CP is associated with high muscle tension and stiffness, which can cause decreased range of motion of an individual’s muscles. Preventing or reversing muscle tension is essential for people with cerebral palsy to engage with the world around them. This grant tests the effectiveness of certain drugs to repair this stiffness.
- Individuals with CP often have stiff and tense muscles.
- Cells responsible for repairing muscles show markers indicative of senescence, a state that indicates premature aging.
- There are drugs that can slow or reverse senescence.
- Is the DNA in these muscle cells modified and is that the cause of aging?
- If the DNA is modified, can the drug 5-azacytidine be repurposed to reverse the aging, therefore encouraging muscle growth?
Post Research Results
- Work from grant presented at ORS, AACPDM, AAP and ASCB and published. The support from the AACPDM significantly contributed to the finding that muscle-forming stem cells in contractures of children with CP are hypermethylated at the DNA level. This epigenetic chemical modification of the DNA drives these important muscle resident stem cells to proliferate faster and “senesce” (deteriorate with age) prematurely, exhausting their number and their capacity to grow muscle. This epigenetic modification of stem cells occurring in CP muscles may lead to a paradigm shift in the treatment of contractures by moving from traditional physical medicine and orthopedic therapies to multimodal approaches that will incorporate drugs that restore normal levels of DNA methylation. DNA hypomethylating agents like azacytidine, caould be used to “prime” or “reset” the muscle biologically before physical therapy. Since azacytidine is already approved by the FDA for treatment of hematopoietic disorders in adults and children, they have an enticing “repurposing” therapeutic potential that will dramatically reduce the time needed to implementation compared to typical drug development pathways. The PI is pursuing this drug repurposing aspect with new basic and clinically-oriented research.
- Dr. Andrea Domenighetti PhD