Alternative splicing induces, under abnormal cholinergic neurotransmission, overproduction of the rare "readthrough" acetylcholinesterase variant AChE-R. We explored the pathophysiological relevance of this phenomenon in patients with myasthenia gravis (MG) and rats with experimental autoimmune MG (EAMG), neuromuscular junction diseases with depleted acetylcholine receptors. In MG and EAMG, we detected serum AChE-R accumulation. In EAMG, we alleviated electromyographic abnormalities by nanomolar doses of EN101, an antisense oligonucleotide that selectively lowers AChE-R in blood and muscle yet leaves unaffected the synaptic variant AChE-S. Whereas animals treated with placebo or conventional anticholinesterases continued to deteriorate, a 4 wk daily oral administration of EN101 improved survival, neuromuscular strength and clinical status in moribund EAMG rats. The efficacy of targeting only one AChE splicing variant highlights potential advantages of mRNA-targeted therapeutics for chronic cholinergic malfunctioning.

clinicaltrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654.

The study failed to show the superiority of memantine in this sample of patients with moderate-to-severe AD with significant baseline agitation and aggression. Methodological limitations could have contributed to these results.

Introduction Heterogeneity of outcomes in Alzheimer's disease (AD) clinical trials necessitates large sample sizes and contributes to study failures. This analysis determined whether mild-to-moderate AD populations could be enriched for cognitive decline based on apolipoprotein ( APOE ) ε4 genotype, family history of AD, and amyloid abnormalities. Methods Modeling estimated the number of randomized patients needed to detect a 2-point treatment difference on the AD Assessment Scale–Cognitive subscale using placebo data from three randomized, double-blind trials ( ClinicalTrials.gov Identifiers: NCT01955161 , NCT02006641 , and NCT02006654 ). Results An 80% power to detect a 2-point treatment effect required the randomization of 148 amyloid-positive patients; 178 ε4 homozygous or amyloid-positive patients; and 231 ε4 homozygous, family history-positive, or amyloid-positive patients, compared with 1619 unenriched patients (per arm). Discussion Enrichment in mild-to-moderate AD clinical trials can be achieved using combinations of biomarkers/risk factors to increase the likelihood of observing potential treatment effects.

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