Current Projects
An induced pluripotent stem cell (iPSC) -based system for diagnosis and investigation of malignant hyperthermia and other skeletal muscle disorders
Malignant Hyperthermia (MH) is an archetypical pharmaco-genetic muscle disease; that is the disorder becomes manifest when susceptible individuals are exposed to certain pharmacologic agents. Despite the availability of a specific treatment (dantrolene), MH still has a mortality rate in the range of 5-9 percent. Genetic testing can label someone as MH susceptible, but this testing is only reliable if a known pathological variant exists in a family.
Individuals that have had a suspected MH event and their family members can be tested for the presence of known pathological variants. Absent one of these variants, a negative CHCT is the only way to exclude the diagnosis of MHS or determine MH negative (MHN) family members. If MHS variant testing and/or a biopsy has not been done, patients and family members are managed as if known MHS. Unfortunately, CHCT is only done in 5 centers in North America, so testing commonly requires expensive and inconvenient travel for patients and families. Therefore, many family members of MHS patients are not tested, and may be treated as MHS unnecessarily. A simpler, less invasive high-specificity diagnostic tool for MHS is clearly needed as is a means to categorically classify putative MHS genetic variants as pathological or benign.
There is evidence in animal models and from isolated human cells to indicate the primary pathology in MH is excessive calcium release from the sarcoplasmic reticulum, resulting in elevated levels of myoplasmic calcium both at rest, and during triggering of a MH event. Therefore, the system we proposed to develop focuses on myoplasmic calcium kinetics. We aim to evolve an in-vitro system that will enable making a diagnosis of MHS or MHN with high confidence, and without the need for an invasive muscle biopsy.
Project Goal
The goal of this project is to develop a novel system to establish a malignant hyperthermia phenotype in patients without the need for an invasive muscle biopsy, and thereby establish a platform for the study of other pharmacogenetic muscle disorders.
