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Abstract Details

Deoxypyrimidine Monophosphates Treatment for Thymidine Kinase 2 Deficiency
Muscle Disease/Neuromuscular Junction
S05 - (-)
005
We generated a Tk2 knock-in mouse model that manifests a phenotype strikingly similar to the human infantile encephalomyopathy. We demonstrated that lack of Tk2 activity cause nucleotide pools unbalance with severe reductions of deoxypyrimidine triphosphates (dTTP and dCTP) in brain and liver, leading to reduction of mtDNA copy number.
To bypass Tk2 deficiency, we administered deoxypyrimidine monophosphates (dCMP+dTMP) to Tk2 H126N knock-in mice by oral gavage from postnatal day 4, when mutant mice are biochemically affected but phenotypically normal.
Treatment with dCMP+dTMP, 200 mg/kg/day each, prolonged the lifespan of Tk2-/- mice (mean survival 34 days vs 13 days without treatment). Analysis of 13-day-old treated mutant mice showed normalization of mtDNA copy number as well as mitochondrial respiratory chain enzyme activities and protein levels in all tissues analyzed. Treatment with dCMP+dTMP, 400 mg/kg/day, showed greater clinical and biochemical improvements than 200 mg/kg/day. No adverse effects were observed with both doses of dCMP+dTMP.
Oral dCMP+dTMP supplementation is the first effective and safe treatment for TK2 deficiency in mice. This treatment can potentially be applied to patients.
Authors/Disclosures
Caterina Garone
PRESENTER 		No disclosure on file
Beatriz Garcia-Diaz No disclosure on file
Valentina Emmanuele, MD, PhD (NYP at CUIMC) Dr. Emmanuele has nothing to disclose.
No disclosure on file
Orhan H. Akman, PhD (Columbia University Medical Center) No disclosure on file
No disclosure on file
Catarina Quinzii Hirano, MD No disclosure on file
Michio Hirano, MD, FAAN (Columbia University Medical Center) Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB Biopharma SRL. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Precision Biosciences. Dr. Hirano has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB Biopharma SRL. Dr. Hirano has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Apollo Communication. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Envision Communications. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for 好色先生. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Cure SMA. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Muscular Dystrophy Association. The institution of Dr. Hirano has received research support from UCB. The institution of Dr. Hirano has received research support from Cyclerion. Dr. Hirano has received research support from Reneo Pharmaceuticals. The institution of Dr. Hirano has received research support from Astellas. Dr. Hirano has received intellectual property interests from a discovery or technology relating to health care. Dr. Hirano has received intellectual property interests from a discovery or technology relating to health care. Dr. Hirano has received personal compensation in the range of $0-$499 for serving as a Study Section Reviewer with NIH. Dr. Hirano has a non-compensated relationship as a Research Advisory Board member with Muscular Dystrophy Association that is relevant to AAN interests or activities. Dr. Hirano has a non-compensated relationship as a Scientific and Medical Advisory Board member with United Mitochondrial Disease Foundation that is relevant to AAN interests or activities. Dr. Hirano has a non-compensated relationship as a Scientific Advisory Board member with Barth Syndrome Foundation that is relevant to AAN interests or activities.
Jeffrey L. Saver, MD, FAAN (UCLA Health) Dr. Saver has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Medtronic. Dr. Saver has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Stryker. Dr. Saver has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cerenovus. Dr. Saver has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Boehringer Ingelheim (prevention only). Dr. Saver has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Medical Association. Dr. Saver has received stock or an ownership interest from Rapid Medical.