Studies Of Hereditary Neurological Disease: Clinical Trials

这项研究计划的目的是开发安全有效的遗传性神经疾病治疗方法。过去一年的具体研究成果包括： (1)我们评估了BVS857的安全性、耐受性和初步疗效，BVS857是一种IGF-1模拟物，用于SBMA患者。SBMA患者的IGF-1水平较低，对IGF-1的研究表明，在SBMA转基因模型中是有益的。一项对健康志愿者的BVS857的研究表明，它的耐受性很好。这是一项随机、双盲和安慰剂对照研究，在丹麦、德国、意大利和美国的三个神经肌肉中心招募的SBMA患者中进行。符合条件的患者年龄为18岁或以上，确诊为SBMA基因诊断，动态，有症状无力，血清IGF-1水平为170 ng/mL。在对8名SBMA患者进行安全性和耐受性评估后，27名患者每周服用BVS857，疗程为12周，药物与安慰剂的比例为2：1。患者、研究人员和研究人员被蒙面接受治疗任务。主要观察指标包括安全性、耐受性以及核磁共振成像显示BVS857对大腿肌肉体积(TMV)的影响。对于TMV的主要结果测量，通过协方差分析分析第13周时基线后与基线的比率。27例患者随机分为治疗组，25例纳入初步疗效分析。BVS857总体安全，无严重不良反应。介入组和安慰剂组的TMV有显著差异，几何均数比为104，安慰剂组的TMV从基线到第13周有所下降，但BVS857治疗组患者的TMV没有下降。在BVS857组和安慰剂组之间报告的不良事件没有显著差异。在肌肉力量和功能的测量上也没有差异。BVS857治疗的18例患者中有11例检测到免疫原性，其中5例与内源性IGF-1有中和能力的交叉反应抗体。BVS857治疗的SBMA患者在服药12周后TMV保持稳定。这种干预与免疫原性的高发生率有关，并且没有改善肌肉力量或功能。更多的研究可能有助于进一步评估激活IGF-1通路在SBMA中的疗效。 (2)脊髓延髓性肌萎缩症(SBMA)对生活质量(QOL)的影响尚不清楚。我们的研究从患者的角度描述了症状以及这些症状对生活质量的影响。我们对21名患有基因确认的SBMA的成年男性进行了开放式访谈。使用定性框架技术，我们对访谈进行了编码和分析，以确定症状和由此产生的主题。从这些采访中，我们提取了729条语录。我们确定了200个SBMA特定症状和20个症状主题。所有受访者都提到了弱点。精神健康领域内的症状以及情感问题和心理影响的具体主题也经常被提及。许多症状影响SBMA患者的生活质量。我们确定了以前未被认识到的症状，这些症状在加强对SBMA患者的临床护理以及开发在未来临床试验中评估疗效的工具方面具有重要意义。

The purpose of this research program is to develop safe and effective treatments for hereditary neurological disorders. Specific research accomplishments in the past year include the following: (1) We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in SBMA patients. SBMA patients have low IGF-1 levels, and studies of IGF-1 showed benefit in a transgenic model of SBMA. A study of BVS857 in healthy volunteers showed it to be well tolerated. This was a randomized, double-blind, and placebo-controlled study in SBMA patients recruited at neuromuscular centers in Denmark, Germany, Italy, and three sites within the US. Eligible patients were age 18 years or older with a confirmed genetic diagnosis of SBMA, ambulatory, with symptomatic weakness, and serum IGF-1 levels of 170 ng/mL. Following a safety and tolerability evaluation with 8 SBMA patients, BVS857 was administered weekly for 12 weeks to 27 patients, with 2:1 drug to placebo randomization by a number scheme. Patients, investigators, and study personnel were masked to treatment assignment. Primary outcome measures included safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) by magnetic resonance imaging. For the primary outcome measure of TMV, the ratio of post-baseline to baseline at week 13 was analyzed by analysis of covariance per protocol. 27 patients were randomly assigned to treatment groups and 25 were included in the preliminary efficacy analysis. BVS857 was generally safe with no serious adverse events. A significant difference in TMV was observed in the interventional arm versus placebo with a geometric-mean ratio of 104, and a decrease in TMV from baseline to week 13 in placebo but not in BVS857 treated patients, respectively. There were no significant differences in reported adverse events between the BVS857 and placebo groups. There were also no differences in measures of muscle strength and function. Immunogenicity was detected in 11 of 18 patients treated with BVS857, including cross-reacting antibodies with neutralizing capacity to endogenous IGF-1 in 5 patients. TMV remained stable in BVS857-treated SBMA patients after 12 weeks of dosing. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies may help to further evaluate the efficacy of activating the IGF-1 pathway in SBMA. (2) The effects of spinal bulbar muscular atrophy (SBMA) on quality of life (QoL) are not well understood. Our study described symptoms from the patient's perspective and the impact these symptoms have on QoL. We conducted open-ended interviews with 21 adult men with genetically confirmed SBMA. Using a qualitative framework technique, we coded and analyzed interviews to identify symptoms and resulting themes. From these interviews, 729 quotations were extracted. We identified 200 SBMA-specific symptoms and 20 symptomatic themes. Weakness was mentioned by all interviewees. Symptoms within the domain of mental health and the specific themes of emotional issues and psychological impact were also frequently mentioned. Numerous symptoms affect QoL for patients with SBMA. We identified previously unrecognized symptoms that are important to address in enhancing clinical care for patients with SBMA and in developing tools to evaluate efficacy in future clinical trials.