A brand new Cleveland Clinic-led examine has recognized sildenafil – an FDA-approved remedy for erectile dysfunction (Viagra) and pulmonary hypertension (Revatio) – as a promising drug candidate to assist stop and deal with Alzheimer’s illness.
In response to findings revealed in Nature Aging, the analysis workforce, led by Feixiong Cheng, Ph.D., of Cleveland Clinic’s Genomic Medicine Institute, used computational methodology to display and validate FDA-approved medication as potential therapies for Alzheimer’s illness. By means of a large-scale evaluation of a database of greater than 7 million sufferers, they decided that sildenafil is related to 69% lowered incidence of Alzheimer’s illness, indicating the necessity for follow-up medical trial testing of the drug’s efficacy in sufferers with the illness.
Feixiong Cheng, Ph.D.
With out the event of efficient new therapies, Alzheimer’s illness is about to influence 13.8 million Individuals by 2050, underscoring the necessity for fast growth of prevention and therapy methods. Drug repurposing – use of an current drug for brand spanking new therapeutic functions – gives a sensible various to the expensive and time-consuming conventional drug discovery course of.
“This paper is an instance of a rising space of analysis in precision medication the place large information is essential to connecting the dots between current medication and a fancy illness like Alzheimer’s,” mentioned Jean Yuan, M.D., Ph.D., program director of Translational Bioinformatics and Drug Improvement on the Nationwide Institute on Growing old (NIA), a part of the Nationwide Institutes of Well being (NIH), which funded this analysis. “That is one in all many efforts we’re supporting to seek out current medication or out there secure compounds for different situations that will be good candidates for Alzheimer’s illness medical trials.”
Dr. Cheng’s workforce has discovered that understanding subtypes (endophenotypes) of neurodegenerative ailments comparable to Alzheimer’s illness could assist to disclose widespread underlying mechanisms and result in discovery of actionable targets for drug repurposing.
The buildup of beta amyloid and tau proteins within the mind results in amyloid plaques and tau neurofibrillary tangles – two hallmarks of Alzheimer’s-related mind adjustments. The quantity and placement of those proteins within the mind could assist outline endophenotypes. Nonetheless, no FDA-approved, anti-amyloid or anti-tau small molecule Alzheimer’s therapies presently exist, with many medical trials for such therapies having failed prior to now decade.
“Latest research present that the interaction between amyloid and tau is a higher contributor to Alzheimer’s than both by itself,” mentioned Dr. Cheng. “Subsequently, we hypothesized that medication focusing on the molecular community intersection of amyloid and tau endophenotypes ought to have the best potential for achievement.”
Utilizing a big gene-mapping community, researchers built-in genetic and different biologic information to find out which of over 1,600 FDA-approved medication could possibly be an efficient therapy for Alzheimer’s illness. They pinpointed medication that focus on each amyloid and tau as having increased scores in comparison with medication that focus on only one or the opposite. “Sildenafil, which has been proven to considerably enhance cognition and reminiscence in preclinical fashions, introduced as the most effective drug candidate,” mentioned Dr. Cheng.
The analysis workforce utilized a big database of claims information of greater than 7 million individuals within the U.S. to look at the connection between sildenafil and Alzheimer’s illness outcomes by evaluating sildenafil customers to non-users. The evaluation included sufferers utilizing comparator medication that both have been in an energetic Alzheimer’s medical trial (losartan or metformin) or weren’t but reported as related to the illness (diltiazem or glimepiride).
They discovered that sildenafil customers have been 69% much less more likely to develop Alzheimer’s illness than non-sildenafil customers after 6 years of follow-up. Particularly, sildenafil had a 55% lowered threat of the illness in comparison with losartan, 63% in comparison with metformin, 65% in comparison with diltiazem and 64% in comparison with glimepiride.
“Notably, we discovered that sildenafil use lowered the probability of Alzheimer’s in people with coronary artery illness, hypertension and kind 2 diabetes, all of that are comorbidities considerably related to threat of the illness, in addition to in these with out,” added Dr. Cheng.
To additional discover sildenafil’s impact on Alzheimer’s illness, the researchers developed an Alzheimer’s patient-derived mind cell mannequin utilizing stem cells. Within the mannequin, they discovered that sildenafil elevated mind cell development and decreased hyperphosphorylation of tau proteins (an indicator which results in neurofibrillary tangles), providing organic insights into how sildenafil could affect disease-related mind adjustments.
“As a result of our findings solely set up an affiliation between sildenafil use and lowered incidence of Alzheimer’s illness, we are actually planning a mechanistic trial and a part II randomized medical trial to check causality and ensure sildenafil’s medical advantages for Alzheimer’s sufferers,” mentioned Dr. Cheng. “We additionally foresee our strategy being utilized to different neurodegenerative ailments, together with Parkinson’s illness and amyotrophic lateral sclerosis, to speed up the drug discovery course of.”
Jiansong Fang, Ph.D., a former analysis scholar in Dr. Cheng’s lab; Pengyue Zhang, Ph.D., an assistant analysis professor at Indiana College College of Medication; Yadi Zhou, Ph.D., a knowledge scientist in Dr. Cheng’s lab; and Chien-Wei Chiang, Ph.D., a analysis scientist at The Ohio State College School of Medication, are co-first authors. Dr. Cheng introduced the preliminary findings on the 2021 Alzheimer’s Affiliation Worldwide Convention. The examine was supported by NIA, NIH grants R01AG066707 and R01AG066707-01S1, and the Translational Therapeutics Core of the Cleveland Alzheimer’s Illness Analysis Heart.
