University of Pittsburgh researchers have used the CRISPR technology to create a new mouse model for a rare, recessive metabolic disorder.
Description
Triosephosphate isomerase deficiency (TPI Df) is a rare and devastating childhood illness. A consequence of several missense mutations with TPI-encoding genes can result in anemia, neuromuscular dysfunction, paralysis, irreversible brain damage and death. The development of this new mouse model will allow for more research of this condition leading to a better understanding and potentially new treatments
Applications
• Triosephosphate isomerase deficiency research
• Development of models for rare missense diseases
Advantages
TPI Df – a rare, recessive metabolic disorder – causes a variety of complications in early childhood from muscle weakness, increased susceptibility to infection, and progressive neurodegeneration to eventually, death. Children with TPI Df rarely survive past childhood. TPI Df is not a genetic deficiency, but a missense mutation leading to deficiencies in a biochemical process with protein stability mutations. Traditional approaches to developing animal models have failed and there is a desperate need for clinical models to advance the research of potential therapeutics.
Identification of common pathogenic mutations associated with TPI Df has led to the development of a mouse model. These mice display the characteristic rapid weight loss and progressive muscle atrophy of children with TPI Df. These are the first known effective models of TPI Df.
Invention Readiness
Research has identified the TPIE104D allele as a common pathogenic mutation in humans with TPI Df. Using CRISPR technology, the E104D human mutation was inserted into C57BL/6J mice. An adjacent silent GAT to GAC codon change was included to prevent the sgRNA binding to the TPIE104D allele. Breeding with TPIindel null animals has led to germ-line transmission with these TPIE104D/null offspring displaying signs commonly seen in children with severe TPI Df, including early onset of severe anemia and markedly reduced TPI levels. TPIE104D/E104D offspring exhibited these traits later, similar to the less severe TPI Df phenotype.
Both of these novel models capture key aspects of TPI Df, allowing researchers to gain a deeper insight into the disease pathology which may lead to the discovery of effective treatment options. This approach could also be applied to other genetic missense diseases leading to the development of useful clinical research models
IP Status
Research Tool
