Big thanks to everyone involved, especially the animal technicians, and Declan, who spent a summer internship meticulously analyzing zebrafish touch-evoked escape response data.⁣ A very tedious (but vital!) part of the work! 🐟

This proof-of-concept study highlights that deoxynucleoside supplementation can mitigate RRM2B dysfunction in vivo. However, more challenges remain in bringing this to patients and determining effective delivery methods, combinations, and dosing of deoxynucleosides still needs to be established.⁣⁣

We subsequently establish that purine deoxynucleoside supplementation in Rrm2b KO larvae prevents mtDNA depletion, attenuates the movement defect and reduces elevated lactate levels⁣. This supports existing in vitro data that deoxynucleoside supplemention could treat RRM2B related MDDS.

In zebrafish🐟, kocking out Rrm2b causes impaired movement, mtDNA depletion & elevated lactate.⁣
Surprisingly, treating larvae with both purine & pyrimidine deoxynucleosides worsened mtDNA depletion, even in WT controls. Likely due to natural nucleotide pool asymmetries in developing zebrafish.

RRM2B mutations disrupt purine & pyrimidine deoxynucleotide pools essential for mtDNA replication and maintenance.⁣
This leads to mtDNA depletion & a severe encephalomyopathic form of MDDS in patients.⁣⁣