Temple Researchers and Biotech Spinoff Chase an HIV Cure
By Mark Terry
May 4, 2023
Three people have been known to have been “cured” of HIV, meaning that the virus was completely eradicated from their bodies, not just suppressed. The first was Timothy Ray Brown, dubbed the Berlin Patient, the second was Adam Castillejo, the London Patient, and an anonymous 53-year-old man known as the Dusseldorf Patient is the third.
All three have similar treatment histories — diagnosed with HIV, treated with anti-retroviral therapy (ART), and later diagnosed with either acute myelogenous leukemia (AML) or nodular sclerosing Hodgkin lymphoma (NSHL). The patients were all treated with aggressive forms of radiation to destroy their bone marrow, then were given some form of modified bone marrow that had mutations in the coding for CCR5 receptors. As a result, the HIV was destroyed in the bone marrow and immune cells from the radiation, then any reservoirs of HIV in the body were unable to attach to newer cells due to the modified CCR5 receptors.
From a practical perspective, it’s unlikely to ever be a broadly feasible way to cure HIV. However, researchers at Temple University and the University of Nebraska Medical Center (UNMC) have developed a CRISPR-based gene-editing therapeutic that appears to do the same thing in laboratory animals, but does not require the harsh radiation treatments and would likely be far less expensive and time-consuming.
Kamel Khalili, Laura H. Carnell Professor and Chair of the Department of Microbiology, Immunology, and Inflammation, Director of the Center for Neurovirology and Gene Editing, and Director of the Comprehensive NeuroAIDS Center at the Lewis Katz School of Medicine at Temple University, took time to speak with BioBuzz about the research.
Khalili said, based on what they knew from the Berlin, London and Dusseldorf patients and CCR5, “we try to target CCR5 by CRISPR in a much simpler version, which is inoculation of CRISPR in humanized mice infected with HIV in order to suppress the spread of the virus. So on one hand, targeting HIV by CRISPR eliminates the virus, and on the other hand, if there is any virus left which can spread later on, we target the CCR5 to prevent the virus from spreading.”
In both cases, they use CRISPR gene-editing technology, which is administered by intravenous inoculation. The first CRISPR edits out the presence of HIV in the genome, targeting the HIV genome that became integrated into the human genome. The second CRISPR introduced a mutation in CCR5, which, Khalili says, “inactivates production of CCR5 in the cells. So when this CCR5 is no longer present in the animal, if any virus escaped from the first treatment, it can no longer spread and infect other cells because they no longer have receptors for the virus.”
CCR5’s normal function is related to immune and inflammatory responses by mediating chemotactic activity (cell migration) in leukocytes. Khalili points out that there is a large population in Northern Europe that is “basically CCR5 negative,” adding that “the data from the Berlin, London and Dusseldorf patients also proved that you can eliminate CCR5 and the patient doesn’t demonstrate drastic adverse effects due to the lack of CCR5.”
Khalili’s partner in the research is Howard E. Gendelman, MD, Professor and Chair of the Department of Pharmacology and Experiential Neuroscience at UNMC. The most recent research was published in The Proceedings of the National Academy of Sciences (PNAS).
Khalili and his co-investigator, Rafal Kaminski, Ph.D., Assistant Professor at the Center for Neurovirology and Gene Editing at the Katz School of Medicine, worked to develop a CRISPR gene-editing technique that targeted HIV-1. Gendelman and Benson Edagwa, Assistant Professor of Pharmacology at UNMC, worked with a therapeutic strategy called long-acting slow-effective release (LASER) antiretroviral therapy (ART), which they co-developed. LASER ART is essentially a way of slowing HIV replication to very low levels for longer periods, which decreases the need for regular ART in laboratory animals.
“When the virus is replicating continuously, it becomes overwhelming, so that the CRISPR may not be able to effectively eliminate all the viral copies. So the best approach is to put the cap on the virus replication and that’s what the LASER ART does,” Khalili said.
He went on to say that in the U.S., at least, patients who are basically HIV positive are taking ART, “so their virus is suppressed. They don’t need to use a LASER ART, they use the regular ART. That is sufficient.”
By just using the CRISPR that targeted HIV with LASER ART, they were able to eliminate HIV in the mice, but the virus could re-emerge and cause rebound infection. The one-two punch of CRISPR targeting HIV and CCR5 eliminated replicating HIV-1 in 58% of infected animals.
Work has also been conducted with the approach in non-human primates with success. That work was conducted by Tricia H. Burdo, Professor and Vice Chair in the Department of Microbiology, Immunology, and Inflammation at the Katz School of Medicine. The data was used to inform the application for a clinical trial and is currently under review for publication.
In September 2022, human clinical trials were launched by a biotech company that spun out of Khalili’s research, Excision BioTherapeutics. The Phase I/II study is evaluating the safety and efficacy of EBT-101. Khalili is co-founder and Chief Scientific Consultant of Excision BioTherapeutics.
Khalili describes forming the company as a “textbook strategy so the research discovery can be translated to the clinical application. And in order to get to this road, you need much more funding and a different structure.”
The company is headquartered in San Francisco. The clinical trial is being run by Rachel M. Presti, MD, PhD, Associate Professor of Medicine at Washington University School of Medicine in St. Louis.
Khalili said, “Our team here at Temple in Philadelphia was the first in the nation, and for that matter, in the whole world, to start using CRISPR technology toward HIV and several other infectious diseases. Not just in cell cultures, we took it to animal models. Our research did not stop in the cell culture, in the petri dish, in the laboratory. We took it to the animal model, first small animals, then larger animal models, and now into the clinic when we formed Excision BioTherapeutics, which was developed here in Philadelphia.”
Of the recently published data, he says, it “shows that the CRISPR technology may serve as a potential tool for the cure of HIV.”
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Mark Terry is a freelance writer, editor, novelist and ghostwriter. He holds a degree in microbiology & public health and spent 18 years in infectious disease research and clinical and research genetics prior to his transition to a writing career. His areas of expertise include biotechnology, pharma, clinical diagnostics, and medical practice management. He has written literally thousands of articles, as well as market research reports, white papers, more than 20 books, and many other written materials. He currently lives in Michigan with his family.
