Existing FDA-Approved HIV/AIDS Drugs Could Be Repurposed to Treat Macular Degeneration

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A retinal photograph of dry AMD

An international research group has reported that HIV/AIDS drugs, in use for the last 30 years, could be repurposed to treat age-related macular degeneration (AMD), as well as other systemic inflammatory disorders.

Their research tested the treatment effects of nucleoside reverse transcriptase inhibitors (NRTIs) on dry AMD in laboratory mice. NRTIs are a class of drugs that were designed to treat cancer in the 1960s. They emerged again in the late 1980s and became the first FDA-approved drugs for the treatment of HIV/AIDS. In persons with HIV, NRTIs block an enzyme the virus uses to create more copies of itself.

The new research demonstrates that NRTIs prevented retinal degeneration in a mouse model of dry AMD by blocking the activity of a biological pathway that activates inflammatory processes in the body. The researchers are planning to begin human clinical trials early next year, with results about the drug's effectiveness expected in two to three years.

From the Journal Science

The research, entitled Nucleoside reverse transcriptase inhibitors [NRTIs] possess intrinsic anti-inflammatory activity was published in the November 21, 2014 edition of Science. Founded in 1880, Science is a peer-reviewed, general science journal that publishes cutting-edge international scientific research, news, commentary, and opinion. It is published by the American Association for the Advancement of Science (AAAS), the world's largest general-science society.

The research was conducted by an international group of scientists who represent the following institutions: the University of Kentucky; Institute of Genetics and Biophysics, Naples, Italy; the National Cancer Institute, National Institutes of Health, Bethesda, MD; Cardiff University, United Kingdom; the University of Calgary, Alberta, Canada; Chapman University School of Pharmacy, Irvine, CA; and Keck School of Medicine of the University of Southern California, Los Angeles, CA.

About Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a gradual, progressive, painless deterioration of the macula, the small sensitive area in the center of the retina that provides clear central vision. Damage to the macula impairs the central (or "detail") vision that helps with essential everyday activities such as reading, preparing meals, watching television, and playing card and board games. AMD is the leading cause of vision loss for people aged 60 and older in the United States.

About Dry Macular Degeneration

The dry (also called atrophic) type of AMD affects approximately 80-90% of individuals with AMD. Its cause is unknown, it tends to progress more slowly than the wet type, and there is not – as of yet – an approved treatment or cure. "Atrophy" refers to the degeneration of cells in a portion of the body; in this case, the cell degeneration occurs in the retina.

In dry age-related macular degeneration, small white or yellowish deposits, called drusen, form on the retina, in the macula, causing it to deteriorate or degenerate over time.

Photograph of a retina with drusen

A retina with drusen

Drusen are the hallmark of dry AMD. These small yellow deposits beneath the retina, near Bruch's membrane, are a buildup of waste materials, composed of cholesterol, protein, and fats. Typically, when drusen first form, they do not cause vision loss. However, they are a risk factor for progressing to vision loss.

Wet (Neovascular) Macular Degeneration

In wet, or exudative, macular degeneration (AMD), the choroid (a part of the eye containing blood vessels that nourish the retina) begins to sprout abnormal new blood vessels that develop into a cluster under the macula, called choroidal neovascularization (neo = new; vascular = blood vessels).

The macula is the part of the retina that provides the clearest central vision. Because these new blood vessels are abnormal, they tend to break, bleed, and leak fluid under the macula, causing it to lift up and pull away from its base. This damages the fragile photoreceptor cells, which sense and receive light, resulting in a rapid and severe loss of central vision.

About the Research

Excerpted from HIV drugs could treat blindness, via IOL SciTech:

HIV drugs called nucleoside reverse transcriptase inhibitors (NRTIs), including AZT and three others, blocked age-related macular degeneration in mice and worked well in experiments involving human retinal cells in the laboratory.

In HIV-infected people, NRTIs block an enzyme the virus uses to create more copies of itself. The new research shows the drugs also block the activity of a biological pathway responsible for activating inflammatory processes in the body.

It is that previously unrecognized quality that makes NRTIs promising for treating macular degeneration as well as graft-versus-host disease, a rarer ailment that can occur after a stem cell or bone marrow transplant, the researchers said.

In the new study, the NRTIs blocked a powerful collection of proteins that can kill cells in the retina, thus preserving vision in mice. Researchers are planning for clinical trials in the coming months and it could be known in as soon as two to three years whether the drugs are effective in treating macular degeneration in people.

Because these inexpensive drugs are already approved by the United States Food and Drug Administration (FDA) and have a good safety record, they could be "repurposed" rapidly to treat other illnesses, said study author Dr. Jayakrishna Ambati.

More about the Research

Excerpted from HIV/AIDS Drugs Could Be Repurposed to Treat AMD, via Drug Discovery and Development Magazine:

In their Science publication, [the authors] report that multiple FDA-approved NRTIs prevented retinal degeneration in a mouse model of dry AMD. Surprisingly, this effect of NRTIs in the eye was not due to the well-known function of these drugs to inhibit reverse transcriptase [i.e., a process that is critical for replication of HIV].

Instead, NRTIs blocked an innate immune pathway called the "inflammasome," even in experimental systems in which the NRTIs were not capable of blocking reverse transcriptase.

In their report, they also showed that NRTIs were effective in other disease models that share common signaling pathways with the dry AMD model, including the "wet" form of AMD - a disease that when treated still does not lead to substantial vision improvement in two-thirds of patients …

"Repurposing of NRTIs could be advantageous … because they are very inexpensive. Since these NRTIs are already FDA-approved, they could be rapidly and inexpensively translated into therapies for a variety of untreatable or poorly treatable conditions," said Benjamin Fowler, the lead author and a postdoctoral fellow. "We are excited at the prospect of testing whether NRTIs could be effective in halting the progression of AMD in patients."

Inflammation and Macular Degeneration

From Risk Factors for Age-Related Macular Degeneration at VisionAware.org:

Age and the environmental factors together produce an increased number of free radicals in the macula. The macula is the small sensitive area in the center of the retina that provides clear central vision. Free radicals are unstable molecules that must be neutralized to keep them from causing damage. Mother Nature has provided anti-oxidants in food to neutralize these free radicals.

However, when we have too many free radicals and not enough anti-oxidants, damage is done. The first signs of damage in the macula are small whitish or yellowish spots called drusen, which the ophthalmologist can see usually before the individual is experiencing vision loss.

This initial damage triggers inflammation, which causes more damage, exacerbated by more free radicals. This results in more inflammation and the cycle continues, eventually scarring the macula and causing central vision loss.

More about the Study from Science

From the Editor's Summary:

Nucleoside reverse transcriptase inhibitors (NRTIs) stop HIV in its tracks by blocking reverse transcription, a process critical for HIV to replicate its genome.

Fowler et al. found that in mice, these drugs also block inflammation caused by a large protein complex called the NLRP3 inflammasome. This activity is independent of the drugs' ability to block reverse transcription.

Instead, the drugs block the activity of the ion channel P2X7, which activates the NLRP3 inflammasome. NRTIs improved outcomes in several NLRP3 inflammasome-dependent mouse models of inflammation, including age-related macular degeneration and graft-versus-host disease.

Additional Information


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