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

Abstract

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.

Mitochondrial transplantation and its impact on infectious disease progression: a pilot study

“…63,64 These children are most affected when the ratio of dysfunctional mitochondria exceeds a certain threshold, generally 60-70%. 65 Thus, we see that mitochondrial energy production is a measurable and predictable number, which can be seen to have predictable consequences for the human body. In a similar way, mitochondrial energy production declines due to age, in some cases 70% in the elderly primate retinas.…”

“…These children might be given mitlet transplants to temporarily make their immune systems “normal” to fight infection. 63,64,65…”

Mitochondria on the move: Horizontal mitochondrial transfer in disease and health

“…It is plausible that mitochondrial therapy, by stimulation of HMT or by mitochondrial transplantation, may be effective in alleviating pathologies, with neurodegenerative or cardiovascular diseases being “hot” candidates for the emerging therapeutic modality ( Emani and McCully, 2018 ; Picard et al, 2016 ; Caicedo et al, 2017 ; Chang et al, 2019 ; McCully et al, 2017 ; Nascimento-Dos-Santos et al, 2021 ; Gorman et al, 2018 ). Mitochondrial transplantation has been used to replace faulty maternal mitochondrial genes ( Gorman et al, 2018 ; Jacoby et al, 2022 ). We have witnessed considerable progress in mitotherapy based on mitochondrial transplantation including sophisticated approaches such as transfer of mitochondria from fetal to adult MSCs using optical tweezers ( Shakoor et al, 2021 ).…”

Platelet extracellular vesicles and their mitochondrial content improve the mitochondrial bioenergetics of cellular immune recipients

“…These studies involved the isolation of mitochondria from peripheral blood mononuclear (PBMC) cell fraction and transplantation into hematopoietic stem and progenitor cells from the diseased recipient to replace the endogenous, defective mitochondria. 68 It is noteworthy that platelets are also abundant in PBMC fractions, and it is thus not excluded that platelet-derived mitochondria contributed to these clinical improvements.…”

“…Furthermore, a recent clinical trial implicating six patients with single large‐scale mitochondrial DNA (mtDNA) deletion (SLSMD) syndromes revealed some potential benefits in mitochondrial transplantation. These studies involved the isolation of mitochondria from peripheral blood mononuclear (PBMC) cell fraction and transplantation into hematopoietic stem and progenitor cells from the diseased recipient to replace the endogenous, defective mitochondria 68 . It is noteworthy that platelets are also abundant in PBMC fractions, and it is thus not excluded that platelet‐derived mitochondria contributed to these clinical improvements.…”