Mitochondrial augmentation of hematopoietic stem cells in children with single large-scale mitochondrial DNA deletion syndromes

Patients with single large-scale mitochondrial DNA (mtDNA) deletion syndromes (SLSMDs) usually present with multisystemic disease, either as Pearson syndrome in early childhood or as Kearns-Sayre syndrome later in life. No disease-modifying therapies exist for SLSMDs. We have developed a method to enrich hematopoietic cells with exogenous mitochondria, and we treated six patients with SLSMDs through a compassionate use program. Autologous CD34+ hematopoietic cells were augmented with maternally derived healthy mitochondria, a technology termed mitochondrial augmentation therapy (MAT). All patients had substantial multisystemic disease involvement at baseline, including neurologic, endocrine, or renal impairment. We first assessed safety, finding that the procedure was well tolerated and that all study-related severe adverse events were either leukapheresis-related or related to the baseline disorder. After MAT, heteroplasmy decreased in the peripheral blood in four of the six patients. An increase in mtDNA content of peripheral blood cells was measured in all six patients 6 to 12 months after MAT as compared baseline. We noted some clinical improvement in aerobic function, measured in patients 2 and 3 by sit-to-stand or 6-min walk testing, and an increase in the body weight of five of the six patients suffering from very low body weight before treatment. Quality-of-life measurements as per caregiver assessment and physical examination showed improvement in some parameters. Together, this work lays the ground for clinical trials of MAT for the treatment of patients with mtDNA disorders. Description In children with mitochondrial DNA deletion syndromes, mitochondrial augmentation therapy is feasible and may lead to functional improvement. Augmenting mitochondria to treat genetic disorders Patients with single large-scale mitochondrial DNA deletion syndromes (SLSMDs) experience multisystemic disease, and no targeted therapies currently exist. Here, Jacoby and colleagues applied mitochondrial augmentation therapy (MAT) to six individuals with SLSMDs as part of a compassionate use program. CD34+ cells were collected from the patients and augmented ex vivo with maternally derived healthy mitochondria, then given back to the patient. MAT resulted in decreased heteroplasmy, increased full-length mitochondrial DNA, and improved ATP content in peripheral blood mononuclear cells and was associated with improved weight in five of six patients and improved muscle strength and endurance in two individuals, suggesting that MAT should be further investigated for the treatment of SLSMDs.--MN