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Einstein Researcher Demonstrates New Potential Use for FDA-Approved Drugs in Fighting Rare Childhood Disorder

April 16, 2004 -- (BRONX, NY) -- Finding alternative — and surprising — uses for FDA-approved drugs is a concept that has greatly intrigued Dr. David Lawrence, a professor of biochemistry at the Albert Einstein College of Medicine of Yeshiva University. Now, in results reported in the current on-line edition of the Journal of the American Chemical Society, he has shown that certain antibiotics may help in treating an invariably fatal genetically inherited disease.

Ataxia telangiectasia (A-T) is caused by mutations in a gene that codes for a protein called ATM. As with many rare childhood diseases, the mutations responsible for A-T are “stop mutations.” In the case of A-T, which occurs in 1 of every 40,000 births, these mutations completely or partially prevent the ATM protein from being formed. The body can’t perform several important functions when it lacks the normal ATM protein. As a result, children with A-T experience a variety of symptoms that can be best described as cancer, immune suppression, and Lou Gehrig’s disease all rolled into one. The disease eventually leads to premature death, usually in the teens or early 20s.

Gene therapy, which seeks to introduce a healthy gene into the patients’ cells to replace the abnormal or mutated gene, is one approach to treating genetic disorders. By contrast, Dr. Lawrence and his colleagues at Einstein sought to identify existing drugs that could “override” some of the mutations responsible for A-T so that cells might produce useful amounts of the ATM protein in its normal form. 

“We knew that the antibiotic gentamicin could cause cells to ignore certain mutations, so it has the potential for treating A-T and other disorders caused by these mutations,” he explains. “Unfortunately, gentamicin is a very toxic drug notorious for causing kidney damage and loss of hearing. Furthermore, it is extremely inefficient with respect to producing normal protein.”

The researchers hit upon a possible way to bolster gentamicin’s impact while simultaneously reducing the amount of drug required for treatment: Increasing the activity of the gene that codes for the ATM protein should allow gentamicin to produce greater amounts of the protein. Nearly 400 different FDA-approved drugs were tested to see if any stimulated the “promoter” region of the ATM gene, which is responsible for the gene’s activity. The Einstein team found several drugs with the desired properties and focused on two: ofloxacin (an antibiotic) and thioguanine (an anti-cancer drug).

“These drugs had the effect we were seeking,” says Dr. Lawrence. “Our results indicate that combining either one with gentamicin greatly increases protein production, overriding the mutation by as much as 40-fold compared with untreated cells.

“So far,” cautions Dr. Lawrence, “studies with these drugs have been limited to cells cultured in the laboratory. Furthermore, the drug combination has been shown to work with a specific type of mutation that is found in some, but not all, children with A-T. However, novel combinations of existing FDA-approved drugs represent a new strategy to ‘trick’ cells containing mutated genes into producing healthy protein. And, since we have focused on drugs already approved for human use, this should markedly reduce the expense and lead-time associated with their application to A-T and other genetic disorders.” 

This study was supported by the National Institutes of Health, the A-T Children's Project, and the A-T Medical Research Foundation.

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 Finding New Uses for Proven Medications In Fighting Rare Childhood Disorders

“With at least 400 FDA-approved drugs at our disposal, we have an abundance of resources, whose biochemical mechanisms of action are well understood, that we can study to determine new possible uses for addressing rare disorders,” says Dr. David Lawrence, professor of biochemistry at the Albert Einstein College of Medicine. “Just as aspirin initially was developed to relieve pain and was later found to prevent heart attacks, other FDA-approved drugs may offer additional applications beyond their initial disease targets.”

Dr. Lawrence and his colleagues at Einstein have recently shown that certain FDA-approved antibiotics may help in treating an invariably fatal genetic disease called ataxia telangiectasia (A-T). A-T is one of a number of rare childhood disorders that each affect less than 5,000 individuals annually. Other such diseases include Niemann Pick (average life span 2 to 3 years), Canavan (average life span 4 to 5 years), and Krabbe (average life span 2 to 3 years).

According to the National Organization for Rare Disorders, there are more than 6,000 rare diseases that afflict 25 million Americans, or 1 out of every 10. However, this averages out to just 4,000 people per disease. Yet, Dr. Lawrence notes, “Children represent a sizable portion of the individuals who suffer from these rare, often fatal, disorders. Since it takes on average of $500 million and 13 years to bring a new drug to market, there is little economic incentive for the pharmaceutical industry to create new drugs for disorders that affect so few people.

“Our goal is to explore the existing resources to identify potential treatments that can address the thousands of rare disorders for which new drug development is cost-prohibitive.” 

Ultimately, Dr. Lawrence and his Einstein colleagues hope to establish a Center for Rare Childhood Disorders through which the diseases and the avenues for their eradication could be studied. “The resources exist. Through screening and research I think the possibilities could be endless.”

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