Background. Wolfram syndrome is a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting endoplasmic reticulum calcium homeostasis, including dantrolene sodium, may be beneficial. Methods: Based on the results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, our group put together the first-ever clinical trial in pediatric and adult patients with Wolfram syndrome. An open-label phase 1b/2a trial design was chosen. The primary objective of the study was to assess the safety and tolerability of dantrolene sodium in adult and pediatric patients with Wolfram syndrome. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic beta-cell functions, visual acuity, quality of life measures related to vision, and neurological functions. Results: The results indicate that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Although the study was small, a select few patients seemed to have improvements in beta-cell function, which might correlate with a positive trend in other outcome measures, including visual acuity and neurological functions. Conclusion. This study justifies further investigation into using dantrolene sodium and other small molecules targeting the endoplasmic reticulum for the treatment of Wolfram syndrome.

中文翻译：

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Wolfram综合征患者中的丹特罗钠1b / 2a期临床试验

背景。Wolfram综合征是一种罕见的内质网疾病，其特征在于胰岛素依赖型糖尿病，视神经萎缩和进行性神经变性。尽管目前尚无延迟，停止或逆转Wolfram综合征进展的治疗方法，但在细胞和啮齿动物模型中进行的临床前研究表明，针对内质网钙稳态（包括丹特罗钠）的治疗策略可能是有益的。方法：根据对丹特罗钠的临床前研究结果和正在进行的纵向研究，我们小组对有儿童和成人的Wolfram综合征患者进行了首次临床试验。选择了开放标签的1b / 2a期试验设计。这项研究的主要目的是评估在患有Wolfram综合征的成年和儿科患者中丹特罗钠的安全性和耐受性。次要目标是评估丹特罗钠对残余胰岛β细胞功能，视敏度，与视力有关的生活质量衡量指标和神经功能的功效。结果：结果表明，Wolfram综合征患者对丹特罗钠的耐受性良好。尽管这项研究规模很小，但少数患者似乎在β细胞功能方面有所改善，这可能与其他结果指标（包括视敏度和神经功能）的积极趋势相关。结论。