Dados do Trabalho

Título

Nucleosides Reposition at TK2d: the first Brazilian cohort of treated patients

Introdução

Thymidine kinase 2 (TK2) is the enzyme responsible for the phosphorylation of deoxyribonucleosides deoxythymidine and deoxycytidine to deoxythymidine and deoxycytidine monophosphates, respectively. Both are phosphorylated to generate the deoxynucleosides triphosphates needed for the replication of mtDNA. Biallelic pathogenic variants within the TK2 gene result in TK2 deficiency (TK2d) and lead to DNA maintenance defects and depletion of mitochondrial DNA. This condition typically presents with a progressive and threatening myopathy. A supplementation therapy using monophostate nucleosides to bypass the biochemical defect was developed and showed pronounced clinical benefits at open-label trials, enhancing the importance of an early diagnosis and early treatment to change the lethal natural history of the disease.

Objetivo

Here we present the clinical findings and follow up of eight Brazilian patients receiving the nucleosides reposition through compassionate program.

Método

Eight patients followed at Medicine School of University of São Paulo (FM/USP) were receiving supplementation therapy with deoxynucleosides (DThd and dCtd) in a compassionate program by the sponsor, offered orally at a dosage of 400mg/kg/day for each compound.

Resultados

Patients were 20(+-16) years old, two presented infantile-onset and the others childhood-onset. All of them were severely affected and attended to the requirements for a compassionate program. The protocol was approved by ANVISA in addition to the Clinical Hospital at FM/USP. One patient received the treatment for 18 months and presented an increase of 40 points at Chop-Intend, increased weight, descreased time-on ventilation and regained the ability to swallow. Two patients were on treatment for 6 months, both presented a significantly increased at MFM-32. Five adult patients with severe presentation of the disease were receiving the reposition for three months. Half of them presente improvement at motor scales (MFM32) and all of them referred subjective improvements. They were more active and feeling less fatigued. Adverse effects (bloating and diarrhea) were reported by half oh the patients. Two adults were not in full dosing because of that.

Conclusão

TK2d is a progressive disease with high mortality rates. However, due to a potential treatment capable of changing the natural history of the diseas, the early recognition of this disease is urgent. We demonstrasted positive from the first patients receiving the treatment in Brazil.

Referências

Dombi E, Marinaki T, Spingardi P, Millar V, Hadjichristou N, Carver J, Johnston IG, Fratter C, Poulton J. Nucleoside supplements as treatments for mitochondrial DNA depletion syndrome. Front Cell Dev Biol. 2024 Apr 2;12:1260496.

Palavras Chave

TK2; nucleoside therapy; mitochondrial depletion