Dr. Christina Pacak

The overarching goal of this research program is to understand underlying mechanisms in rare disorders that impact mitochondrial function to guide therapeutic development relevant to both rare and common disorders. Using mouse models and human patient-derived, differentiated induced pluripotent stem cells these researchers examine cardiac, neuronal, and skeletal muscle samples in search of common effectors of mitochondrial function that can be targeted using adeno-associated virus (AAV) based delivery or other treatment strategies.

• Cardiac – The group recently described the downregulation of a protein called TMEM65 in Barth syndrome (a mitochondrial cardioskeletal myopathy). As TMEM65 is involved in maintenance of mtDNA copy numbers and localization of Cx43 to the polar ends of cardiomyocytes, it may represent a critical link between mitochondrial dysfunction and the development of arrhythmias. Studies to evaluate this in a variety of arrhythmogenic models are underway.
• Neuronal – The group's work to evaluate mitochondrial function in Cockayne syndrome (a premature aging, neurodegenerative disorder) has revealed several mechanistic parallels with Alzheimer’s disease. These include both metabolic and the unfolded/misfolded protein response pathways. A gene therapy development for Cockayne syndrome project has demonstrated the ability to correct these features of the disease in the brain and provides proof-of-concept support that this can be rectified. Studies to evaluate and eventually manipulate these pathways in patient iPSC-derived cerebral organoids have commenced.
• Skeletal Muscle – The researchers are performing comparative analyses of mitochondrial function across multiple forms of Limb Girdle Muscular Dystrophy (LGMD) to determine similarities and differences between LGMD subtypes, throughout disease progression, and between individual patients. Their goal is to identify alterations in mitochondrial function for LGMDs of known and unknown genotype, determine whether they are unique or shared across subtypes, establish how they change with and influence LGMD progression, and reveal novel pathways for therapeutic targeting to augment precise aspects of mitochondrial function.