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Subspecialties Basic & Translational Research, Retina

Serving One’s (Re)Purpose

Jayakrishna Ambati

Dry AMD and geographic atrophy (GA) are subsequent stages of the same condition, with no current therapeutics available to stop the irreversible progression to blindness. For patients, it is an arduous wait in the hope that an effective treatment will be approved and save their eyesight. So how can we identify a treatment for this disease before it’s too late? Could the answer be a drug that already exists – but has not yet been applied to this condition?

My team and I have discovered that dry AMD and GA can be treated by repurposing the HIV drug class [...] NRTIs

Repurposing drugs that are already approved for other applications could knock years off the drug development pipeline – and millions of dollars off the cost of early-stage pre-clinical and clinical trials. My team and I have discovered that dry AMD and GA can be treated by repurposing the HIV drug class nucleoside reverse transcriptase inhibitors (NRTIs) (1) and we will be performing clinical trials for this purpose. This ties in with our discovery that Alu DNA causes death of the retinal pigment epithelium (RPE) and – crucially – is not produced when NRTIs are administered.

Digging for answers

This discovery tracks back to 2014, when we originally published research showing that NRTIs can block a mouse model of dry AMD in mice (2) – a completely different application to NRTIs’ original purpose. All we knew at the time, in terms of the mechanism of action, was that these drugs inhibit inflammatory activity, which led us to investigate them further and decipher more details. Fortunately, the advent of big data archeology – which mines large databases of patient records for drug-disease associations – enabled us to test our hypothesis. The analysis of four distinctly different databases from both public and private health insurance carriers supported our notion that NRTIs are beneficial to treatment of dry AMD. We also identified (through big data archaeology) that Alu DNA, which we had previously identified as present in high levels in dry AMD eyes, was made in the cytoplasm. These findings are the culmination of work that started a decade ago and drove us to seek a deeper understanding of the biology of the disease.

NRTIs work by two mechanisms: blocking reverse transcriptase and blocking the inflammasome of the immune system. Blocking reverse transcriptase is beneficial to dry AMD because it stops the conversion of Alu RNA to Alu cDNA, preventing the toxic Alu effect that causes RPE death in GA. The second mechanism of action, blocking the inflammasome, reduces the damage caused by the immune response to the disease – further increasing retinal protection. The combination of these two mechanisms helps to explain NRTIs’ tremendous beneficial effects against dry AMD.

NRTIs are not perfect; they can be pretty nasty drugs, especially the early versions. Newer generations have been more tolerable, but still feature side effects that HIV patients tolerate due to the drugs’ survival benefits. Dry AMD patients are mostly middle-aged or elderly and may stand to lose their sight – but not their lives – so may be less tolerant of side effects. This led us to create NRTI derivatives – called Kamuvudines – that retains the beneficial aspects of the drug, but lacks its toxicity. It is these derivative drugs that we are now taking forward into clinical trials.

When starting from scratch, drug development may take 12 to 15 years and cost anywhere from US$2–3 billion to bring to market

Looking to the future

There are multiple benefits to repurposing a well-classified drug class with copious amounts of real-world data. When starting from scratch, drug development may take 12 to 15 years and cost anywhere from US$2–3 billion to bring to market. This takes into account the immense failures inherent in this process; many drugs fail the expensive tests along the development pipeline, sometimes even when they are potentially beneficial, but may cause adverse effects. Repurposed drugs have already achieved this extensive, expensive, and time-consuming stamp of approval. Because they are already used in patients, we know that they meet reasonable safety and tolerability standards. We know the dosing regimen and pharmacokinetics of the drug. All of these factors shorten the runway for launching a clinical trial and may allow researchers to skip phase I and II clinical trials (designed to establish safety) and initiate phase III trials as a first step.

The discovery of DNA synthesis in the cytoplasm also opens up a new chapter in biology and disease, teaching us that DNA is not produced in the nucleus alone. Our new understanding of Alu is similarly enlightening – with evidence that Alu is involved in the pathology of Alzheimer’s disease, multiple sclerosis, lupus, and several other diseases, it is perfectly reasonable to hypothesize that these diseases may see a similar benefit from Alu-targeting treatments. In fact, we are actively looking at wider disease applications in addition to dry AMD – and our early results are intriguing.

In addition to this work, I’ve formed a company called Inflammasome Therapeutics that has licensed this technology. Our next step is to run clinical trials through the company for dry AMD and some other diseases, including systemic conditions, to bring this drug into use. As the world slowly begins to move past COVID-19, we hope to advance our clinical trials as soon as possible.

Disclosures:  Jayakrishna Ambati is a co-founder of Inflammasome Therapeutics, iVeena Holdings, iVeena Delivery Systems, and DiceRx, and has been a consultant for Allergan, Boehringer-Ingelheim, Olix Pharmaceuticals, Retinal Solutions, and Saksin LifeSciences unrelated to this work.

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  1. S Fukuda et al., “Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration,” PNAS, 118, e2022751118 (2021). PMID: 33526699.
  2. BJ Fowler et al., “Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity,”  Science. 346, 1000 (2014). PMID: 25414314.

About the Author

Jayakrishna Ambati

Professor and Vice Chair for Research, and Founding Director of the Center for Advanced Vision Science at the University of Virginia, Charlottesville, USA.

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