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

Kinga Szigeti; Ivanna Ihnatovych; Barbara Birkaya; Ziqiang Chen; Aya Ouf; Dinesh C. Indurthi; Jonathan E. Bard; Julien Kann; Alexandrea Adams; Lee Chaves; Norbert Sule; Joan S. Reisch; Valory Pavlik; Ralph H.B. Benedict; Anthony Auerbach; Gregory Wilding

doi:10.1016/j.ebiom.2020.102892

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

Kinga Szigeti, Ivanna Ihnatovych, Barbara Birkaya, Ziqiang Chen, Aya Ouf, Dinesh C. Indurthi, Jonathan E. Bard, Julien Kann, Alexandrea Adams, Lee Chaves, Norbert Sule, Joan S. Reisch, Valory Pavlik, Ralph H.B. Benedict, Anthony Auerbach, Gregory Wilding

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

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.

Original language	English (US)
Article number	102892
Journal	EBioMedicine
Volume	59
DOIs	https://doi.org/10.1016/j.ebiom.2020.102892
State	Published - Sep 2020

Keywords

Alzheimer's disease
CHRFAM7A
Pharmacogenetic
iPSC
α7 nAChR

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.ebiom.2020.102892

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Szigeti, K., Ihnatovych, I., Birkaya, B., Chen, Z., Ouf, A., Indurthi, D. C., Bard, J. E., Kann, J., Adams, A., Chaves, L., Sule, N., Reisch, J. S., Pavlik, V., Benedict, R. H. B., Auerbach, A., & Wilding, G. (2020). CHRFAM7A: A human specific fusion gene, accounts for the translational gap for cholinergic strategies in Alzheimer's disease. EBioMedicine, 59, Article 102892. https://doi.org/10.1016/j.ebiom.2020.102892

Szigeti, K, Ihnatovych, I, Birkaya, B, Chen, Z, Ouf, A, Indurthi, DC, Bard, JE, Kann, J, Adams, A, Chaves, L, Sule, N, Reisch, JS, Pavlik, V, Benedict, RHB, Auerbach, A & Wilding, G 2020, 'CHRFAM7A: A human specific fusion gene, accounts for the translational gap for cholinergic strategies in Alzheimer's disease', EBioMedicine, vol. 59, 102892. https://doi.org/10.1016/j.ebiom.2020.102892

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

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",

author = "Kinga Szigeti and Ivanna Ihnatovych and Barbara Birkaya and Ziqiang Chen and Aya Ouf and Indurthi, {Dinesh C.} and Bard, {Jonathan E.} and Julien Kann and Alexandrea Adams and Lee Chaves and Norbert Sule and Reisch, {Joan S.} and Valory Pavlik and Benedict, {Ralph H.B.} and Anthony Auerbach and Gregory Wilding",

note = "Funding Information: This study was made possible in part by the Texas Alzheimer's Research Consortium (TARCC) funded by the state of Texas through the Texas Council on Alzheimer's Disease and Related Disorders . This work was supported by Alzheimer Association AARG-16–443615 , Edward A. and Stephanie E. Fial Fund, Community Foundation for Greater Buffalo. Funding Information: NCRAD receives government support under a cooperative agreement grant ( U24 AG21886 ) awarded by the National Institute on Aging (NIA). We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. The funding agencies had no role in study design, data collection, data analysis, interpretation or writing of the report. Funding Information: This study was made possible in part by the Texas Alzheimer's Research Consortium (TARCC) funded by the state of Texas through the Texas Council on Alzheimer's Disease and Related Disorders. This work was supported by Alzheimer Association AARG-16?443615, Edward A. and Stephanie E. Fial Fund, Community Foundation for Greater Buffalo. NCRAD receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA). We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. The funding agencies had no role in study design, data collection, data analysis, interpretation or writing of the report. Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2020",

month = sep,

doi = "10.1016/j.ebiom.2020.102892",

language = "English (US)",

volume = "59",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier BV",

}

TY - JOUR

T1 - CHRFAM7A

T2 - A human specific fusion gene, accounts for the translational gap for cholinergic strategies in Alzheimer's disease

AU - Szigeti, Kinga

AU - Ihnatovych, Ivanna

AU - Birkaya, Barbara

AU - Chen, Ziqiang

AU - Ouf, Aya

AU - Indurthi, Dinesh C.

AU - Bard, Jonathan E.

AU - Kann, Julien

AU - Adams, Alexandrea

AU - Chaves, Lee

AU - Sule, Norbert

AU - Reisch, Joan S.

AU - Pavlik, Valory

AU - Benedict, Ralph H.B.

AU - Auerbach, Anthony

AU - Wilding, Gregory

N1 - Funding Information: This study was made possible in part by the Texas Alzheimer's Research Consortium (TARCC) funded by the state of Texas through the Texas Council on Alzheimer's Disease and Related Disorders . This work was supported by Alzheimer Association AARG-16–443615 , Edward A. and Stephanie E. Fial Fund, Community Foundation for Greater Buffalo. Funding Information: NCRAD receives government support under a cooperative agreement grant ( U24 AG21886 ) awarded by the National Institute on Aging (NIA). We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. The funding agencies had no role in study design, data collection, data analysis, interpretation or writing of the report. Funding Information: This study was made possible in part by the Texas Alzheimer's Research Consortium (TARCC) funded by the state of Texas through the Texas Council on Alzheimer's Disease and Related Disorders. This work was supported by Alzheimer Association AARG-16?443615, Edward A. and Stephanie E. Fial Fund, Community Foundation for Greater Buffalo. NCRAD receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA). We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. The funding agencies had no role in study design, data collection, data analysis, interpretation or writing of the report. Publisher Copyright: © 2020 The Author(s)

PY - 2020/9

Y1 - 2020/9

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - CHRFAM7A

KW - Pharmacogenetic

KW - iPSC

KW - α7 nAChR

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

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