A Novel Porcine Model of CLN2 Batten Disease that Recapitulates Patient Phenotypes
Abstract CLN2 Batten disease is a lysosomal disorder in which pathogenic variants in CLN2 lead to reduced activity in the enzyme tripeptidyl peptidase 1. The disease typically manifests around 2 to 4 years of age with developmental delay, ataxia, seizures, inability to speak and walk, and fatality between 6 and 12 years of age. Multiple Cln2 mouse models exist to better understand the etiology of the disease; however, these models are unable to adequately recapitulate the disease due to differences in anatomy and physiology, limiting their utility for therapeutic testing. Here, we describe a new CLN2R208X/R208X porcine model of CLN2 disease. We present comprehensive characterization showing behavioral, pathological, and visual phenotypes that recapitulate those seen in CLN2 patients. CLN2R208X/R208X miniswine present with gait abnormalities at 6 months of age, ERG waveform declines at 6–9 months, vision loss at 11 months, cognitive declines at 12 months, seizures by 15 months, and early death at 18 months due to failure to thrive. CLN2R208X/R208X miniswine also showed classic storage material accumulation and glial activation in the brain at 6 months, and cortical atrophy at 12 months. Thus, the CLN2R208X/R208X miniswine model is a valuable resource for biomarker discovery and therapeutic development in CLN2 disease..
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
|---|---|
| Enthalten in: |
NeuroRX - 19(2022), 6 vom: 13. Sept., Seite 1905-1919 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Swier, Vicki J. [VerfasserIn] |
|---|
| Links: |
Volltext [lizenzpflichtig] |
|---|
| Themen: |
CLN2 Batten disease |
|---|
| Anmerkungen: |
© The American Society for Experimental Neurotherapeutics, Inc. 2022. Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
|---|
| doi: |
10.1007/s13311-022-01296-7 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
SPR048811971 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | SPR048811971 | ||
| 003 | DE-627 | ||
| 005 | 20230913064715.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 221206s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s13311-022-01296-7 |2 doi | |
| 035 | |a (DE-627)SPR048811971 | ||
| 035 | |a (SPR)s13311-022-01296-7-e | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Swier, Vicki J. |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A Novel Porcine Model of CLN2 Batten Disease that Recapitulates Patient Phenotypes |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a © The American Society for Experimental Neurotherapeutics, Inc. 2022. Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. | ||
| 520 | |a Abstract CLN2 Batten disease is a lysosomal disorder in which pathogenic variants in CLN2 lead to reduced activity in the enzyme tripeptidyl peptidase 1. The disease typically manifests around 2 to 4 years of age with developmental delay, ataxia, seizures, inability to speak and walk, and fatality between 6 and 12 years of age. Multiple Cln2 mouse models exist to better understand the etiology of the disease; however, these models are unable to adequately recapitulate the disease due to differences in anatomy and physiology, limiting their utility for therapeutic testing. Here, we describe a new CLN2R208X/R208X porcine model of CLN2 disease. We present comprehensive characterization showing behavioral, pathological, and visual phenotypes that recapitulate those seen in CLN2 patients. CLN2R208X/R208X miniswine present with gait abnormalities at 6 months of age, ERG waveform declines at 6–9 months, vision loss at 11 months, cognitive declines at 12 months, seizures by 15 months, and early death at 18 months due to failure to thrive. CLN2R208X/R208X miniswine also showed classic storage material accumulation and glial activation in the brain at 6 months, and cortical atrophy at 12 months. Thus, the CLN2R208X/R208X miniswine model is a valuable resource for biomarker discovery and therapeutic development in CLN2 disease. | ||
| 650 | 4 | |a CLN2 Batten disease |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Miniswine |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Cortical atrophy |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Electroretinogram a- and b-waves |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Gait |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Seizures |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a White, Katherine A. |4 aut | |
| 700 | 1 | |a Johnson, Tyler B. |4 aut | |
| 700 | 1 | |a Sieren, Jessica C. |4 aut | |
| 700 | 1 | |a Johnson, Hans J. |4 aut | |
| 700 | 1 | |a Knoernschild, Kevin |4 aut | |
| 700 | 1 | |a Wang, Xiaojun |4 aut | |
| 700 | 1 | |a Rohret, Frank A. |4 aut | |
| 700 | 1 | |a Rogers, Christopher S. |4 aut | |
| 700 | 1 | |a Pearce, David A. |4 aut | |
| 700 | 1 | |a Brudvig, Jon J. |4 aut | |
| 700 | 1 | |a Weimer, Jill M. |0 (orcid)0000-0003-2504-4942 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t NeuroRX |d Springer-Verlag, 2006 |g 19(2022), 6 vom: 13. Sept., Seite 1905-1919 |w (DE-627)SPR031264964 |7 nnns |
| 773 | 1 | 8 | |g volume:19 |g year:2022 |g number:6 |g day:13 |g month:09 |g pages:1905-1919 |
| 856 | 4 | 0 | |u https://dx.doi.org/10.1007/s13311-022-01296-7 |z lizenzpflichtig |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_SPRINGER | ||
| 951 | |a AR | ||
| 952 | |d 19 |j 2022 |e 6 |b 13 |c 09 |h 1905-1919 | ||