PUBLICATION
PDE10A inhibition reduces the manifestation of pathology in DMD zebrafish and represses the genetic modifier PITPNA
- Authors
- Lambert, M.R., Spinazzola, J.M., Widrick, J.J., Pakula, A., Conner, J.R., Chin, J.E., Owens, J.M., Kunkel, L.M.
- ID
- ZDB-PUB-201123-10
- Date
- 2020
- Source
- Molecular therapy : the journal of the American Society of Gene Therapy 29(3): 1086-1101 (Journal)
- Registered Authors
- Kunkel, Louis M.
- Keywords
- DMD, Genetic Modifier, PDE10A, Pathology, Pitpna, Therapy, Zebrafish
- MeSH Terms
-
- Animals
- Dogs
- Dystrophin/genetics
- Dystrophin/metabolism*
- Humans
- Larva/drug effects
- Larva/genetics
- Larva/metabolism
- Muscular Dystrophy, Animal/genetics
- Muscular Dystrophy, Animal/metabolism
- Muscular Dystrophy, Animal/pathology
- Muscular Dystrophy, Animal/prevention & control*
- Muscular Dystrophy, Duchenne/genetics
- Muscular Dystrophy, Duchenne/metabolism
- Muscular Dystrophy, Duchenne/pathology
- Muscular Dystrophy, Duchenne/prevention & control*
- Myoblasts/drug effects*
- Myoblasts/metabolism
- Myoblasts/pathology
- Phospholipid Transfer Proteins/antagonists & inhibitors*
- Phospholipid Transfer Proteins/genetics
- Phospholipid Transfer Proteins/metabolism
- Phosphoric Diester Hydrolases/chemistry*
- Phosphoric Diester Hydrolases/genetics
- Phosphoric Diester Hydrolases/metabolism
- Pyrazoles/pharmacology*
- Quinolines/pharmacology*
- Zebrafish
- PubMed
- 33221436 Full text @ Mol. Ther.
Citation
Lambert, M.R., Spinazzola, J.M., Widrick, J.J., Pakula, A., Conner, J.R., Chin, J.E., Owens, J.M., Kunkel, L.M. (2020) PDE10A inhibition reduces the manifestation of pathology in DMD zebrafish and represses the genetic modifier PITPNA. Molecular therapy : the journal of the American Society of Gene Therapy. 29(3):1086-1101.
Abstract
Duchenne Muscular Dystrophy (DMD) is a severe genetic disorder caused by mutations in the DMD gene. Absence of dystrophin protein leads to progressive degradation of skeletal and cardiac function and leads to premature death. Over the years, zebrafish have been increasingly used for studying DMD and are a powerful tool for drug discovery and therapeutic development. In our study, a birefringence screening assay led to identification of PDE10A inhibitors that reduced the manifestation of dystrophic muscle phenotype in dystrophin-deficient sapje-like zebrafish larvae. PDE10A has been validated as a therapeutic target by pde10a morpholino-mediated reduction in muscle pathology and improvement in locomotion, muscle, and vascular function as well as long-term survival in sapje-like larvae. PDE10A inhibition in zebrafish and DMD patient-derived myoblasts were also associated with reduction of PITPNA expression that has been previously identified as a protective genetic modifier in two exceptional dystrophin-deficient GRMD dogs that escaped the dystrophic phenotype. The combination of a phenotypic assay and relevant functional assessments in the sapje-like zebrafish enhances the potential for the prospective discovery of DMD therapeutics. Indeed, our results suggest a new application for a PDE10A inhibitor as a potential DMD therapeutic to be investigated in a mouse model of DMD.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping