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

Elsevier, EBioMedicine, Volume 59, September 2020
Szigeti K., Ihnatovych I., Birkaya B., Chen Z., Ouf A., Indurthi D.C. et al.
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. Funding:



Adult; Allele; Alleles; Alpha7 Nicotinic Acetylcholine Receptor; Alzheimer Disease; Alzheimer's Disease; Amyloid Beta Protein; Amyloid Beta-Peptides; Apoptosis; Article; Biological Marker; Biomarkers; Bungarotoxin Receptor; CHRFAM7A; CHRFAM7A Gene; Caspase; Cell Differentiation; Cell Line; Cholinergic Antagonists; Cholinergic Nerve Cell; Cholinergic Neurons; Cholinergic Receptor Blocking Agent; Cholinesterase Inhibitor; Chrna7 Protein, Human; Clinical Article; Clinical Outcome; Cognitive Defect; Cohort Analysis; Confocal Microscopy; Controlled Study; Cytotoxicity Assay; Donepezil; Double Blind Procedure; Drug Evaluation, Preclinical; Drug Response; Electrophysiology; Electroporation; Encenicline; Enzyme Linked Immunosorbent Assay; Expression Vector; Female; Flow Cytometry; Fluorescence Microscopy; Fluorescent Antibody Technique; Follow Up; Fusion Gene; Fusion Protein; Gene Dosage; Gene Editing; Gene Expression; Gene Frequency; Gene Overexpression; Genetic Transfection; Genetics; Genotype; Genotype Phenotype Correlation; HEK293 Cell Line; Human; Human Cell; Humans; IPSC; Immunophenotyping; Induced Pluripotent Stem Cell; Induced Pluripotent Stem Cells; Lactate Dehydrogenase; Lactate Dehydrogenase A; Male; Memantine; Metabolism; Middle Aged; Mini Mental State Examination; Mouse; Nonhuman; Outcome Assessment; Pharmacogenetic; Pharmacogenetic Testing; Phenotype; Preclinical Study; Priority Journal; Real Time Polymerase Chain Reaction; Recombinant Fusion Proteins; Rivastigmine; Skin Biopsy; Synaptic Transmission; Translational Medical Research; Translational Research; Treatment Outcome; Whole Genome Sequencing; Α7 NAChR; Global