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How HIV drugs may be able to treat blindness

November 22, 2014, 3:00 PM UTC
Dollar Sign made of pills
Photograph by Dwight Eschliman—Getty Images

“Screw the FDA. I’m gonna be… D.O.A.”

So says Ron Woodroof (played by Matthew McConaughey) to Dr. Eve Saks (Jennifer Garner) in the 2013 film Dallas Buyers Club, when she tells him the drugs he wants aren’t FDA-approved. The film was set during the beginning of the HIV outbreak in the United States, and moved audiences to tears with its truths. But three decades after the global dissemination of HIV, another plague is threatening our nation and the rest of the world as well. And the urgency to eradicate it is as great as ever.

No, it’s not Ebola. The untreatable, blinding disease called “dry” age-related macular degeneration (AMD) afflicts as many people as Alzheimer’s disease, and rivals all solid cancers combined.

According to a recent national public opinion poll, Americans feared losing their eyesight more than any other sense, and were just as scared of going blind as they were of getting Alzheimer’s disease, cancer, or HIV/AIDS. In fact, when the earliest HIV/AIDS patients were given the cruel choice between medications that would preserve eyesight, or medications that could save their life at the cost of sight, they opted to save their eyes. If we fail to bend the trajectory of this disease, by 2020, 30 million Americans (and 200 million around the world) are projected to have AMD. While AMD doesn’t kill, its threat is both frightening and inevitable to the aging Baby Boomer.

There’s hope. As we reveal this week in the medical journal Science, an old class of HIV/AIDS therapeutics, known as “nucleoside reverse transcriptase inhibitors” (NRTIs), has a surprising anti-inflammatory activity that could be harnessed to treat blindness—and other ailments as well. Although NRTIs are typically thought of as anti-HIV drugs, they were originally designed to treat cancer. Jerome Horwitz discovered the chemical known as AZT in 1964, but it failed to cure cancer and was forgotten for decades. In the 1980s, when AZT famously re-emerged (many readers may know of it only from the Broadway musical Rent), it became the first FDA-approved treatment for HIV/AIDS, and has since helped save millions of lives. Fifty years after Horwitz’s seminal work, AZT and sister compounds are getting another makeover—to treat blindness.

In AMD, the cells that support the retina can deteriorate, which leads to blindness. In 2011, we discovered that one reason these cells die off is that they accumulate toxic molecules derived from “junk” DNA. This junk DNA, known as Alu, originated around the time when dinosaurs went extinct. Since then, Alu has reproduced in our bodies to over 1 million copies, making up, today, an astounding 11 percent of a person’s DNA by mass. AZT and other NRTI drugs block the life cycle of both Alu and HIV. Blocking this life cycle in HIV patients, of course, is therapeutic; we wondered what would happen if we used NRTIs to block Alu replication in the eyes of mice that have AMD-like symptoms.

We found that multiple FDA-approved NRTI drugs did stave off cell death in the mice, but not for the reasons we expected. The NRTIs were effective even without successfully blocking Alu. What the NRTIs did block was unexpected: a group of proteins called the inflammasome. An overactive inflammasome is thought to give rise to many other diseases, including Alzheimer’s disease, diabetes, and atherosclerosis.

A major advantage to re-purposing NRTIs to treat dry AMD is that many common obstacles to their development have already been addressed. Thankfully, most of the negative side effects originally associated with NRTI use can be avoided today through reduced dosing regimens and the use of newer compounds with better safety profiles. For example, one of the NRTI drugs we tested, lamivudine, is remarkably safe and has been given to some HIV and Hepatitis-B patients for many years, with almost no negative effects. (Interestingly, lamivudine is also being considered right now as a potential treatment for Ebola.) In our work, we found that dry AMD in mice could be treated using NRTIs in even lower doses than the equivalent amount given safely to humans. (Normally, with all drug trials on mice, the mice need higher doses than humans, due to their high metabolism.) This finding, in combination with a wealth of clinical data garnered over decades of human NRTI use, should help guide the development of new, safe approaches for people with AMD.

Another important benefit of re-purposing NRTIs is that they can be used immediately “off-label”—that is, to treat diseases for which they were not originally intended. If we started a trial today, and NRTIs were effective in treating AMD, they could be approved for use in as little as 2-3 years, for less than $10 million.

By contrast, the typical time for FDA approval of new drugs is 10-15 years, a process that can cost over $2 billion. The cost to Medicare (and therefore ultimately to all taxpayers) could be relatively low at the current dirt-cheap prices of generic NRTIs. Recently, yes, some generic and off-patent drug prices have skyrocketed. One reason for that is the FDA’s removal of over 1,000 unapproved medications from the market through the Unapproved Drug Act of 2006. Although well intended, and in the interest of patient safety, the subsequent re-approval of these drugs can result in dramatic price increases, especially if only one company chooses to front the costs of drug re-development. This is how the price of colchicine, a drug commonly used to treat gout, increased an astonishing 5,000 percent in 2009. Because NRTIs are already FDA-approved, they should be less prone to such price gouging.

Even so, there are examples of price-hikes for existing FDA-approved drugs. When asthma inhalers were reformulated to remove chlorofluorocarbon propellants, a fresh batch of patents ensured that many inexpensive generics would no longer be available. The cost of albuterol went up 700 percent after such re-patenting. Expensive drug recycling is not uncommon with other hard-to-copy drug reformulations, such as gels, creams, patches, and combinations of drugs. But such absurd price increases are unlikely to affect NRTIs, which exist as pills with a single active ingredient that is easy to make.

Our work also raises the possibility that NRTIs could be re-designed and improved. For example, we created a next-generation NRTI that retains anti-inflammatory activity but lacks the chemical group thought to be largely responsible for adverse effects.

We have exciting plans to begin clinical trials using NRTIs for AMD. We hope that our findings will encourage others to leverage the newfound anti-inflammatory function of NRTIs in the treatment of other diseases, and to explore new areas where re-purposing old drugs can have a huge impact.

After his failed attempts to cure cancer, Horwitz joked that NRTIs were, “A very interesting set of compounds that were waiting for the right disease.” Let’s not wait any longer.

Benjamin Fowler is a postdoctoral fellow at the University of Kentucky College of Medicine. Balamurali Ambati is Professor of Ophthalmology and Visual Sciences and Director of Cornea Research at the University of Utah John A. Moran Eye Center. Jayakrishna Ambati is Professor & Vice Chair of Ophthalmology and Visual Sciences at the University of Kentucky College of Medicine.