Ancient HIV drug could be a treatment for Down syndrome

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A team of Spanish researchers has found that a drug used to fight HIV has potential to treat Down syndrome, improving cognition in mice with one version of the disease.

Scientists from the Center for Genomic Regulation (CRG) in Barcelona and the Institute for AIDS Research IrsiCaixa have focused on a new way of treating Down syndrome, focusing on rogue segments of DNA called “retrotransposons “, which are implicated in the cognitive impairment caused by Down syndrome.

These rogue human genes make copies of themselves and then insert themselves randomly into the genome, just like some viruses, including HIV.

Spanish researchers have found that a drug used to fight HIV has potential to treat Down syndrome, improving cognition in mice with one version of the disease.

“HIV and retrotransposons need the same molecule to reproduce: the reverse transcriptase enzyme,” said Bonaventura Clotet, director of IrsiCaixa.

And thanks to decades of HIV research, we have several drugs that block this molecule, called “reverse transcriptase inhibitors.” Previous research has revealed that one of them, called lamivudine, can also interfere with retrotransposons.

“Therefore, we thought it might be useful to counter the cognitive impairment associated with Down syndrome,” Clotet said.

What causes Down syndrome? Down syndrome, first described in 1866 by English physician John Langdon Down, is caused by an extra copy of a chromosome.

Chromosomes are like gene books; humans have 23, and each person typically has two copies of each chromosome, one from each parent.

Some babies, however, have a third copy of the 21st chromosome, which can change the way the baby’s body and brain develop. According to the CDC, Down syndrome is the most commonly diagnosed chromosomal disorder in the United States, occurring in approximately 1 in 700 infants.

Down syndrome is the most commonly diagnosed chromosomal disorder in the United States, occurring in approximately 1 in 700 infants.

People with Down syndrome typically have mild to moderate cognitive impairment, and adults with Down syndrome age faster, putting them at much higher risk for Alzheimer’s disease.

Treatment for Down syndrome currently relies on psychosocial techniques such as cognitive stimulation therapy, but there is currently no medication for this disorder.

The surprise treatment: A possible treatment for cognitive impairment in Down syndrome may come from an unexpected direction: anti-HIV drugs.

HIV and other retroviruses have a unique step in their replication cycle: they convert their viral RNA back into DNA and then insert it into the host genome.

Retrotransposons are human genes that perform a similar trick, creating RNA copies of themselves in the cell, converting them back into DNA, and then coming back into the genome at random new locations.

These jumps occur more frequently as people age, which may explain why people’s cognitive abilities often decline with old age. They may also be the mechanism by which Down syndrome causes cognitive impairment, advanced aging, and Alzheimer’s disease.

“Elevated retrotransposon activity is increasingly recognized as being implicated in a wide range of neurodegenerative and neurodevelopmental diseases,” the researchers wrote in their study, published in the Journal of Cellular and Molecular Medicine, among them the disease of Alzheimer’s, frontotemporal dementia and Down syndrome.

Down syndrome model mice that received lamivudine showed improved cognitive function, although it slightly increased anxious behavior in wild-type mice.

A potential Down syndrome treatment: Because HIV and retrotransposons share some similarities in how they make and insert their copies, the team tested lamivudine, which has already been shown to be effective against the virus, as a potential treatment for the increased activity of retrotransposons in Down syndrome.

Extensively studied mouse models of Down syndrome and wild-type control mice were randomly assigned to receive plain water or water containing lamivudine for four months. Cognitive function tests were carried out before the start of treatment, one month after and at the end of the four-month period.

Mice that received lamivudine showed improved cognitive function, although it slightly increased anxious behavior in wild-type mice.

Next steps: Although far from proving that lamivudine is an effective treatment for Down syndrome, the study shows promise for further investigation, especially since there are currently no other drugs to treat the condition.

“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,” said Mara Dierssen, researcher at the CRG and co-author of the study.

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