Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations:lessons from recent clinical trials  

作　　者：Bruno P.Imbimbo Viviana Triaca Camillo Imbimbo Robert Nisticò 

机构地区：[1]Department of Research&Development,Chiesi Farmaceutici,Parma,Italy [2]Institute of Biochemistry and Cell Biology,National Research Council,Rome,Italy [3]Department of Brain and Behavioral Sciences,University of Pavia,Pavia,Italy [4]School of Pharmacy,Department of Biology,University of Tor Vergata,and European Brain Research Institute(EBRI),Rome,Italy

出　　处：《Neural Regeneration Research》2023年第8期1679-1683,共5页中国神经再生研究（英文版）

摘　　要：We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors.Specifically,we discussed randomized clinical trials in subjects with Alzheimer's disease,Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations,and glucocerebrosidase-associated Parkinson's disease.Learning potential lessons to improve future therapeutic approaches is the aim of this review.Two long-term,controlled trials on three anti-β-amyloid monoclonal antibodies(solanezumab,gantenerumab and crenezumab)in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits.A major trial on tominersen,an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease,was prematurely interrupted because the drug failed to show higher efficacy than placebo and,at highest doses,led to worsened outcomes.A 28-week trial of tofersen,an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy.A trial of venglustat,a potent and brain-penetrant glucosylceramide synthase inhibitor,in Parkinson's disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo.We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies,antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type va

关 键 词：Alzheimer's disease amyotrophic lateral sclerosis amyloid precursor protein GLUCOCEREBROSIDASE HUNTINGTIN Huntington's disease Parkinson's disease presenilin 1 presenilin 2 superoxide dismutase 1 

分 类 号：R749[医药卫生—神经病学与精神病学]