EBT-101 is an investigational, in-vivo CRISPR-based gene-editing therapy developed by Excision BioTherapeutics. Its primary goal is to offer a potential one-time treatment that could lead to a functional cure for Human Immunodeficiency Virus (HIV).
The Scientific Approach
A significant challenge with HIV infection stems from the virus’s ability to integrate its genetic code, known as proviral DNA, directly into the host cell’s DNA. This integration means the virus can persist within the body, making it impossible for current antiretroviral drugs to completely clear the infection. EBT-101 aims to overcome this persistence by targeting the integrated viral DNA.
The therapy utilizes CRISPR-Cas9 technology, which is delivered into cells using an adeno-associated virus (AAV). EBT-101 is specifically engineered with two guide RNAs (gRNAs) that direct the Cas9 enzyme to three distinct sites within the integrated HIV genome. This precise targeting allows for the excision of substantial segments of the viral DNA.
By removing these large portions of the HIV genome, the treatment intends to permanently disable the virus within the infected cell. Preclinical studies demonstrated EBT-101’s ability to excise HIV proviral DNA in various cell lines and animal models, including non-human primates.
The Clinical Investigation
The scientific principles behind EBT-101 are now being explored in human subjects through a Phase 1/2 clinical trial. This early-stage trial is primarily designed to assess the safety and tolerability of the therapy in people living with HIV-1 who are already on stable antiretroviral therapy (ART). Beyond safety, the trial also evaluates the therapy’s biodistribution and immunogenicity.
This investigation marks a notable development as EBT-101 represents the first in-vivo CRISPR-based systemic treatment for an infectious disease to be evaluated in a clinical trial. Initial findings from the trial have indicated that the therapy has been well-tolerated at the doses studied. Reports show no serious adverse events or dose-limiting toxicities, with any mild adverse events observed resolving without intervention.
The presence of EBT-101 was detectable in the bloodstream of participants. However, some initial data from participants who underwent an analytical treatment interruption (ATI) showed viral rebound. This indicates that, at the initial dose levels tested, the therapy did not consistently maintain viral suppression without ART.
The Concept of a Functional Cure
EBT-101’s objective is to achieve a “functional cure” for HIV. A functional cure means the virus is controlled by the body’s own immune system without the need for daily medication, even though some inactive viral DNA may still remain within cells. This state implies durable suppression of viral replication in the absence of ongoing antiretroviral therapy. The virus would remain at very low or undetectable levels, preventing illness progression and significantly reducing the risk of transmission.
This approach contrasts with the current standard-of-care, Antiretroviral Therapy (ART), which requires lifelong daily adherence to suppress the virus. While ART is highly effective at controlling viral load and preventing disease progression, it cannot eliminate the integrated HIV DNA from the host’s genome. The ongoing requirement for ART can pose a significant burden on patients due to daily medication schedules and potential side effects.
Long-Term Considerations and Next Steps
A significant next step in evaluating EBT-101’s efficacy involves the Analytical Treatment Interruption (ATI). During an ATI, a patient’s standard ART is carefully paused under close medical supervision to determine if EBT-101 has successfully enabled the body to control the virus independently. While initial ATI results showed viral rebound in some participants, suggesting the initial dose may not have reached all latent HIV reservoirs, these findings inform future dosing strategies.
Patients participating in the trial will undergo long-term monitoring for an extended period to assess the sustained safety and effects of the treatment. A primary scientific consideration for any gene-editing therapy is the assessment of potential “off-target” edits, which are unintended cuts in the DNA. However, EBT-101’s design, using dual guide RNAs targeting specific viral sequences, aims to minimize such unintended alterations to human genes. Excision BioTherapeutics is also exploring higher doses of EBT-101 and alternative delivery methods to potentially enhance the therapy’s reach and effectiveness in the body.