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 language | English (US) |
|---|---|
| Pages (from-to) | 4817-4831 |
| Number of pages | 15 |
| Journal | Journal of Clinical Investigation |
| Volume | 129 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2019 |
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ASJC Scopus subject areas
- Medicine(all)
Cite this
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 journal › Article
}
TY - JOUR
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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UR - http://www.scopus.com/inward/citedby.url?scp=85074379239&partnerID=8YFLogxK
U2 - 10.1172/JCI124120
DO - 10.1172/JCI124120
M3 - Article
C2 - 31589162
AN - SCOPUS:85074379239
VL - 129
SP - 4817
EP - 4831
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 11
ER -