Source：SciPhi

Since its development, the gene-editing technology CRISPR has been used for biodiversity conservation, agricultural breeding, drug discovery, and the treatment of genetic diseases such as sickle cell disease and cystic fibrosis, and now scientists are using CRISPR technology in a new exploration - an attempt to permanently cure HIV infection.

At the 30th Annual Meeting of the European Society for Gene and Cell Therapy (ESGCT), Excision BioTherapeutics, a gene-editing therapy developer, has published partial data from its first human trial of CRISPR multiple gene-editing therapy (EBT-101) for HIV infection.

Excision reported positive safety and biodistribution data up to 48 weeks, no serious adverse events or dose-limiting toxicity were detected in all trial participants, and EBT-101 was detected in the blood of all participants. In addition, four were judged to be treatment-related mild adverse events, two of which were elevated liver enzymes and two of which were fatigue and low white blood cell counts, all of which resolved without medical intervention.

The clinical trial (EBT-101-001/2) is an open-label, multicenter, single-dose escalation study designed to evaluate the safety, tolerability, biodistribution and pharmacodynamics of EBT-101 therapy in nine people with HIV, as well as to observe initial efficacy. The first participant completed a single intravenous administration a year ago.

▲图｜Daniel Dornbusch, CEO of Excision

EBT-101 is a CRISPR-based gene editing therapy that we hope will be a potential functional treatment for HIV. We are focused on developing CRISPR-based therapies for patients with infectious diseases, and sharing these initial safety and biodistribution data is important for the HIV/AIDS community, the large infectious disease community, and for other indications of gene therapies under development." Excision CEO Daniel Dornbusch.

▲图｜William Kennedy, senior Vice President of Clinical Development, Excision

"Determining the safety and biodistribution data for EBT-101 is a critical first step in clinical planning." In the first three participants, treatment with EBT-101 resulted in no serious adverse events or dose-limiting toxics, while all reported adverse events were mild and reversible and also showed a positive biological distribution at this dose level. These preliminary observations provide important clinical data to support the entry of EBT-101-001 into the next dosing cohort." William Kennedy, Excision's senior vice president of clinical development.

The clinical trial of EBT-101, according to Excision, will continue next year with higher doses of the treatment, given that the treatment did not cause major side effects, and participants will receive three or even 10 times the dose of the drug. Specifically, the dose will be increased to the next dose level (3.0x1012 vg/kg) in the fourth quarter of this year and the evaluation of the biological distribution of EBT-101 in the blood will continue, with more new trial data expected to be published in 2024.

In response to Excision's "part of the data" released at the meeting, some insiders questioned whether there is a lack of data on the effectiveness of the treatment, only from the disclosed data, this treatment is safe, no major side effects, but did not reveal the early data on the effect of this treatment, let the outside world speculate whether this treatment is really effective.

Patients in the clinical study were taking antiretrovirals, and the plan was to stop taking them 12 weeks after the gene-editing treatment to see if the virus rebounded (a step known as "analysis of treatment interruption"). If the virus did not relapse, it could mean that CRISPR had damaged the viral gene. For two patients who had previously been treated, the company appears to have the data, but Kennedy said, "The third patient only recently received the gene editing treatment, and full data results for the three patients in this group will not be available until 2024."

▲图｜Kamel Khalili, Excision co-founder and Chief Scientific Advisor

Professor Kamel Khalili, co-founder and chief scientific Advisor at Temple University in the US, said: "This research may be just one step on the road to a cure for HIV, and even if we don't cure HIV completely, we may significantly delay the rebound of the virus, allowing us to move to the next stage of research. As with any drug, there will be iterations of the first generation, the second generation, and so on."

AIDS is caused by infection with HIV, a virus that attacks the body's immune system, primarily by attacking T lymphocytes that render the body immune. The U.S. Centers for Disease Control and Prevention (CDC) first reported five cases of AIDS in 1981 in the journal Morbidity and Mortality Weekly. There is still no cure or vaccine available to prevent AIDS.

Latency is a major obstacle in the fight against HIV, and although antiretroviral therapy can suppress HIV to prevent the development of AIDS, it is difficult to eliminate latent HIV. Excision seeks to use gene-editing technology to eliminate the virus, and claims that EBT-101 therapy can theoretically overcome the shortcomings of antiretroviral therapy.

EBT-101 is known to treat AIDS by destroying the genome of the HIV virus. Specifically, it uses an adeno-associated virus (AAV) to deliver CRISPR-Cas9 and two guide Rnas that act as guides to direct editing to sites on the HIV genome, allowing multiple edits to be made simultaneously at three different sites in the HIV genome.

▲ Figure | EBT-101 gene editing therapy

EBT-101 is the world's first CRISPR-based in-vivo gene editing technology to treat HIV infection, which is an "ambitious" clinical application of CRISPR gene editing technology. It is worth noting that EBT-101 has shown long-term efficacy and safety in mice and non-human primates in previous preclinical trials, has the potential to treat HIV, and EBT-101 was also granted a "fast track" designation by the FDA in July this year.

▲ Figure | Excision is researching pipeline

Founded in 2015 and headquartered in San Francisco, California, Excision is a clinical-stage biotechnology company focused on developing CRISPR-based gene editing tools as potential treatments for viral infectious diseases. At this stage, in addition to EBT-101, the lead pipeline for the treatment of HIV infection, the company also has EBT-103, EBT-104, EBT-107 pipelines for the treatment of human polyoma virus, herpes simplex virus, hepatitis B virus infection.

参考资料：

1.https://www.technologyreview.com/2023/10/25/1082306/gene-editing-crispr-hiv-experiment/
2.https://www.biopharmadive.com/news/excision-crispr-gene-editing-in-vivo-hiv-safety/697739/
3.https://www.excision.bio/technology
4.https://www.excision.bio/team
5.https://www.excision.bio/_files/ugd/80a6fd_de98df6a38d042658595374af17d658a.pdf