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

Although clinical studies will be needed to confirm whether lamivudine therapy elicits a similarly beneficial effect in humans, the preclinical study highlights the potential to use pharmacological interventions such as lamivudine—or other drugs capable of blocking the same therapeutic target—to help ameliorate cognitive impairment in people with DS.

“Our work aims to support people with Down syndrome and their families by providing them more options to live independent lives, particularly those affected by early-stage Alzheimer’s disease,” explained Mara Dierssen, PhD, a researcher at the CRG and co-author of the team’s published paper in the Journal of Cellular and Molecular Medicine, which is titled, “Lamivudine, a reverse transcriptase inhibitor, rescues cognitive deficits in a mouse model of Down syndrome.” In their report, Dierssen and colleagues concluded, “Despite 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 disorder that results 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 a total or partial trisomy of the autosomal chromosome 21 (HSA21) and a genetic form of Alzheimer’s disease (AD),” the authors explained. The disorder affects, to varying degrees, general cognition traits such as memory, attention span, and speaking ability. Adults with DS also experience accelerated aging, resulting in relatively rapid cognitive decline more commonly seen in much older adults in the general population.

Individuals with DS are also at increased risk of AD. Chromosome 21 plays an important role in this relationship as it carries a gene—amyloid precursor protein (APP)—which produces amyloid proteins that build up in the brain and are associated with disrupting brain function. Amyloid accumulation is common in most adults over the age of 40 with DS.

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

Retrotransposons are segments of DNA that change their location within the genome by making RNA copies of themselves that jump back into DNA at another location. Retrotransposons can insert themselves into specific areas of the genome and, by chance, position themselves in gene-promoting regions associated with neurodegenerative diseases, enhancing their activity. Rates of retrotransposition increase with age and cellular senescence.

Researchers at IrsiCaixa, including authors of the study. [IrsiCaixa]
“Increased retrotransposition is observed in cell 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’s syndrome, autism, or fragile X syndrome,” the investigators continued.

Retrotransposons show some similarities to HIV, rapidly replicating within cells, though not necessarily with pathological implications. The authors hypothesized that using existing nucleoside reverse transcriptase inhibitors (NRTIs) that currently target the replication of HIV—such as the enzyme reverse transcriptase—could also work to block retrotransposons.

“Both HIV and retrotransposons need the same molecule to make copies of themselves: the reverse transcriptase enzyme,” explained Bonaventura Clotet, PhD, director of IrsiCaixa. “We know that lamivudine, a reverse transcriptase inhibitor used against HIV, was shown in aged mice to decrease the activation of retrotransposons which could be linked to age-associated disorders. Therefore, we thought that it could be useful to counteract the cognitive impairment associated with Down syndrome.”

The investigators further noted, “Importantly, in patients with HIV-1, NRTIs treatment is associated with reduced risk of HIV-associated neurocognitive disorder, AD, Parkinson’s disease, and other dementias … Last year, a clinical trial to investigate the safety and feasibility of antiretroviral therapy with lamivudine 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 of DS with 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 widely studied DS animal model. “TS mice present hyperactivity and hippocampal-dependent learning deficits, and recapitulate several of the DS neurobehavioural and cognitive phenotypes,” the investigators wrote. For their study, the researchers treated TS mice with lamivudine for four months, while a control group received water. Following treatment various behavioral experiments were designed to test locomotor activity, recognition memory, and anxiety.

The results indicated that mice receiving lamivudine showed improved cognition. “We detected a significant improvement of neurobehavioural phenotypes, and a complete rescue of the hippocampal-dependent recognition memory upon treatment with lamivudine,” 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 new potential treatment for ameliorating cognitive impairment in DS.”

The investigators hypothesized that the observed benefits of lamivudine could 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,” said Dierssen. “This study is one step aiming to change that, revealing retrotransposition as an interesting mechanism to pursue not only in ageing but also in neurodevelopmental disorders.”

The team plans to initiate clinical trials with evaluating 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.