Common HIV treatment improves cognition in mice with Down syndrome

Lamivudine, an antiretroviral drug commonly used to treat HIV, improves cognition in a mouse model of Down syndrome (DS), according to the results of a new study by researchers from the Center for Genomic Regulation (CRG) and the IrsiCaixa AIDS Research Institute, a center promoted jointly by the “la Caixa” Foundation and the Department of Health of the Generalitat de Catalunya.

Although clinical studies are needed to confirm whether lamivudine treatment causes a similar beneficial effect in humans, the preclinical study highlights the potential for using pharmacological interventions such as lamivudine – or other drugs capable of blocking the same therapeutic target – to help improve cognitive impairment in humans. people with DS.

“Our work aims to support people with Down syndrome and their families by providing them with more options for independent living, especially those affected by early-stage Alzheimer’s disease,” explained Mara Dierssen, PhD, researcher at the CRG and co-author of the article published by the team in the Journal of Cellular and Molecular Medicinewhich is called “Lamivudine, a reverse transcriptase inhibitor, rescues cognitive deficits in a mouse model of Down syndrome.” In their report, Dierssen and colleagues concluded, “While clinical studies in patients with DS are warranted, this study lays the groundwork for a novel and actionable therapeutic approach.

Down syndrome is a genetic condition that occurs when an individual is born with an extra chromosome 21. “DS is the most common known genetic disorder associated with moderate to severe intellectual disability due to full or partial trisomy of autosomal chromosome 21 (HSA21) and a genetic form of Alzheimer’s disease (AD),” explain the authors. The disorder affects, to varying degrees, general cognitive traits such as memory, attention span, and slurred speech. Adults with DS also experience accelerated aging, resulting in relatively rapid more frequently seen in much older adults in the general population.

People with DS are also at increased risk for AD. Chromosome 21 plays an important role in this relationship because it carries a gene, amyloid precursor protein (APP), which produces amyloid proteins that accumulate in the brain and are associated with disruption of brain function. Amyloid accumulation is common in most adults over the age of 40 with DS.

To facilitate independent living, most people with DS undergo psychosocial interventions such as cognitive stimulation therapy, one of the only treatment options currently available. No pharmacological intervention exists to date.

Retrotransposons are segments of DNA that change location in the genome by creating RNA copies of themselves that come back into the DNA at another location. Retrotransposons can insert into specific areas of the genome and, by chance, position themselves in promoter regions of genes associated with neurodegenerative diseases, thus enhancing their activity. Retrotransposition rates increase with age and cellular senescence.

IrsiCaixa researchers, including the authors of the study. [IrsiCaixa]

“Increased retrotransposition is observed in cellular senescence and with aging and has been implicated in several neurodegenerative diseases including AD, frontotemporal dementia, prion disease, but also in developmental disorders such as Rett syndrome, l ‘autism or fragile X syndrome,’ the researchers continued.

Retrotransposons bear some similarities to HIV, reproducing rapidly in cells, but not necessarily with pathological implications. The authors hypothesized that the use of existing nucleoside reverse transcriptase inhibitors (NRTIs) that currently target HIV replication, such as the enzyme reverse transcriptase, might also block retrotransposons.

“HIV and retrotransposons need the same molecule to reproduce: the reverse transcriptase enzyme,” explains Bonaventura Clotet, PhD, director of IrsiCaixa. “We know that lamivudine, a reverse transcriptase inhibitor used against HIV, has shown in aged mice a decrease in retrotransposon activation which could be linked to age-related disorders. Therefore, we thought it might be useful to counter the cognitive impairment associated with Down syndrome.

The investigators further noted, “Importantly, in patients with HIV-1, NRTI therapy is associated with a reduced risk of HIV-associated neurocognitive disorders, Alzheimer’s disease, Parkinson’s disease and other dementias… Last year, a clinical trial to study the safety and feasibility of lamivudine antiretroviral therapy for Alzheimer’s disease was launched. However, they pointed out: “Although a contribution of retrotransposition to developmental disorders has also been suggested and despite the close relationship between DS and AD, NRTIs have not been explored in DS.” Targeting retrotransposons is a new, unexplored option for DS.

For their studies, the researchers used Ts65Dn mice (TS mice), which represent the most studied DS animal model. “TS mice exhibit hyperactivity and hippocampus-dependent learning deficits, and recapitulate several of the DS neurobehavioral and cognitive phenotypes,” the researchers wrote. For their study, the researchers treated TS mice with lamivudine for four months, while a control group received water. After treatment, various behavioral experiments were designed to test locomotor activity, recognition memory and anxiety.

The results indicated that mice given lamivudine showed improved cognition. “We detected significant improvement in neurobehavioral phenotypes and complete rescue of hippocampus-dependent recognition memory upon lamivudine treatment,” the scientists wrote. “…our study demonstrated for the first time that lamivudine improves cognition in a mouse model of DS, providing experimental evidence for the use of reverse transcriptase inhibitors as a potential new treatment to improve cognitive impairment in the DS.”

The researchers hypothesized that the observed benefits of lamivudine may be due to its effect on one or more variants of the APP gene. “We still need pharmacological treatments that consistently help improve memory, attention, and language functions, or prevent cognitive decline associated with aging,” Dierssen said. “This study is a step towards changing that, revealing retrotransposition as an interesting mechanism to pursue not only in aging but also in neurodevelopmental disorders.”

The team plans to initiate clinical trials to evaluate lamivudine in people with DS and AD. “Further studies to assess safety and tolerability in DS patients with early-stage AD are warranted,” they concluded in their paper.

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