Sopuruchi Onwuka

The United States health regulator, the Food and Drug Administration, has cleared Excision BioTherapeutics Incorporated to proceed with its CRISPR gene-editing technology which presents new hopes for cure of the lingering Human Immuno-deficiency Virus popularly called HIV which has killed over 40 million people in the past 40 years.

The one-time IV infusion therapy is trying to eliminate enough of the AIDS virus to narrow the population of cells that drive the viral rebound. That essentially would leave viral junk, and the immune system could wipe out any remaining infectious virus.

In that way, Excision BioTherapeutics would eliminate the need for antiretroviral therapy which has extended the lives of people infected with HIV, turning the virus from a death sentence to a manageable chronic condition kept at bay by the drugs.

According to information from our foreign media reviews yesterday, the gene-editing technology of the San Francisco based biotech company brings the world closer to permanent resolution of the global HIV-AIDS conundrum.

The development comes as a man now known as the Geneva Patient has been officially determined to be potentially free of HIV after undergoing stem cell treatment for blood cancer. The stem cell treatment for blood cancer is known previously to simultaneously cure HIV in some patients.

The man who is in his 50s has caught HIV in 1990 and started taking antiretroviral drugs in 2005 before adding the extramedullary myeloid tumor, a rare blood cancer, in 2018. He was treated with radiation, chemotherapy and a stem cell transplant, according to the reports.

It remains unethical for a person with HIV who does not already qualify for a stem cell transplant due to cancer to undergo such a treatment in hopes of curing the virus, given such treatment’s considerable toxicity. Scientists generally expect that any success in the effort to develop a widely scalable HIV cure therapy will likely take decades.

But the innovation from Excision BioTherapeutics Inc.’s treatment, called EBT-101, might bring the time for resolution of the HIV cure quite closer, explaining the reason why the US FDA granted it fast track designation to push its treatment beyond its current early-stage clinical trial.

The company, according to reports, expects to release data by the end of the year from the first three-person cohort in its Phase I/II clinical trial looking at safety and early signs of efficacy in a low-dose version of EBT-101.

CEO Daniel Dornbusch whi hinted that “we’re very encouraged by what we see” said the company was about to start a cohort with about four times more drug than the first group and then a third higher dose cohort.

The company was founded on work in the lab of Kamel Khalili, a professor at Temple University in Philadelphia and director of its Center for Neuroviology and Gene Editing. The other scientific cofounder is Jennifer Doudna of the University of California, Berkeley, whose co-discovery of CRISPR as a genome-editing tool landed a share of the 2020 Nobel Prize in chemistry.

Excision’s board includes Jeff Kindler, the former CEO of Pfizer Inc., and Bill Carson, the chairman and former CEO of Otsuka Pharmaceutical Development & Commercialization Inc.

According to scientists, HIV targets what are known as CD 4 T lymphocytes, or “helper cells,” that normally act as a command center for coordinating the immune system’s response to a viral invader; they stimulate other immune cells to attack. HIV, however, weakens those CD4 cells and the body’s ability to fight off infection and slow the virus’ replication.

Previous efforts to broadly disable HIV by cutting its DNA, including an attempt by the Bay Area’s Sangamo Therapeutics Inc. using “zinc finger” enzymes as cutting tools, still allowed the virus to mutate and continue to replicate.

Excision BioTherapeutics say CRISPR is the key to Excision’s EBT-101. The CRISPR-based approach makes two cuts, removing any of the viral DNA’s essential replication genes in between.

CRISPR finds very specific sequences — the genetic alphabet that encodes biological information — where it can cut the viral DNA. That specificity is needed not only for the dual cuts to be effective, Dornbusch said, but to prevent CRISPR from cutting human DNA.

“We’ve never seen any off-target DNA cut,” Dornbusch said. “It is orders of magnitude less likely to cut human DNA than any other gene editing or gene therapy approach.”

EBT-101 is one of the first CRISPR therapies in the clinic against an infectious disease, according to scientific reports. It currently uses a shelled out virus, called AAV9 that is like a cassette packaging delivering the guide RNA that marks the cutting sites and a Cas9 protein that acts as the “molecular scissors.”

 But Dornbusch said the technology is agnostic to delivery vehicles; for hepatitis B therapy, Excision’s therapy is carried by lipid nanoparticles, like those used in mRNA vaccines against Covid-19.

There are big caveats with Excision’s therapy that only deeper clinical trials will answer. One of those issues centers on the durability of treatment: Will Excision’s therapy translate into a lifelong cure or free patients from daily antiretroviral pill-popping for a year or a few years?

HIV can pull back its viral troops to sanctuary sites, harboring in those reservoirs in the gut, lymph nodes, spleen and the brain and remaining undetected for long periods before relaunching their attack when the coast is clear of protective treatments.

But what HIV doctors and researchers have found is that 95% to 98% of HIV is junk, so knocking out the pro-viral part of the virus is key, Dornbusch said. If EBT-101 can stop HIV from replicating for a year, “we probably will see it (gone) forever.”

Other studies have shown the average time for HIV to rebound after patients go off antiretroviral therapy is 3-1/2 weeks; after eight weeks, HIV reemerges in nearly everyone who goes off therapy.

“Our goal is one-and-done for the lifetime of a patient,” Dornbusch said.

Patients in Excision’s trials will be monitored for 15 years, Excision’s senior vice president, clinical, Dr. William Kennedy, said in a February meeting.

The FDA’s fast-track designation is key as Excision looks to start talks with “strategic partners” — namely deep-pocketed drug developers — this year or next, Dornbusch said.

It also gives Excision more-frequent feedback meetings with regulators to shape EBT-101’s development. It also means EBT-101 would be eligible for priority review by the FDA and accelerated approval if it successfully completes its clinical trials.

“For us, it’s a recognition that AIDS and HIV are still a key unmet medical need that is a serious condition,” Dornbusch said. “This is still something we absolutely need to cure.”

In the case of the European man who has been in a state of remission from HIV infection for nearly two years after receiving a stem cell transplant to treat blood cancer, he could join the rarefied club of five people who are considered either definitely or possibly cured of HIV if enough time passes with no signs of viable virus.

All six people had HIV when they received stem cell transplants to treat blood cancers such as leukemia or lymphoma. But unlike the five other cases, this new one involves a person whose donor did not have a rare genetic abnormality that generates resistance to HIV in the immune cells that the virus targets for infection.

The man’s case will be presented at the International AIDS Society Conference on HIV Science in Brisbane, Australia. This major biennial gathering of scientists will also hear noteworthy presentations regarding post-treatment control of HIV in infant boys, circumcision’s impact on HIV risk in gay men, and the relationship between HIV and mpox (formerly known as monkeypox).

President of the IAS and Director of the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia, Dr. Sharon Lewin, called the new viral remission case “great news.”

Such case reports, she said, “help in many ways in the work toward a cure.”

The ‘Geneva Patient’ was overseen by a research team led by Asier Sáez-Cirión, head of the viral reservoirs and immune control unit at the Institut Pasteur in Paris.

HIV is vexingly difficult to cure. This is in large part because even when suppressed by antiretrovirals, the virus hides in nonreplicating immune cells, known collectively as the viral reservoir. Such standard HIV treatment only works on cells that are actively producing new viral copies. So the virus remains under the radar of antiretrovirals within these latently infected cells, each of which can take months or even years to return to a replicating state.

Since the first such case was announced in 2008, three people have definitely been cured and two additional people, pending more time passing without a viral rebound, have possibly been cured of HIV.

Prior to the Geneva Patient’s case, a handful of other people with HIV who developed cancer also received stem cell transplants from donors without the rare genetic mutation conferring natural resistance to the virus. But none from this group went more than 10 months after stopping antiretroviral treatment without a resurgent virus. Hopes that they had been cured were dashed.

The man in Switzerland has now spent 20 months with no viral rebound, having been taken off of antiretrovirals in November 2021. Sáez-Cirión and his colleagues have conducted a battery of ultrasensitive tests in search of HIV in his body and have only been able to detect trace amounts of defective virus. But they still cannot rule out that the man retains even a single cell infected with viable virus, one that could spring to action at any moment and repopulate the body with HIV.

“The possibility of viral rebound is indeed a concern,” Sáez-Cirión said. “The virus may persist in rare infected blood cells or anatomical sites that we have not analyzed.”

It remains unclear why the Geneva Patient’s case has been so successful, at least thus far, while others who received similar treatment were not so fortunate.

Dr. Steven Deeks, a leading HIV cure researcher at the University of California, San Francisco, who was not involved in the study of the Geneva Patient, said the details of the case “suggest that what we once assumed was impossible might in fact be possible.”

Speculating about the drivers of this man’s lengthy HIV remission, Deeks said, “Eliminating most if not all of the reservoir with chemotherapy was certainly the key intervention.” Deeks also noted the man’s repeated episodes of what is known as graft-versus-host disease, a powerful and potentially dangerous immune reaction that occurs as a consequence of a stem cell transplant. This might have also played a crucial role, Deeks said, “as the newly rebuilt immune system may have been attacking and clearing the old immune system, including any residual T cells harboring HIV.”

Sáez-Cirión said it is also possible that the immunosuppressive drugs that the Geneva Patient continues to receive to prevent graft-versus-host disease may be preventing any residual HIV from replicating.