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

Elad Jacoby*, Omer Bar-Yosef, Noah Gruber, Einat Lahav, Nira Varda-Bloom, Yoav Bolkier, Diana Bar, Moriya Ben-Yakir Blumkin, Sharon Barak, Etzyona Eisenstein, Jaana Ahonniska-Assa, Tamar Silberg, Tal Krasovsky, Orly Bar, Neta Erez, Bella Bielorai, Hana Golan, Benjamin Dekel, Michal J. Besser, Gat PoznerHanan Khoury, Alan Jacobs, John Campbell, Eli Herskovitz, Noa Sher, Natalie Yivgi-Ohana, Yair Anikster, Amos Toren

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 procedurewaswell tolerated and that all study-related severe adverse eventswere either leukapheresisrelated 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.

Original languageEnglish
Article numbereabo3724
JournalScience Translational Medicine
Volume14
Issue number676
DOIs
StatePublished - 21 Dec 2022

Funding

FundersFunder number
Minovia Therapeutics
Champ Foundation

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