Abstract
Using a canine model of classical late-infantile neuronal ceroid lipofuscinosis (CLN2 disease), a study was conducted to evaluate the potential pharmacological activity of recombinant human tripeptidyl peptidase-1 (rhTPP1) enzyme replacement therapy administered directly to the cerebrospinal fluid (CSF). CLN2 disease is a hereditary neurodegenerative disorder resulting from mutations in CLN2, which encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Infants with mutations in both CLN2 alleles develop normally but in the late-infantile/early-childhood period undergo progressive neurological decline accompanied by pronounced brain atrophy. The disorder, a form of Batten disease, is uniformly fatal, with clinical signs starting between 2 and 4 years of age and death usually occurring by the early teenage years. Dachshunds homozygous for a null mutation in the canine ortholog of CLN2 (TPP1) exhibit a similar disorder that progresses to end stage at 10.5-11 months of age. Administration of rhTPP1 via infusion into the CSF every other week, starting at approximately 2.5 months of age, resulted in dose-dependent significant delays in disease progression, as measured by delayed onset of neurologic deficits, improved performance on a cognitive function test, reduced brain atrophy, and increased life span. Based on these findings, a clinical study evaluating the potential therapeutic value of rhTPP1 administration into the CSF of children with CLN2 disease has been initiated.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1591-1598 |
| Number of pages | 8 |
| Journal | Journal of Neuroscience Research |
| Volume | 92 |
| Issue number | 11 |
| DOIs | |
| State | Published - Jan 1 2014 |
| Externally published | Yes |
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Keywords
- Batten disease
- Cerebrospinal fluid
- CLN2
- Dachshund
- Lysosomal storage disease
- NCL
- TPP1
- Tripeptidyl peptidase-1
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
Cite this
Enzyme replacement therapy attenuates disease progression in a canine model of late-infantile neuronal ceroid lipofuscinosis (CLN2 disease). / Katz, Martin L.; Coates, Joan R.; Toedebusch, Christine; Taylor, Jacob D.; Carpentier, Melissa; Young, Whitney M.; Wininger, Fred A.; Kennedy, Derek; Vuillemenot, Brian R.; O'Neill, Charles A.
In: Journal of Neuroscience Research, Vol. 92, No. 11, 01.01.2014, p. 1591-1598.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Enzyme replacement therapy attenuates disease progression in a canine model of late-infantile neuronal ceroid lipofuscinosis (CLN2 disease)
AU - Katz, Martin L.
AU - Coates, Joan R.
AU - Toedebusch, Christine
AU - Taylor, Jacob D.
AU - Carpentier, Melissa
AU - Young, Whitney M.
AU - Wininger, Fred A.
AU - Kennedy, Derek
AU - Vuillemenot, Brian R.
AU - O'Neill, Charles A.
PY - 2014/1/1
Y1 - 2014/1/1
N2 - Using a canine model of classical late-infantile neuronal ceroid lipofuscinosis (CLN2 disease), a study was conducted to evaluate the potential pharmacological activity of recombinant human tripeptidyl peptidase-1 (rhTPP1) enzyme replacement therapy administered directly to the cerebrospinal fluid (CSF). CLN2 disease is a hereditary neurodegenerative disorder resulting from mutations in CLN2, which encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Infants with mutations in both CLN2 alleles develop normally but in the late-infantile/early-childhood period undergo progressive neurological decline accompanied by pronounced brain atrophy. The disorder, a form of Batten disease, is uniformly fatal, with clinical signs starting between 2 and 4 years of age and death usually occurring by the early teenage years. Dachshunds homozygous for a null mutation in the canine ortholog of CLN2 (TPP1) exhibit a similar disorder that progresses to end stage at 10.5-11 months of age. Administration of rhTPP1 via infusion into the CSF every other week, starting at approximately 2.5 months of age, resulted in dose-dependent significant delays in disease progression, as measured by delayed onset of neurologic deficits, improved performance on a cognitive function test, reduced brain atrophy, and increased life span. Based on these findings, a clinical study evaluating the potential therapeutic value of rhTPP1 administration into the CSF of children with CLN2 disease has been initiated.
AB - Using a canine model of classical late-infantile neuronal ceroid lipofuscinosis (CLN2 disease), a study was conducted to evaluate the potential pharmacological activity of recombinant human tripeptidyl peptidase-1 (rhTPP1) enzyme replacement therapy administered directly to the cerebrospinal fluid (CSF). CLN2 disease is a hereditary neurodegenerative disorder resulting from mutations in CLN2, which encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Infants with mutations in both CLN2 alleles develop normally but in the late-infantile/early-childhood period undergo progressive neurological decline accompanied by pronounced brain atrophy. The disorder, a form of Batten disease, is uniformly fatal, with clinical signs starting between 2 and 4 years of age and death usually occurring by the early teenage years. Dachshunds homozygous for a null mutation in the canine ortholog of CLN2 (TPP1) exhibit a similar disorder that progresses to end stage at 10.5-11 months of age. Administration of rhTPP1 via infusion into the CSF every other week, starting at approximately 2.5 months of age, resulted in dose-dependent significant delays in disease progression, as measured by delayed onset of neurologic deficits, improved performance on a cognitive function test, reduced brain atrophy, and increased life span. Based on these findings, a clinical study evaluating the potential therapeutic value of rhTPP1 administration into the CSF of children with CLN2 disease has been initiated.
KW - Batten disease
KW - Cerebrospinal fluid
KW - CLN2
KW - Dachshund
KW - Lysosomal storage disease
KW - NCL
KW - TPP1
KW - Tripeptidyl peptidase-1
UR - http://www.scopus.com/inward/record.url?scp=84906326721&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84906326721&partnerID=8YFLogxK
U2 - 10.1002/jnr.23423
DO - 10.1002/jnr.23423
M3 - Article
C2 - 24938720
AN - SCOPUS:84906326721
VL - 92
SP - 1591
EP - 1598
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
SN - 0360-4012
IS - 11
ER -