The buildup of beta amyloid and tau proteins in the brain leads to amyloid plaques and tau neurofibrillary tangles– two trademarks of Alzheimers- associated brain modifications. No FDA-approved, anti-amyloid or anti-tau little molecule Alzheimers treatments currently exist, with numerous clinical trials for such treatments having actually stopped working in the previous years.
Using a big gene-mapping network, scientists integrated other and genetic biologic data to determine which of over 1,600 FDA-approved drugs could be a reliable treatment for Alzheimers illness. Dr. Cheng provided the initial findings at the 2021 Alzheimers Association International Conference. The research study was supported by NIA, NIH grants R01AG066707 and R01AG066707-01S1, and the Translational Therapeutics Core of the Cleveland Alzheimers Disease Research.
A new Cleveland Clinic-led research study has determined sildenafil– an FDA-approved treatment for impotence (Viagra) and lung hypertension (Ravatio)– as a promising drug prospect to assist treat and avoid Alzheimers disease.
According to findings published in Nature Aging, the research group, led by Feixiong Cheng, Ph.D., of Cleveland Clinics Genomic Medicine Institute, utilized computational methodology to screen and verify FDA-approved drugs as potential therapies for Alzheimers disease. Through a large-scale analysis of a database of more than 7 million clients, they figured out that sildenafil is connected with 69% decreased incidence of Alzheimers disease, showing the requirement for follow-up clinical trial testing of the drugs effectiveness in patients with the illness.
” Recent research studies reveal that the interplay in between amyloid and tau is a higher factor to Alzheimers than either by itself,” stated Dr. Cheng. “Therefore, we hypothesized that drugs targeting the molecular network intersection of amyloid and tau endophenotypes should have the greatest potential for success.”
Without the development of effective brand-new treatments, Alzheimers illness is set to impact 13.8 million Americans by 2050, underscoring the need for rapid advancement of prevention and treatment techniques. Drug repurposing– usage of an existing drug for brand-new restorative purposes– uses a practical option to the time-consuming and costly standard drug discovery process.
According to findings released in Nature Aging, the research group, led by Feixiong Cheng, Ph.D., of Cleveland Clinics Genomic Medicine Institute, identified that sildenafil is related to 69% minimized incidence of Alzheimers disease. Credit: Cleveland Clinic
” This paper is an example of a growing area of research study in accuracy medicine where big information is key to connecting the dots between existing drugs and a complex disease like Alzheimers,” said Jean Yuan, M.D., Ph.D., program director of Translational Bioinformatics and Drug Development at the National Institute on Aging (NIA), part of the National Institutes of Health (NIH), which funded this research. “This is one of numerous efforts we are supporting to discover existing drugs or readily available safe compounds for other conditions that would be good candidates for Alzheimers illness clinical trials.”
Dr. Chengs team has found that comprehending subtypes (endophenotypes) of neurodegenerative diseases such as Alzheimers disease may help to expose typical underlying mechanisms and cause discovery of actionable targets for drug repurposing.
The accumulation of beta amyloid and tau proteins in the brain results in amyloid plaques and tau neurofibrillary tangles– two trademarks of Alzheimers- related brain modifications. The amount and location of these proteins in the brain may assist specify endophenotypes. No FDA-approved, anti-tau or anti-amyloid little particle Alzheimers treatments currently exist, with lots of medical trials for such treatments having actually failed in the past years.
” Recent studies show that the interplay in between amyloid and tau is a greater factor to Alzheimers than either by itself,” stated Dr. Cheng. “Therefore, we hypothesized that drugs targeting the molecular network intersection of amyloid and tau endophenotypes should have the best capacity for success.”
Utilizing a large gene-mapping network, scientists incorporated other and hereditary biologic data to determine which of over 1,600 FDA-approved drugs could be an efficient treatment for Alzheimers disease. They determined drugs that target both amyloid and tau as having actually greater scores compared to drugs that target just one or the other. “Sildenafil, which has actually been revealed to considerably improve cognition and memory in preclinical models, presented as the finest drug prospect,” stated Dr. Cheng.
The research team utilized a big database of claims data of more than 7 million individuals in the U.S. to take a look at the relationship between sildenafil and Alzheimers illness results by comparing sildenafil users to non-users. The analysis included clients using comparator drugs that either were in an active Alzheimers clinical trial (losartan or metformin) or were not yet reported as relevant to the disease (diltiazem or glimepiride).
They found that sildenafil users were 69% less most likely to establish Alzheimers illness than non-sildenafil users after 6 years of follow-up. Specifically, sildenafil had a 55% minimized risk of the illness compared to losartan, 63% compared to metformin, 65% compared to diltiazem and 64% compared to glimepiride.
” Notably, we discovered that sildenafil use reduced the likelihood of Alzheimers in individuals with coronary artery illness, high blood pressure, and type 2 diabetes, all of which are comorbidities considerably connected with risk of the disease, along with in those without,” added Dr. Cheng.
To further explore sildenafils result on Alzheimers disease, the scientists established an Alzheimers patient-derived brain cell model using stem cells. In the model, they found that sildenafil increased brain cell growth and decreased hyperphosphorylation of tau proteins (a hallmark that results in neurofibrillary tangles), offering biological insights into how sildenafil might affect disease-related brain changes.
” Because our findings just develop an association between sildenafil use and lowered incidence of Alzheimers disease, we are now planning a mechanistic trial and a phase II randomized scientific trial to check causality and confirm sildenafils clinical benefits for Alzheimers patients,” stated Dr. Cheng. “We likewise anticipate our technique being applied to other neurodegenerative diseases, consisting of Parkinsons illness and amyotrophic lateral sclerosis, to speed up the drug discovery process.”
Recommendation: “Endophenotype-based in silico network medicine discovery integrated with insurance record information mining identifies sildenafil as a candidate drug for Alzheimers disease” 6 December 2021, Nature Aging.DOI: 10.1038/ s43587-021-00138-z.
Jiansong Fang, Ph.D., a previous research scholar in Dr. Chengs laboratory; Pengyue Zhang, Ph.D., an assistant research professor at Indiana University School of Medicine; Yadi Zhou, Ph.D., an information scientist in Dr. Chengs lab; and Chien-Wei Chiang, Ph.D., a research study researcher at The Ohio State University College of Medicine, are co-first authors. Dr. Cheng provided the initial findings at the 2021 Alzheimers Association International Conference. The study was supported by NIA, NIH grants R01AG066707 and R01AG066707-01S1, and the Translational Therapeutics Core of the Cleveland Alzheimers Disease Research.
Cleveland Clinic research study recognizes sildenafil as prospect drug for Alzheimers illness.
Findings published in Nature Aging show 69% minimized probability of developing the disease.
