RTI International, Research Triangle Park, NC, USA.
Parent Project Muscular Dystrophy, Hackensack, NJ, USA.
Mol Genet Genomic Med. 2021 May;9(5):e1664. doi: 10.1002/mgg3.1664. Epub 2021 Mar 23.
Gene therapy offers an etiologically targeted treatment for genetic disorders. Little is known about the acceptance of mortality risk among patients with progressive, fatal conditions. We assessed patients' and caregivers' maximum acceptable risk (MAR) of mortality for gene therapy when used to treat Duchenne muscular dystrophy (DMD).
The threshold technique was used to assess tolerance for mortality risks using a hypothetical vignette. Gene therapy was described as non-curative and resulting in a slowing of progression and with a 10-year benefit duration. MAR was analyzed using interval regression for gene therapy initiated "now"; in the last year of walking well; in the last year of being able to bring arms to mouth; and in newborns (for caregivers only).
Two hundred eighty-five caregivers and 35 patients reported the greatest MAR for gene therapy initiated in last year of being able to lift arms (mean MAR 6.3%), followed by last year of walking well (mean MAR 4.4%), when used "now" (mean MAR 3.5%), and when used in the newborn period (mean MAR 2.1%, caregivers only). About 35% would accept ≥200/2000 risk in the last year of being able to lift arms. Non-ambulatory status predicted accepting 1.8 additional points in MAR "now" compared with ambulatory status (p = 0.010). Respondent type (caregiver or patient) did not predict MAR.
In this first quantitative study to assess MAR associated with first-generation DMD gene therapy, we find relatively high tolerance for mortality risk in response to a non-curative treatment scenario. Risk tolerance increased with disease progression. Patients and caregivers did not have significantly different MAR. These results have implications for protocol development and shared decision making.
基因治疗为遗传性疾病提供了一种针对病因的治疗方法。对于进展性致命疾病患者接受死亡率风险的情况知之甚少。我们评估了患者和护理人员对用于治疗杜氏肌营养不良症 (DMD) 的基因治疗的最大可接受死亡率风险 (MAR)。
使用假设情节使用阈技术评估对死亡率风险的容忍度。基因治疗被描述为非治愈性的，可减缓进展速度，受益期为 10 年。使用区间回归分析了基因治疗在“现在”开始；在行走良好的最后一年；在能够将手臂举到嘴边的最后一年；以及在新生儿期（仅适用于护理人员）的 MAR。
285 名护理人员和 35 名患者报告了在能够举起手臂的最后一年开始的基因治疗的最大 MAR（平均 MAR 6.3%），其次是行走良好的最后一年（平均 MAR 4.4%），“现在”使用时（平均 MAR 3.5%），以及在新生儿期使用时（仅适用于护理人员的平均 MAR 2.1%）。大约 35%的人会接受在能够举起手臂的最后一年中≥200/2000 的风险。与能行走的状态相比，不能行走的状态预测“现在”MAR 增加 1.8 分（p=0.010）。受访者类型（护理人员或患者）不能预测 MAR。
在这项首次评估第一代 DMD 基因治疗相关 MAR 的定量研究中，我们发现对非治愈性治疗方案的死亡率风险具有相对较高的容忍度。风险容忍度随着疾病的进展而增加。患者和护理人员的 MAR 没有显著差异。这些结果对方案制定和共同决策具有重要意义。
