Navigation Links
Study targets key molecule to reverse kidney damage in mice
Date:3/7/2012

BOSTON -- In findings that may lead to clinical trials of a promising new drug for kidney disease, researchers at Beth Israel Deaconess Medical Center (BIDMC) and their colleagues have identified a key molecular player and shown how a targeted experimental drug can reverse kidney damage in mouse models of diabetes, high blood pressure, genetic kidney disease, and other kidney injuries.

The study builds on a discovery that, in mice, a key protein can repair and reverse renal fibrosis, the critical damage caused by different kidney diseases in humans. The new paper details 10 years of methodical follow-up experiments to understand, verify and harness the protective molecular process with a new drug that can be tested in people. The paper appears in the March 2012 issue of Nature Medicine.

"This paper reports the discovery of one of the first targeted drugs specifically developed to reverse fibrosis and regenerate the kidney," said senior author Raghu Kalluri, MD, PhD, Chief of the Division of Matrix Biology at BIDMC and Professor of Medicine at Harvard Medical School (HMS). "We're optimistic about the benefits, but the real proof will come from clinical testing."

Chronic kidney disease is becoming a major public health problem, partly due to the increase in obesity, diabetes, hypertension and an aging population. It affects one out of every 10 people older than 20, and is most prevalent in those over 60. Most people with impaired kidney function are in the early stages and have no symptoms, but deteriorating kidneys significantly raise the risk of death by cardiovascular disease. Those who survive heart attacks and strokes can progress to end-stage renal disease, which requires dialysis in most cases or transplants when donor kidneys are available.

"The field is desperate for new interventions that can halt or slow the progression of renal failure," said nephrologist Qais Al-Awqati, MB, ChB, a professor of medicine and physiology at Columbia University and immediate past editor of the journal Kidney International. Al-Awqati, who was not involved in the study, notes that kidney disease is the third leading cause of death in the U.S.

In the kidneys and other organs, fibrosis develops from normal repair mechanisms that do not stop. Scar tissue slowly builds up and replaces the working cells of the organ. In 2003, Kalluri's lab reported that the destructive fibrosis in mice can be countered by the human protein BMP-7, originally named for its ability to spur bone growth. A manmade version of BMP-7 is approved by the U.S. Food & Drug Administration (FDA) to help repair long bones and vertebrate disks. However, the large protein needs to be injected or surgically implanted and, therefore, is not useful for long-term treatment protocols.

Kalluri and his colleagues continued their studies, seeking a smaller molecule that could be taken by mouth in a pill form in order to more specifically exert its protective effect on the kidney. Probing deeper into the biology of the kidney, they identified the protein Alk3, which is not the protein's primary partner in bone.

Soon after the BIDMC team identified the key receptor Alk3 in the lab, they collaborated with a Canadian biotechnology company, Thrasos Therapeutics, interested in developing targeted therapies for the prevention and treatment of severe organ failure, especially kidney disease. Based on the details about the molecular interaction between the BMP protein and the ALK receptor, company scientists developed a class of small functional peptides, including THR-123, which then underwent further testing.

Researchers in the Kalluri lab used the experimental compound to document the role of the receptor in reversing the fibrosis and allowing normal tissue to regenerate in one mouse model after another. "This receptor must be present for the new molecule to function," said Kalluri. Working through the receptor, the molecule suppressed inflammation, cell death and fibrosis formation, as well as reversing established fibrosis and allowing kidneys to regenerate functional cells, he adds.

Further experiments showed that the test drug worked even better in the mice when given in combination with ACE inhibitors, the anti-hypertensive drugs now considered a standard therapy for chronic kidney disease which work by targeting another molecular process.

"Targeting the receptor not only stops fibrosis, it removes established fibrosis, and it works in combination with an existing drug used in patients," Kalluri notes. "The next step is to test this molecule in the clinic."

The mice studies are "a good first step," said Al-Awqati. "It will be interesting to pin down the role of the BMP-7 pathway in kidney fibrosis in people."

Going forward, Kalluri's group will continue to study these molecular players and their roles in fibrosis in other organs, including the liver, lung, intestine and heart in the hopes of expanding the experimental-drug pipeline. "If you don't have a pipeline of experimental drugs, how will you succeed in coming up with new drugs?" he asks.


'/>"/>

Contact: Bonnie Prescott
bprescot@bidmc.harvard.edu
617-667-7306
Beth Israel Deaconess Medical Center
Source:Eurekalert

Related medicine news :

1. Despite Treatment, Employees with Depression Generate Higher Absentee Costs, According to Thomson Reuters Study
2. American Council on Exercise (ACE) Study Reveals Kettlebells Provide Powerful Workout in Short Amount of Time
3. TV drama can be more persuasive than news program, study finds
4. Study carried out into biological risks of eating reptiles
5. Neuroimaging study may pave way for effective Alzheimers treatments
6. Study finds racial gaps continue in heart disease awareness
7. Luth Researchs IndicatorEDG(TM) Study Finds Americans Hopes of Achieving Their Dreams Are Fading
8. First blinded study of venous insufficiency prevalence in MS shows promising results
9. Soothing infants with food focus of childhood obesity study
10. People with anxiety disorder less able to regulate response to negative emotions, study shows
11. American Heart Association Rapid Access Journal Report: Study Finds Racial Gaps Continue in Heart Disease Awareness, Low Knowledge of Heart Attack Warning Signs Among Women
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/12/2016)... ... February 12, 2016 , ... Donor Network West, the organ procurement ... announced a partnership with San Ramon Regional Medical Center. Under the collaboration, the first ... a way to accommodate a more certain time frame for donor families for the ...
(Date:2/12/2016)... NY (PRWEB) , ... February 12, 2016 , ... ... of “Revolutionizing Cancer Care.” , The print component of “Revolutionizing Cancer ... Dallas, Pittsburgh/Cleveland, New York, Washington DC/Baltimore, and Seattle, with a circulation of approximately ...
(Date:2/12/2016)... San Rafael, CA (PRWEB) , ... February 12, 2016 , ... ... camps outside Des Moines, Iowa. Legacy Golf Club, located in Norwalk, serves as the ... Teacher of the Year, Rob Randall. , “We have had successful camps in recent ...
(Date:2/12/2016)... ... February 12, 2016 , ... ... growth in the field of long term care. With that, says Patrick Loughney, ... healthcare professionals in administrative roles in long term care environments. His company, which ...
(Date:2/12/2016)... , ... February 12, 2016 , ... With the exception of restorative dentistry, to date ... decay. With the recent approval by the FDA, there is a now a new ... fluoride varnish, SDF is very simple and quick to apply. The application is as ...
Breaking Medicine News(10 mins):
(Date:2/11/2016)...   Health 2.0 , the premiere showcase and ... today " 10 Year Global Retrospective ", a platform ... past ten years.   --> ... has served as the preeminent thought-leader in the health ... technologies, companies, innovators, and patient-activists through an array of ...
(Date:2/11/2016)... N.C. , Feb. 11, 2016 ... leading provider of custom manufacturing and development services ... expanded sterile fill-finish capabilities and capacity in its ... growth in demand has driven several recent investments. ... 2001 it had one filling line with small-scale ...
(Date:2/11/2016)... 11 de fevereiro de 2016  A Proliant ... fábrica de soroalbumina bovina (BSA -- Bovine ... fica na Ilha Norte da Nova Zelândia, em ... estabelecido na fábrica da Proliant nos EUA, localizada ... projeto e instalação dos equipamentos foram feitos de ...
Breaking Medicine Technology: