Abstract
Intrathecal (IT) gene transfer using adeno-associated virus (AAV) may be clinically promising as a treatment for chronic pain if it can produce sufficiently high levels of a transgene product in the cerebrospinal fluid (CSF). Although this strategy was developed in rodents, no studies investigating CSF levels of an analgesic or antiallodynic protein delivered by IT AAV have been performed in large animals. Interleukin-10 (IL-10) is an antiallodynic cytokine for which target therapeutic levels have been established in rats. The present study tested IT AAV8 encoding either human IL-10 (hIL-10) or enhanced green fluorescent protein (EGFP) in a dog model of IT drug delivery. AAV8/hIL-10 at a dose of 3.5 × 10 12 genome copies induced high hIL-10 levels in the CSF, exceeding the target concentration previously found to be antiallodynic in rodents by >1000-fold. AAV8/EGFP targeted the primary sensory and motor neurons and the meninges. hIL-10, a xenogeneic protein in dogs, induced anti-hIL-10 antibodies detectable in the CSF and serum of dogs. The high hIL-10 levels demonstrate the efficacy of AAV for delivery of secreted transgenes into the IT space of large animals, suggesting a strong case for further development toward clinical testing.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 202-208 |
| Number of pages | 7 |
| Journal | Gene Therapy |
| Volume | 22 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 7 2015 |
Fingerprint
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
Cite this
High cerebrospinal fluid levels of interleukin-10 attained by AAV in dogs. / Pleticha, J.; Malkmus, S. A.; Heilmann, L. F.; Veesart, S. L.; Rezek, R.; Xu, Q.; Yaksh, T. L.; Beutler, Andreas S.
In: Gene Therapy, Vol. 22, No. 2, 07.02.2015, p. 202-208.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - High cerebrospinal fluid levels of interleukin-10 attained by AAV in dogs
AU - Pleticha, J.
AU - Malkmus, S. A.
AU - Heilmann, L. F.
AU - Veesart, S. L.
AU - Rezek, R.
AU - Xu, Q.
AU - Yaksh, T. L.
AU - Beutler, Andreas S
PY - 2015/2/7
Y1 - 2015/2/7
N2 - Intrathecal (IT) gene transfer using adeno-associated virus (AAV) may be clinically promising as a treatment for chronic pain if it can produce sufficiently high levels of a transgene product in the cerebrospinal fluid (CSF). Although this strategy was developed in rodents, no studies investigating CSF levels of an analgesic or antiallodynic protein delivered by IT AAV have been performed in large animals. Interleukin-10 (IL-10) is an antiallodynic cytokine for which target therapeutic levels have been established in rats. The present study tested IT AAV8 encoding either human IL-10 (hIL-10) or enhanced green fluorescent protein (EGFP) in a dog model of IT drug delivery. AAV8/hIL-10 at a dose of 3.5 × 10 12 genome copies induced high hIL-10 levels in the CSF, exceeding the target concentration previously found to be antiallodynic in rodents by >1000-fold. AAV8/EGFP targeted the primary sensory and motor neurons and the meninges. hIL-10, a xenogeneic protein in dogs, induced anti-hIL-10 antibodies detectable in the CSF and serum of dogs. The high hIL-10 levels demonstrate the efficacy of AAV for delivery of secreted transgenes into the IT space of large animals, suggesting a strong case for further development toward clinical testing.
AB - Intrathecal (IT) gene transfer using adeno-associated virus (AAV) may be clinically promising as a treatment for chronic pain if it can produce sufficiently high levels of a transgene product in the cerebrospinal fluid (CSF). Although this strategy was developed in rodents, no studies investigating CSF levels of an analgesic or antiallodynic protein delivered by IT AAV have been performed in large animals. Interleukin-10 (IL-10) is an antiallodynic cytokine for which target therapeutic levels have been established in rats. The present study tested IT AAV8 encoding either human IL-10 (hIL-10) or enhanced green fluorescent protein (EGFP) in a dog model of IT drug delivery. AAV8/hIL-10 at a dose of 3.5 × 10 12 genome copies induced high hIL-10 levels in the CSF, exceeding the target concentration previously found to be antiallodynic in rodents by >1000-fold. AAV8/EGFP targeted the primary sensory and motor neurons and the meninges. hIL-10, a xenogeneic protein in dogs, induced anti-hIL-10 antibodies detectable in the CSF and serum of dogs. The high hIL-10 levels demonstrate the efficacy of AAV for delivery of secreted transgenes into the IT space of large animals, suggesting a strong case for further development toward clinical testing.
UR - http://www.scopus.com/inward/record.url?scp=84922397857&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84922397857&partnerID=8YFLogxK
U2 - 10.1038/gt.2014.96
DO - 10.1038/gt.2014.96
M3 - Article
C2 - 25354684
AN - SCOPUS:84922397857
VL - 22
SP - 202
EP - 208
JO - Gene Therapy
JF - Gene Therapy
SN - 0969-7128
IS - 2
ER -