CHRFAM7A: A human specific fusion gene, accounts for the translational gap for cholinergic strategies in Alzheimer's disease

EBioMedicine. 2020 Sep;59:102892. doi: 10.1016/j.ebiom.2020.102892. Epub 2020 Aug 17.

Abstract

Background: Cholinergic neuronal loss is one of the hallmarks of AD related neurodegeneration; however, preclinical promise of α7 nAChR drugs failed to translate into humans. CHRFAM7A, a uniquely human fusion gene, is a negative regulator of α7 nAChR and was unaccounted for in preclinical models.

Methods: Molecular methods: Function of CHRFAM7A alleles was studied in vitro in two disease relevant phenotypic readouts: electrophysiology and Aβ uptake. Genome edited human induced pluripotent stem cells (iPSC) were used as a model system with the human context. Double blind pharmacogenetic study: We performed double-blind pharmacogenetic analysis on the effect of AChEI therapy based on CHRFAM7A carrier status in two paradigms: response to drug initiation and DMT effect. Mini Mental Status Examination (MMSE) was used as outcome measure. Change in MMSE score from baseline was compared by 2-tailed T-test. Longitudinal analysis of clinical outcome (MMSE) was performed using a fitted general linear model, based on an assumed autoregressive covariance structure. Model independent variables included age, sex, and medication regimen at the time of the first utilized outcome measure (AChEI alone or AChEI plus memantine), APOE4 carrier status (0, 1 or 2 alleles as categorical variables) and CHRFAM7A genotype.

Findings: The direct and inverted alleles have distinct phenotypes. Functional CHRFAM7A allele classifies the population as 25% non-carriers and 75% carriers. Induced pluripotent stem cell (iPSC) models α7 nAChR mediated Aβ neurotoxicity. Pharmacological readout translates into both first exposure (p = 0.037) and disease modifying effect (p = 0.0048) in two double blind pharmacogenetic studies.

Interpretation: CHRFAM7A accounts for the translational gap in cholinergic strategies in AD. Clinical trials not accounting for this uniquely human genetic factor may have rejected drug candidates that would benefit 25% of AD. Reanalyses of the completed trials using this pharmacogenetic paradigm may identify effective therapy.

Keywords: Alzheimer's disease; CHRFAM7A; Pharmacogenetic; iPSC; α7 nAChR.

MeSH terms

  • Alleles
  • Alzheimer Disease / diagnosis
  • Alzheimer Disease / etiology
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / therapy*
  • Amyloid beta-Peptides / metabolism
  • Biomarkers
  • Cell Line
  • Cholinergic Antagonists / pharmacology
  • Cholinergic Antagonists / therapeutic use
  • Cholinergic Neurons / metabolism*
  • Drug Evaluation, Preclinical
  • Fluorescent Antibody Technique
  • Gene Dosage
  • Gene Frequency
  • Genotype
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Phenotype
  • Recombinant Fusion Proteins*
  • Synaptic Transmission
  • Translational Research, Biomedical
  • Treatment Outcome
  • alpha7 Nicotinic Acetylcholine Receptor / genetics*
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism

Substances

  • Amyloid beta-Peptides
  • Biomarkers
  • Cholinergic Antagonists
  • Chrna7 protein, human
  • Recombinant Fusion Proteins
  • alpha7 Nicotinic Acetylcholine Receptor