CRISPR gene therapy appears safe, but claims of an imminent HIV cure are premature

A CRISPR-based gene-editing therapy known as EBT-101 was not associated with serious adverse effects in the first three treated study participants, researchers reported last week at the European Society for Gene & Cell Therapy annual meeting in Brussels. The presentation, however, was devoid of any data about whether the treatment works to control HIV.

That didn’t stop the Daily Mail from proclaiming that a cure for HIV “could be months away” – just the latest in a string of media reports exaggerating the state of functional cure research.

Antiretroviral therapy can keep HIV replication suppressed indefinitely, but the virus inserts its genetic blueprints into the DNA of human cells and establishes a long-lasting reservoir that is invisible to the immune system and unreachable by the drugs. These ‘proviruses’ lie dormant in resting T cells during treatment, but they start producing new virus when antiretrovirals are stopped, making a cure nearly impossible.

Professor Kamel Khalili at Temple University in Philadelphia and colleagues have been studying gene therapy with the aim of curing HIV for more than a decade. Their work employs CRISPR/Cas9 – sometimes referred to as ‘molecular scissors’ – a technology that combines guide RNAs that home in on specific segments of DNA and a nuclease enzyme that cuts the genetic material at the desired sites. (The first CRISPR-based therapy, for sickle cell disease, is currently awaiting approval in the United States.)

In 2016, Khalili and colleagues reported that the technique could excise HIV genomes from CD4 cells in the laboratory. Other researchers have also seen promising results using CRISPR/Cas9 to remove HIV genes from infected cells in preclinical studies. At the 2019 Conference on Retroviruses and Opportunistic Infections, Dr Tricia Burdo from the Temple University team reported that a CRISPR therapy successfully removed segments of an HIV-like virus called SIV from infected cells in monkeys.

This work led to the development of EBT-101, a CRISPR-based therapy delivered by an adeno-associated virus that uses two guide RNAs to target three sites on the integrated HIV genome. Making cuts at these locations prevents the production of intact new virus. This past August, Burdo and colleagues reported that a single dose of a simian version of the gene therapy safely and effectively removed SIV from viral reservoirs in monkeys on antiretroviral therapy, but they did not undergo a treatment interruption.

The first human clinical trial of EBT-101 (NCT05144386) started last year, testing the therapy in people on antiretroviral treatment with a stable undetectable viral load. In September 2022, Excision BioTherapeutics announced that the first participant in the phase I/II trial received EBT-101 in July of that year.

At the recent presentation in Brussels, Professor Rachel Presti of Washington University St. Louis School of Medicine reported that all three participants in the first dose cohort have now received EBT-101. Initial results indicated no serious adverse events or dose-limiting toxicities. There were four mild adverse events that might have been related to the gene therapy, all of which resolved. Two people experienced transient liver enzyme elevations. None of the three withdrew from the study.

EBT-101 was detectable in the blood of all participants four weeks after receiving a single IV infusion using the first dose level to be evaluated. There was no evidence of “horizontal transmission of gene vector shedding of EBT-101 in two tissue compartments associated with male reproductive function,” suggesting the therapy is not passed on in semen, according to Excision. These findings support testing of a higher dose of EBT-101 in a second cohort of six people, which will happen this year.

“Establishing the safety and biodistribution of EBT-101 is an important first step in the clinical program,” Dr William Kennedy, Excision’s senior vice president of clinical development, said in a press release. “These initial observations provide important clinical data that support the advancement of the EBT-101-001 trial to the next dosing cohort.”

According to the company, study participants will be followed for 48 weeks after EBT-101 administration, and those who are eligible will be assessed for sustained viral suppression after stopping antiretrovirals in an analytical treatment interruption starting at week 12.
The first participant, who received the gene therapy in the summer of 2022, is already well past the 12-week mark, but Excision has not provided any further information about his status.

While these initial results appear promising, it is far too early to say – as the Daily Mail did – that researchers are “on the cusp of curing HIV” or that a cure “could be closer on the horizon than ever thought before.”

Excision indicated that additional data would be presented in 2024. Hopefully this will reveal whether the participants stopped antiretroviral therapy and whether EBT-101 delays HIV rebound or maintains viral suppression.

But even if it does, there’s still a long road ahead to test EBT-101 in a larger number of people, determine if it has long-term side effects, secure the approval of regulatory authorities and commercialise the therapy. What’s more, given the price of existing gene therapies for other conditions, the cost of CRISPR-based therapy could be out of reach for most people living with HIV worldwide.

This is not the first time the mainstream media has prematurely announced a cure for HIV. For example, the Daily Telegraph ran a headline in 2016 suggesting that a CRISPR-based cure could be available within three years, recalls Richard Jefferys, an advocate with the Treatment Action Group.

Jefferys sent a letter to the Daily Mail this week pointing out its inaccuracies. “The headline of this article is hugely, egregiously wrong and unconscionably toys with the hopes of people with HIV and everyone seeking a cure for HIV,” he wrote. “It's encouraging that this research is progressing, but there is as yet zero evidence that this approach can cure HIV in people, let alone within months.” He asked that the headline and opening paragraph be amended “so that they accord with reality and don’t mislead people and create false hopes.”

Many lessons have been learned from the small number of people who naturally control HIV, the somewhat larger group of post-treatment controllers and the handful of people who have been cured after stem cell transplants. But today, a broadly applicable functional cure remains a prospect for the long-term future.