Antiretroviral drug shows potential for Alzheimer’s disease treatment in early clinical trials
Posted on: Wednesday, July 31st, 2024
Scientists from The University of Texas Health Science Center at San Antonio, also known as UT Health San Antonio, led a pilot study of the Food and Drug Administration-approved antiretroviral drug lamivudine, to determine if it could be a potential treatment for Alzheimer’s disease.
Almost half of what makes up the human genome are mysterious viral sequences thought to be left over from various infections throughout evolution. These normally quiet genetic elements are a part of who we are but can cause disruption when activated. Recent evidence shows these activated retrotransposons, or jumping genes, play a part in Alzheimer’s disease.
In retroviruses, the viruses replicate in bodies by turning their RNA copies into new DNA copies. Those DNA copies then insert themselves into the genome. Similarly, activated retrotransposons make RNA copies that turn into DNA copies that can be inserted into the genome. The body then views these transcripts as viruses to attack, even though they are activated parts of the body’s own DNA sequence.
Antiviral drugs like lamivudine stop the RNA from going to the DNA step in retroviruses and in disorders like Alzheimer’s disease, the drug stops the activation of the retrotransposons which can be viewed as an endogenous virus.
In animal model studies, lamivudine dampened the activation of viral sequences and reduced the neurotoxicity associated with pathogenic forms of tau.
A. Campbell Sullivan, PsyD, and researchers from UT Health San Antonio’s Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases and the Barshop Institute for Longevity and Aging Studies developed the clinical trial to see if the drug could benefit people with cognitive impairment.
The phase 2A, open-label study included 12 participants with mild cognitive impairment. They were placed on lamivudine for six months with blood and cerebrospinal fluid collected three times during the period to study biomarkers.
The study was designed to evaluate the safety and feasibility of using antiretroviral therapy for Alzheimer’s disease, but the researchers were pleasantly surprised to find significant improvement in two markers of neurodegeneration as well as a reduction in inflammation. This provided encouraging results that they hope to explore with the next study.
For the next phase, the research team would like to conduct the trial for approximately one year with a larger cohort to observe if there are significant changes or markers of neurodegeneration with lamivudine compared to a placebo. Since the first study was designed, biomarkers have been discovered that correspond to levels of tau in the brain of people with Alzheimer’s disease that the team could now use for participant enrollment, along with cognitive assessments.
Sullivan said it is an exciting time for Alzheimer’s disease research with many promising trials coming out. Treatments for the disease are limited and many patients do not respond to the current medications available.
“If there is a response, it is usually time-limited, maybe six months. We might see some brightening, or they are just a bit more coherent at times, then those effects stop,” Sullivan said.
She stresses the implementation of lifestyle factors even before a person is symptomatic, including eating a nutritious diet, getting deep, restorative sleep, regular exercise for vascular health and engagement in challenging yet interesting activities.
“Many of these lifestyle factors are not the easiest to implement but cannot be overstated. It is important, especially as we age, so in middle age when we are in our 40s, that is when we want people to start implementing those,” Sullivan said.
Over the past few decades, Sullivan said there have been phenomenal improvements in biomarker identification and brain imaging, meaning they can detect problems earlier, especially in patients with a genetic predisposition for the condition. With earlier detection, problems could be kept at bay longer or possibly even prevented from developing.
Biomarkers related to various health conditions have been game-changers for prevention and treatment. Sullivan said in the future, biomarker assessment may become as common as getting a mammogram or colonoscopy.
“We are going to get to that point and then we will have options, drugs we can start in mid-life so that eventually these neurodegenerative diseases do not progress. That is the ultimate goal. We want to live in a world without Alzheimer’s disease or tauopathies, and I think we are getting close,” Sullivan said.
Sullivan, A. Campbell, Zuniga, Gabrielle, Ramirez, Paulino, Fernandez, Roman, Wang, Chen-Pin, Li, Ji, Davila, Lisa, Pelton, Kristine, Gomez, Sandra, Sohn, Claira, Gonzalez, Elias, Lopez-Cruzan, Marisa, Gonzalez, David A., Parker, Alicia, Zilli, Eduardo, de Erausquin, Gabriel A., Seshadri, Sudha, Espinoza, Sara, Musi, Nicolas, Frost, Bess. (Feb. 28, 2024) “A pilot study to investigate the safety and feasibility of antiretroviral therapy for Alzheimer’s disease (ART-AD)” Preprint, non-peer reviewed release on MedRXIV, https://www.medrxiv.org/content/10.1101/2024.02.26.24303316v1