Virus World

A new paradigm for HIV treatment is on the horizon as FDA gives nod for startup to begin trials of CRISPR-based gene therapy as a HIV cure.  The US Food and Drug Administration (FDA) has given the nod for Excision BioTherapeutics to begin trials testing CRISPR gene editing as a treatment for HIV. EBT-101 will be a first-in-human, CRISPR-based one-time gene therapy to be evaluated in individuals with HIV. On 15 September Excision announced that the FDA had accepted its Investigational New Drug (IND) application for EBT-101 as a potential functional cure for chronic HIV. The IND clearance will allow the firm to start a first-in-human Phase I/II trial to evaluate the safety, tolerability and efficacy of EBT-101 in healthy individuals living with HIV. “The clearance of our IND application for EBT-101 represents an important milestone for Excision and is the result of years of commitment to developing a functional cure for individuals living with HIV,” said Excision CEO Daniel Dornbusch. “Although antiviral treatments can manage HIV infection, they require life-long treatment, cause side effects, and do not provide the possibility of a functional cure. We are grateful for the FDA’s engaged review and acceptance of the IND for EBT-101 and look forward to initiating the Phase I/II clinical trial later this year.” EBT-101 uses CRISPR to cut out or excise HIV that has wrapped around the DNA in cells. It has been HIV’s ability to coil itself into DNA that has made it so difficult to treat and largely the reason that past curative efforts have fallen flat. The therapy harnesses an adeno-associated virus (AAV) at a relatively low dose to deliver the one-time treatment.  Excision said that the investigational programme employs CRISPR-Cas9 and two guide RNAs that target three sites within the HIV genome, “thereby excising large portions of the HIV genome and minimizing potential viral escape”.

The upcoming trial will be one of the first attempts to directly extract the latent virus from DNA. In preclinical studies, the therapy demonstrated the ability to excise HIV proviral DNA in human primary cells as well as multiple animal models including non-human primates. In later studies, after evaluating the safety and tolerability of the therapy, Excision hopes to take patients off their regular antiviral meds to test EBT-101 as a cure. “EBT-101 has demonstrated removal of proviral DNA in multiple animal models and offers an opportunity for individuals living with HIV to potentially cease life-long therapies,” said Excision’s CMO Lisa Danzig. “The Excision team looks forward to this important collaboration with our principal investigators, scientific advisors and regulators, to conduct a safe and informative trial with this first-in-class approach to a viral disease target previously considered to be incurable.” The news of the trial comes just weeks after it was announced that J&J’s recent efforts at an HIV vaccine had failed and news broke that Moderna is set to begin trials of its HIV vaccine based on mRNA technology. HIV can now be well managed with antiretroviral medications, but these are a lifelong commitment and cause side effects. For the last few decades, an elusive HIV vaccine has been considered ‘the holy grail’ in stopping the spread of the highly stigmatised disease, but CRISPR-based gene editing would represent a brand-new therapeutic approach.

Excision BioTherapeutics, Inc. (Excision) has secured $60 million in investor financing to advance CRISPR-based gene editing constructs developed by Kamel Khalili, PhD, Laura H. Carnell Professor and Chair of the Department of Neuroscience, Director of the Center for Neurovirology, and Director of the Comprehensive NeuroAIDS Center at the Lewis Katz School of Medicine at Temple University (LKSOM). The funding will allow these treatments to be advanced into a Phase 1/2 clinical trial in patients with chronic HIV infection. The funding secured by Excision will also provide Temple scientists and Excision the ability to research CRISPR technology on other viral diseases at LKSOM including JC Virus for Progressive Multifocal Leukoencephalopathy, Herpes Simplex Virus and other viral diseases. Those additional studies will be led by Ilker K. Sariyer, DVM, PhD, Associate Professor of Neuroscience and Neurovirology at LKSOM. “The funding secured is a momentous occasion for Excision and Temple and the many individuals living with HIV and other viral diseases,” said John M. Daly, MD, FACS, Interim Dean & Dean Emeritus and Harry C. Donahoo Professor of Surgery at LKSOM. “These continued research and clinical trials bring us one step closer to having new technology available to suppress and eradicate multiple viral diseases.”

In research recently published by Nature Communications, Dr. Khalili along with Tricia H. Burdo, PhD, Associate Professor and Associate Chair of Education in the Department of Neuroscience at LKSOM, who is an expert on the utilization of the SIV (simian immunodeficiency virus)-infected antiretroviral therapy (ART)-treated rhesus macaque model for HIV pathogenesis and cure studies; Dr. Sariyer; Rafal Kaminski, PhD, Assistant Professor of Neuroscience and Assistant Professor in the Center for Neurovirology at LKSOM; Pietro Mancuso, PhD, an Assistant Scientist in Dr. Khalili’s laboratory; Chen Chen, a Research Technician in Dr. Khalili’s laboratory; other scientists in Dr. Khalili's, Dr. Burdo’s, Dr. Sariyer’s and Dr. Kaminski’s laboratories; and colleagues demonstrated success in editing the genome of simian immunodeficiency virus (SIV), a virus closely related to HIV, the cause of AIDS, from non-human primates. Dr. Khalili and Dr. Burdo were senior co-investigators on the study and Dr. Mancuso was first author.  The success of Dr. Khalili’s HIV discoveries has led Temple into a partnership with Excision to support the continued development of the CRISPR technology. In this partnership Dr. Khalili serves as Co-Founder and Chief Scientific Consultant, and holds equity in Excision, which has licensed the viral gene editing technology from Temple University. Dr. Burdo contributes to preclinical research and development, serves on the Scientific Advisory Board and holds equity in Excision. “This transformative financing will accelerate and support the research we have developed over the past decade,” said Dr. Khalili. “We have proven the technology and candidate programs in vitro and in vivo in both small animal models and primate models. We are optimistic that ongoing research will demonstrate the potential for a future therapeutic to generate functional cures for viral infectious diseases.”

Editor’s Note: Kamel Khalili is Co-Founder and Chief Scientific Consultant, and holds equity in Excision BioTherapeutics, which has licensed the viral gene editing technology from Temple University. Kamel Khalili and Rafal Kaminski are named inventors on patents that cover the viral gene editing technology. Tricia Burdo is a consultant for and holds equity in Excision BioTherapeutics. Ilker Sariyer is a consultant for Excision. Dr. Khalili , Dr. Burdo, Dr. Sariyer and Dr. Kaminski are employed by Temple University, and both they and LKSOM faculty within the department conduct research activities sponsored by the company. Questions regarding their affiliations with Temple University may be directed to coisom@temple.edu.  In addition to owning the viral gene editing technology that Excision is licensing, Temple University also holds an equity interest in Excision. As a result of these interests, Temple University could ultimately potentially benefit financially from the outcome of this research. These interests have been reviewed and approved by Temple University in accordance with its Institutional Conflict of Interest policy. Questions about this can be directed to coitemple@temple.edu.