Published October 6, 2020
New research reveals that certain studies — clinical trials on drugs that appeared not to benefit patients with Alzheimer’s disease — should now be reanalyzed in light of recent discoveries about a gene called CHRFAM7A.
The research builds on previous work led by Kinga Szigeti, MD, PhD, professor of neurology and director of UB’s Alzheimer’s Disease and Memory Disorders Center.
That work found that CHRFAM7A, which is unique to humans but isn’t present in everyone in its active form, can determine whether or not they will respond to three out of the four Alzheimer’s disease treatments approved by the Food and Drug Administration that increase acetylcholine, a neurotransmitter involved in learning and memory.
The previous work illuminated why promising mice studies of potential Alzheimer’s drugs targeting the alpha 7 nicotinic receptor appeared to be unsuccessful when they advanced to human trials.
“This uniquely human gene modifies the alpha 7 nicotinic receptor, and as a consequence, drugs that are optimized in mice are insufficient for 75 percent of the population that has the active CHRFAM7A gene and the humanized receptor,” says Szigeti, corresponding author, who practices through UBMD Neurology.
“This underlying, previously unknown genetic heterogeneity, especially with this ratio, undermined drug development efforts,” she explains. “Our data indicate that drugs that target the nerve cells in which acetylcholine acts as a neurotransmitter, known as the cholinergic system, may benefit 25 percent of the individuals, and now we can identify who they are.”
“For Alzheimer’s, if we can treat 25 percent of patients, that is 1.5 million people,” says Szigeti. “That would be a major advance.”
The research was conducted on induced pluripotent stem cells (iPSC) converted from the skin cells of patients with Alzheimer’s disease and validated in clinical data from a 10-year, longitudinal, multicenter cohort study by the Texas Alzheimer’s Research and Care Consortium (TARCC) on 345 Alzheimer’s patients, as well as data from the University at Buffalo cohort.
The new research reports results from the iPSC model and the pharmacogenetic studies.
“This system that we created models the 25 percent of patients who could respond to the cholinergic drugs that supposedly failed in clinical trials” says Szigeti. She explains that it contrasts the patients with the 75 percent of people likely needing a different approach.
“This is the best evidence so far that those clinical trials should be reanalyzed,” she notes.
The research also provides evidence that individualizing treatment to patients’ genotypes will be key to attacking Alzheimer’s disease.
The paper reports that this is the first proof of concept study that genotype and mechanism specific treatment is feasible in Alzheimer’s disease.
The researchers have concluded that instead of one disease for which a single drug is the solution, Alzheimer’s disease may, like cancer, represent a number of diseases, each of which will require its own targeted treatment.
“It takes a simple blood test to determine a patient’s genotype, which will reveal whether or not a patient will respond to this class of drugs,” Szigeti says.
The research was published online in EBioMedicine in August.
It would need to be validated in larger, double-blind clinical trials, Szigeti says.
She notes that this can be achieved by reanalyzing the completed trials, saving millions of dollars.
The research was supported by the TARCC and funded by the state of Texas through the Texas Council on Alzheimer’s Disease and Related Disorders; the Alzheimer’s Association; the Edward A. and Stephanie E. Fial Fund and the Community Foundation for Greater Buffalo.
Co-authors on “CHRFAM7A: A Human Specific Fusion Gene, Accounts for the Translational Gap for Cholinergic Strategies in Alzheimer’s Disease” are: