■DNA聚合酶γ(POLG)相关疾病是由POLG的致病变异引起的一组罕见的神经退行性线粒体疾病,编码POLG的基因。患者可能会出现一系列的体征和症状,包括癫痫发作,视力丧失,肌病,神经病,发育障碍或退化,和肝功能衰竭。这些疾病是渐进的,退化过程,大多数受影响的人在诊断后3个月至12年内死亡。目前,没有有效的治疗POLG相关疾病。
■在这项研究中,我们报告了长期开放标签的中期6个月数据,单臂第二阶段试验,其中我们评估了脱氧胞苷和脱氧胸苷(dC/dT)联合治疗POLG相关疾病儿童的安全性和有效性。dC/dT以粉末形式肠内给予,溶解在水中。主要结局指标包括纽卡斯尔线粒体疾病量表(NMDS)评分,血清生长分化因子15(GDF-15;线粒体功能障碍的生物标志物),脑电图(EEG),癫痫发作日记,血液和尿液检查以评估终末器官和线粒体功能。次要结果指标包括记录所有不良事件以评估干预措施的安全性。该试验已在ClinicalTrials.gov注册,NCT04802707(https://clinicaltrials.gov/ct2/show/NCT04802707)。数据收集自10月14日,2021年至12月13日,2023年。
我们提供了纳入试验的前10名POLG相关疾病患者的6个月中期数据,六个患有阿尔伯斯-赫滕洛克综合征,两个患有共济失调-神经病,和两个不适合经典POLG相关表型的人。在6个月的治疗中,NMDS评分从基线时的平均27.3改善至6个月时的20.7(估计差异6.0;95%CI2.5-∞)。所有患者的GDF-15值保持稳定或下降;平均值从1031pg/ml降至729pg/ml(估计差异200;95%CI12-∞)。8/10的患者有异常的基线EEG;在这8个中有5个看到EEG的改善。其他血液和尿液检测无明显变化。关于不良事件,两名患者出现腹泻,并自发缓解。
■dC/dT是POLG相关疾病患者的一种有前途的治疗选择。需要进一步的研究来评估POLG相关疾病的长期安全性和有效性。以及其他线粒体DNA耗竭疾病的安全性和有效性。
■这项研究主要由利亚姆基金会资助,在萨沃伊基金会的额外资助下,大Défi皮埃尔·拉沃伊基金会,和魁北克养牛基金会。
UNASSIGNED: DNA polymerase gamma (POLG)-related disorders are a group of rare neurodegenerative mitochondrial diseases caused by pathogenic variants in POLG, the gene encoding POLG. Patients may experience a range of signs and symptoms, including seizures, vision loss, myopathy, neuropathy, developmental impairment or regression, and liver failure. The diseases follow a progressive, degenerative course, with most affected individuals dying within 3 months-12 years of diagnosis. At present, there are no effective treatments for POLG-related disorders.
UNASSIGNED: In this study we report the interim 6-month data from a long term open-label, single arm phase 2 trial, in which we assessed the safety and efficacy of combination therapy with deoxycytidine and deoxythymidine (dC/dT) in children with POLG-related disorders. dC/dT was given enterally in powder form, dissolved in water. The primary outcome measures included Newcastle Mitochondrial Disease Scale (NMDS) score, serum growth differentiation factor 15 (GDF-15; a biomarker of mitochondrial dysfunction), electroencephalography (EEG), seizure diary, and blood and urine tests to assess end organ and mitochondrial function. Secondary outcome measures included recording of all adverse events to evaluate the safety of the intervention. The trial is registered with ClinicalTrials.gov, NCT04802707 (https://clinicaltrials.gov/ct2/show/NCT04802707). Data were collected from 14 October, 2021 to 13 December, 2023.
UNASSIGNED: We present 6-month interim data from the first ten people with POLG-related disorders enrolled in the trial, six with Alpers-Huttenlocher syndrome, two with ataxia-neuropathy spectrum, and two who do not fit into a classical POLG-related phenotype. During the 6 months of treatment, NMDS score improved from a mean of 27.3 at baseline to 20.7 at 6 months (estimated difference 6.0; 95% CI 2.5-∞). GDF-15 values remained stable or decreased in all patients; the mean decreased from 1031 pg/ml to 729 pg/ml (estimated difference 200; 95% CI 12-∞). 8/10 patients had abnormal baseline EEG; improvement in EEG was seen in 5 of these 8. There were no significant changes in other blood and urine testing. Regarding adverse events, two patients experienced diarrhea that spontaneously resolved.
UNASSIGNED: dC/dT is a promising treatment option for people with POLG-related disorders. Further research is needed to assess the long-term safety and efficacy in POLG-related disorders, as well as safety and efficacy in other mitochondrial DNA depletion disorders.
UNASSIGNED: This study was primarily funded by the Liam Foundation, with additional funding from the Savoy Foundation, Grand Défi Pierre Lavoie Foundation, and Fonds de Recherche du Québec - Santé.