein, Stephanie K.

AU - Norris, Daniel A.

AU - Matson, John

AU - Taylor, Shannon J.

AU - Zaworski, Phillip G.

AU - Prior, Thomas W.

AU - Snyder, Pamela J.

AU - Valdivia, David

AU - Hatem, Christine L.

AU - Waters, Ian

AU - Gupte, Nikhil

AU - Swoboda, Kathryn J.

AU - Rigo, Frank

AU - Frank Bennett, C.

AU - Naryshkin, Nikolai

AU - Paushkin, Sergey

AU - Crawford, Thomas O.

AU - Sumner, Charlotte J.

PY - 2019/11/1

Y1 - 2019/11/1

N2 - 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.

AB - 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.

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