Mitochondrial DNA Depletion Disorders

Mitochondria are organelles that contain DNA which encode proteins to generate energy required for essential functions in all cells. TK2 deficiency belongs to a growing subset of mitochondrial diseases – mitochondrial DNA (mtDNA) depletion disorders (MDDs). MDDs are caused by mutations in nuclear genes with essential roles in the replication of mtDNA and are inherited in an autosomal recessive fashion.

Biology of TK2 Deficiency

When thymidine kinase 2 (TK2) activity is deficient, the result is an imbalance of the nucleotide pool inside the mitochondria that are used to replicate mtDNA. With mtDNA unable to replicate properly, cells cannot produce adequate energy. Production of energy in cells is decreased in tissues throughout the body — especially those that have greater energy requirements, predominantly skeletal muscle in patients with TK2 deficiency.

TK2 deficient graphic

TK2d leads to progressive, severe muscle weakness

TK2 deficiency presents primarily as progressive and severe muscle weakness that profoundly impairs movement, breathing, eating/nutrition and other normal functions. Symptom onset can start as early as the first year of life or as late as adulthood. Like other inborn errors of metabolism, generally, onset early in life will predict faster progression of disease. Patients with TK2d most often die from respiratory failure. TK2 deficiency may be misdiagnosed as other diseases such as Spinal Muscular Atrophy or Muscular Dystrophy. There are currently no approved therapies for TK2 deficiency.

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Recent advances in understanding mitochondrial diseases

Underlying genetics guiding therapeutic development

Over the past decade, tremendous progress has been made in the understanding of the genetic causes of mitochondrial diseases. In addition to clinical sequelae which distinguish one MDD from another, DNA sequencing can definitively diagnose patients, which enables development of treatments targeted to specific genetic defects. Advances in DNA sequencing technology have revealed that mitochondrial diseases as a class are comprised of many distinct genetic disorders.

Insights and knowledge gleaned during development of MT1621 position Modis to leverage the increasing understanding and genetic characterization of mitochondrial diseases to develop targeted high impact therapies for these underserved diseases.