Modified Acvr1 Rodent Model for Nonlethal FOP Phenotyping
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing genetically modified rodent models with Acvr1 mutations associated with fibrodysplasia ossificans progressiva (FOP) suffer from perinatal lethality, limiting their use as effective models for studying and treating the disease.
Innovation Solution
Development of genetically modified rodents with a modified Acvr1 gene encoding a human ACVR1 ectodomain and endogenous rodent transmembrane and cytoplasmic domains, excluding specific substitutions, under the control of the rodent Acvr1 promoter, to create a model that exhibits FOP-like phenotypes without neonatal lethality.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a rodent model with Acvr1 R206H mutation is created to study FOP, then the model exhibits FOP-like phenotype, but the model suffers from perinatal lethality
Solution Approach 1:
The invention applies local quality by creating a chimeric Acvr1 protein with heterogeneous structure: the ectodomain is derived from human ACVR1 (containing the R206H FOP mutation) while the transmembrane and cytoplasmic domains are from endogenous rodent Acvr1. This localized substitution of specific domains allows the model to exhibit FOP-like phenotypes (congenital toe malformations and heterotopic ossification) while avoiding perinatal lethality through the rodent-specific signaling domains that regulate BMP pathway activity.
2Reliability
If the Acvr1 gene is modified to encode human ACVR1 ectodomain with FOP mutation, then FOP-like features are exhibited, but neonatal lethality occurs
Solution Approach 1:
The invention applies parameter changes by modifying specific amino acid residues in the Acvr1 protein structure. The chimeric protein contains the R206H substitution (a critical parameter change) in the ectodomain that confers FOP pathology, while maintaining rodent sequences in other domains. This selective parameter modification enables accurate FOP phenotyping in surviving rodents, allowing measurement and observation of disease features without the confounding factor of neonatal death.
3Reliability
If a complete human ACVR1 gene is introduced into rodent, then FOP phenotype is achieved, but germline transmission becomes difficult
Solution Approach 1:
The invention applies segmentation by dividing the Acvr1 protein into functional domains and selectively combining them from different species. The ectodomain (residues 1-123) is derived from human ACVR1 containing the FOP mutation, while the transmembrane domain (residues 124-146) and cytoplasmic domain (residues 147-509) are from endogenous rodent Acvr1. This segmented, chimeric approach creates a gene that can be stably maintained in the rodent germline and transmitted through breeding, unlike complete human gene introduction.
Data Source
AI summary
This disclosure relates to a genetically modified rodent whose genome comprises a modified Acvr1 gene which encodes a modified Acvr1 polypeptide that is expressed in the rodent, causing the rodent to display a phenotypical feature of fibrodysplasia ossificans progressiva (FOP) such as ectopic bone formation without neonatal lethality This disclosure also relates to nucleic acid vectors and methods for making the genetically modified rodent, as well as methods of using the genetically modified rodent as an animal model of human diseases.