First-in-Human Trial of CRISPR Gene Therapy for HIV

The first in-human trial of a CRISPR Cas system delivered by adeno-associated virus 9 gene therapy to treat HIV was able to target only the intended DNA and cleared the blood within 6 months.

EBT-101-001 is the first gene therapy administered intravenously designed to attack the latent HIV proviral genome with an adeno-associated virus 9 CRISPR Cas9 multiplex.

The results of the phase 1/2, presented at the International AIDS Conference 2024 are “a first step,” said Rachel Presti, MD, PhD, medical director of the infectious disease clinical research unit at Washington University, St. Louis, Missouri.

“This study is highly unique,” added Chantelle Ahlenstiel, PhD, a senior research fellow in immunovirology and pathogenesis at the Kirby Institute at the University of New South Wales in Sydney, Australia. “It was a high-risk study that showed a very promising safety profile,” she said.

The trial enrolled six patients split between two dose-level groups: 0.9 x 10¹² and 3 x 10¹² vector genes per kg with the latter known as the high-dose group. Adeno-associated virus 9 targets CD4+ T cells that harbor the latent HIV provirus. Four of the six participant’s antiretroviral was interrupted at 12 weeks after the infusion. Post-dose intervals ranged from 2 years to 10 weeks.

“There was no off-target DNA damage that’s been identified so far,” Presti said.

Treatment Finds Its Target

The therapy has its target, Presti explained, ” but obviously we’re continuing to follow these patients.”

HIV RNA levels rebounded in all four participants who had antiretroviral interruption, but one patient had a delayed rebound of almost 16 weeks along with a significant drop in the HIV reservoir.

“This is the most promising result but only seen in one person,” Presti said during an interview. One participant had a drop in CD4+ count so could not do antiretroviral interruption, and another had not reached the 12-week milestone for treatment interruption.

During treatment interruption, none of the patients had acute retroviral syndrome, Presti said.

“Those exploratory endpoints promise that maybe there was some effect in at least one participant, and we’re trying to figure out what was different about that person and how we can continue to make this better,” Presti said.

“I think with the next-generation products, we could get more efficient targeting of the vector; we could improve the specificity of the therapy as well.”

None of the trial participants had any serious adverse events, although nine low-grade treatment-emergent adverse events manifested in the six patients.

Ahlenstiel said that the small study showed “quite varied decreases” in the HIV latent reservoir among participants, with the two subtype B designed CRISPR gRNA sequences having multiple mismatches to subtype B virus sequences in some of the six participants.

“It will be important to design further gRNA that are highly conserved across all HIV subtypes in order to develop a globally applicable HIV gene therapy,” Ahlenstiel said.

It is likely that people with a smaller, simpler reservoir with consistent antiretroviral therapy will be more likely to see benefit, Presti said. “Because there is less variability in the reservoir and immune system that you need to measure and target,” she said.