Abstract
Neurotrophic factors as candidates for ALS therapeutics have previously been studied in the context of attempts to slow disease progression. For a variety of reasons, clinical trials of neurotrophic factors have failed to show efficacy in ALS patients. Previous studies in Parkinson's Disease (PD) models have shown promise with the use of recombinant adeno-associated virus serotype-2 (rAAV2)-neurturin (NRTN) [AAV2-NRTN] providing neuroprotection and behavioral improvements in preclinical models which subsequently resulted in several clinical studies in patients with PD. Given that this neurotrophic compound has not been studied in the context of ALS, we conducted a study of AAV2-NRTN to assess the preclinical safety, tolerability, biodistribution, and efficacy of this compound in an ALS mouse model. SOD1G93A mice were injected with AAV2-NRTN intraspinally at several doses into the cervical spinal cord at 60 days of age. NRTN expression was noted in motor neurons (MNs) of the targeted cervical spinal cord as well as in their neuromuscular junction projections but not in the lumbar spinal cord, which was not targeted. Neuropathologically, a dose-dependent neuroprotective effect was seen in cervical MNs and neuromuscular junctions that was reflected in a slowing of forelimb grip strength decline. As expected, this neuroprotection was found to be focal and was not seen beyond the immediate region of injection. Overall, there were no increases in morbidity, changes in serum chemistries or blood counts and no cases of drug-related mortality. Because there is a broad clinical experience for this compound, these data provide evidence to support further investigation of AAV2-NRTN as a potential ALS therapeutic.
| Original language | English (US) |
|---|---|
| Article number | 113091 |
| Journal | Experimental Neurology |
| Volume | 323 |
| DOIs | |
| State | Published - Jan 2020 |
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Keywords
- Amyotrophic lateral sclerosis
- Gene therapy
- Neurodegeneration
- Neuroprotection
- Viral vector
ASJC Scopus subject areas
- Neurology
- Developmental Neuroscience
Cite this
Focal and dose-dependent neuroprotection in ALS mice following AAV2-neurturin delivery. / Gross, Sarah K.; Shim, Bo Sung; Bartus, Raymond T.; Deaver, Dan; McEachin, Zachary; Bétourné, Alexandre; Boulis, Nicholas M.; Maragakis, Nicholas J.
In: Experimental Neurology, Vol. 323, 113091, 01.2020.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Focal and dose-dependent neuroprotection in ALS mice following AAV2-neurturin delivery
AU - Gross, Sarah K.
AU - Shim, Bo Sung
AU - Bartus, Raymond T.
AU - Deaver, Dan
AU - McEachin, Zachary
AU - Bétourné, Alexandre
AU - Boulis, Nicholas M.
AU - Maragakis, Nicholas J.
PY - 2020/1
Y1 - 2020/1
N2 - Neurotrophic factors as candidates for ALS therapeutics have previously been studied in the context of attempts to slow disease progression. For a variety of reasons, clinical trials of neurotrophic factors have failed to show efficacy in ALS patients. Previous studies in Parkinson's Disease (PD) models have shown promise with the use of recombinant adeno-associated virus serotype-2 (rAAV2)-neurturin (NRTN) [AAV2-NRTN] providing neuroprotection and behavioral improvements in preclinical models which subsequently resulted in several clinical studies in patients with PD. Given that this neurotrophic compound has not been studied in the context of ALS, we conducted a study of AAV2-NRTN to assess the preclinical safety, tolerability, biodistribution, and efficacy of this compound in an ALS mouse model. SOD1G93A mice were injected with AAV2-NRTN intraspinally at several doses into the cervical spinal cord at 60 days of age. NRTN expression was noted in motor neurons (MNs) of the targeted cervical spinal cord as well as in their neuromuscular junction projections but not in the lumbar spinal cord, which was not targeted. Neuropathologically, a dose-dependent neuroprotective effect was seen in cervical MNs and neuromuscular junctions that was reflected in a slowing of forelimb grip strength decline. As expected, this neuroprotection was found to be focal and was not seen beyond the immediate region of injection. Overall, there were no increases in morbidity, changes in serum chemistries or blood counts and no cases of drug-related mortality. Because there is a broad clinical experience for this compound, these data provide evidence to support further investigation of AAV2-NRTN as a potential ALS therapeutic.
AB - Neurotrophic factors as candidates for ALS therapeutics have previously been studied in the context of attempts to slow disease progression. For a variety of reasons, clinical trials of neurotrophic factors have failed to show efficacy in ALS patients. Previous studies in Parkinson's Disease (PD) models have shown promise with the use of recombinant adeno-associated virus serotype-2 (rAAV2)-neurturin (NRTN) [AAV2-NRTN] providing neuroprotection and behavioral improvements in preclinical models which subsequently resulted in several clinical studies in patients with PD. Given that this neurotrophic compound has not been studied in the context of ALS, we conducted a study of AAV2-NRTN to assess the preclinical safety, tolerability, biodistribution, and efficacy of this compound in an ALS mouse model. SOD1G93A mice were injected with AAV2-NRTN intraspinally at several doses into the cervical spinal cord at 60 days of age. NRTN expression was noted in motor neurons (MNs) of the targeted cervical spinal cord as well as in their neuromuscular junction projections but not in the lumbar spinal cord, which was not targeted. Neuropathologically, a dose-dependent neuroprotective effect was seen in cervical MNs and neuromuscular junctions that was reflected in a slowing of forelimb grip strength decline. As expected, this neuroprotection was found to be focal and was not seen beyond the immediate region of injection. Overall, there were no increases in morbidity, changes in serum chemistries or blood counts and no cases of drug-related mortality. Because there is a broad clinical experience for this compound, these data provide evidence to support further investigation of AAV2-NRTN as a potential ALS therapeutic.
KW - Amyotrophic lateral sclerosis
KW - Gene therapy
KW - Neurodegeneration
KW - Neuroprotection
KW - Viral vector
UR - http://www.scopus.com/inward/record.url?scp=85074687813&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85074687813&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2019.113091
DO - 10.1016/j.expneurol.2019.113091
M3 - Article
C2 - 31678350
AN - SCOPUS:85074687813
VL - 323
JO - Experimental Neurology
JF - Experimental Neurology
SN - 0014-4886
M1 - 113091
ER -