A functional cure for HIV is the goal of Addimmune, a new spinoff company of Rockville-based biotech American Gene Technologies (AGT).
โThink about how thatโs a dream come true for nearly 40 million people in the world and 1.2 million people in the United States,โ says Jeff Galvin, AGTโs CEO and the expected future CEO of Addimmune, in reference to statistics from, respectively, the World Health Organization and the Centers for Disease Control and Prevention. The National Institutes of Health defines a functional cure in this case as โthe long-term control of HIV replication without treatment.โ
AGT has spent the last 15 years developing gene and cell therapies and running programs for immuno-oncology and a cure for phenylketonuria, an inherited metabolic disorder. Addimmune was launched in June after AGTโs successfulโif smallโPhase 1 clinical trial of its single-infusion HIV gene therapy, AGT103-T. Creating Addimmune as a spinoff allows the company to accelerate research and focus resources on future clinical trials, Galvin says.
There are thousands of people in Addimmuneโs backyard hoping for a cure. In Montgomery County, more than 3,600 people were living with HIV at the end of 2021, according to the Maryland Department of Health.
Melvin Cauthen, the administrator for HIV/STI services at Montgomery Countyโs Department of Health and Human Services, says funding from a federal initiative, Ending the HIV Epidemic, has helped the county address the health issue. The county is working on making its clinics and services visible and accessible to those in need of care.
Cauthen says that when it comes to the research and development of treatments and cures for HIV/AIDS , county officials keep an eye on the latest news but ultimately look to the CDC for guidance.
โRight now, weโre focused on making sure that [people living with HIV /AIDS] are healthy while the folks who are working in the labs are coming up with hopefully what will be a cure,โ Cauthen says.
Results from AGTโs Phase 1 trial were published in November 2022 in Frontiers in Medicine, a peer-reviewed scientific journal for medical advancement. Thirteen participants with HIV were enrolled in the trial.
Published results from the Phase 1 trial show no serious adverse events were observed among participants and 100% of participants demonstrated an active immune response to HIV, even after they stopped taking HIV treatment (antiretroviral therapy).
According to Addimmune, its gene and cell therapy modifies the genes of HIV-infected CD4 T cells to prevent HIV/AIDS infection, reduce depletion of the CD4 cells and prevent infected cells from releasing new HIV/AIDS virus particles. Per the National Institutes of Health, CD4 T cells coordinate the bodyโs immune response but HIV destroys CD4 cells, thus weakening the immune system.
Scientists use a lentivirus in the HIV cure research
Galvin explains that scientists use a lentivirusโan RNA virus commonly used in gene therapyโto modify the CD4 cell by stripping a receptor off the cellโs surface that HIV/AIDS uses as a door handle to get inside.
According to Galvin, there is a long path ahead as its work moves through the regulatory process to prove to the Food and Drug Administration that the therapy is safe and effective.
This year, AGT submitted the final report of the Phase 1 trial to the FDA and is now concentrating on the next steps toward a Phase 2 clinical trial, which is expected to begin in late 2024 to early 2025, according to a spokesperson for Addimmune. The Phase 2 trial will seek to further evaluate the potential effects of AGT103-T on immune response in a larger patient population.
Since the regulatory process can take years, a spokesperson for Addimmune was hesitant to put a deadline on when a cure might be available, but says in a statement, โOur team of dedicated scientists and researchers is diligently working on this critical challenge.โ
Biotech companies have been on a mission to develop an HIV cure using CRISPR
More recently, in September 2022, it was announced that Excision BioTherapeutics had dosed the first participant in a phase 1/2 trial of its CRISPR-based drug, EBT-101, which is designed to cure HIV infections after a single intravenous infusion.
It employs an adeno-associated virus (AAV) to deliver CRISPR-Cas9 and dual guide RNAs, enabling a multiplex editing approach that simultaneously targets three distinct sites within the HIV/AIDS genome. This allows for the excision of large portions of the HIV genome, thereby minimizing potential viral escape.
EBT-101 is the result of a collaboration between the Lewis Katz School of Medicine at Temple University and Excision โ which spun out of Temple. The decision to move the therapy into a clinical trial was bolstered by the success of an analog of the drug, called EBT-001, in rhesus macaques infected with simian immunodeficiency virus (SIV). EBT-001 is identical to EBT-101, except that it uses gRNAs that are specific to SIV sequences.
For their preclinical trial, researchers at Temple packaged an SIV-specific CRISPR gene-editing construct that included the Cas9 endonuclease and the guide RNAs into an adeno-associated virus 9 (AAV9) carrier that could be injected intravenously into SIV-infected animals.
The results of the study showed that EBT-001 was broadly distributed throughout the monkeysโ tissue samples, and there was also evidence of edited SIV proviral DNA in their cells and tissues. Additionally, there was no evidence that the drug was toxic at any of the doses tested, and no off-target effects were observed. Ultimately, this was exactly the evidence that Excision needed to secure federal approval to take EBT-101 into human trials.
There is still a very long way to go for Excisionโs CRISPR-based drug candidate, but it could prove to be the best solution for curing HIV if it reaches the finishing line.
What are the challenges in finding a cure for HIV?
HIV brings with it multiple challenges when it comes to finding a cure for the virus. Although there are several approaches that could eventually lead to functional HIV cure, from CRISPR gene editing to immunotherapy, there are plenty of hurdles that need to be overcome in clinical trials, with no investigative โcuresโ having even reached late-stage clinical testing yet.
One of the biggest challenges around any HIV treatment is the fact that the virus can rapidly mutate and develop resistance. This resistance is caused by changes in the genetic structure of HIV that affect the ability of medicines to block the replication of the virus.
In fact, according to WHO, all antiretroviral drugs, including those from newer drug classes, are at risk of becoming partially or fully inactive due to the emergence of drug-resistant virus.
Furthermore, turning our attention back to CRISPR, it is worth noting that it comes with safety concerns, including off-target consequences. This means that an extremely cautionary approach must be taken during clinical trials for CRISPR-based HIV therapies, and long-term studies are a necessity to assess the possibility of any long-term side effects; off-target consequences of CRISPR could take years to become apparent.
Therefore, a CRISPR-based therapy could take a very long time to reach the market and become widely available to the millions of people living with the disease. However, if it does eventually prove successful, it could certainly be one of the most promising solutions for developing a curative treatment for HIV.