Rahman Oladigbolu, a 52-year-old Harvard-educated film maker with sickle cell disease, poses for a ... [+]
Earlier this year, a group of scientists in the Netherlands used the gene editing tool CRISPR to eliminate HIV from immune cells in the lab, an eye-catching approach that is forming the basis of potentially curative therapies for the disease.
HIV impacts an estimated 39 million people around the world and while it is no longer a death sentence thanks to antiretroviral drugs, there is still no recognized cure. Research groups around the world believe that gene editing - which seeks to disable the virus through cutting large swaths of its genetic code - could finally offer a solution.
However, translating promising results in cells or animals to humans is always a big leap, and earlier this month it was revealed that a pioneering clinical trial run by San Francisco-based biotech Excision BioTherapeutics had ended in relative failure. The company released interim data from five HIV patients who had participated in its Phase 1 trial, showing that while using gene editing to make cuts in the HIV genome seemed to be relatively safe, it did not lead to meaningful suppression of the virus.
The company is planning to refine the approach in a future clinical trial using a different method of delivering CRISPR to patient immune cells. Elena Herrera-Carrillo, an assistant professor at the University of Amsterdam who led the Dutch HIV study, is still hopeful gene editing will provide a pathway to a cure.
One day, she believes, CRISPR could offer a new way of targeting a range of chronic viral infections, not just HIV. “With its precise gene-editing capabilities, CRISPR can potential target and disrupt viral genomes, both DNA and RNA, offering new avenues for the treatment and prevention of infectious diseases,” she says. “It has been utilized to target the SARS-CoV-2 genome, and it could be employed to combat hepatitis B.”
The Excision BioTherapeutics trial is a particularly big step because until now, the majority of CRISPR applications have been targeted at rare diseases. In December, CRISPR Therapeutics and Vertex Pharmaceuticals made history when their gene editing therapy Casgevy was approved by the Food and Drug Administration as a treatment for the blood disorders beta thalassemia and sickle cell disease. While this marked the first time that a CRISPR-based therapy was greenlighted by regulators in the U.S., there are thought to be only 16,000 patients who are eligible to receive the treatment.
Yet with the next generation of gene editing tools also on the horizon, many patients could benefit in the long run from this nascent field. Metagenomi, a biotech based in Emeryville, California that received an investment from Leaps in 2020 and went public earlier this year, has a series of preclinical programs targeting diseases ranging from familial and spontaneous ALS to cardiovascular disease and cystic fibrosis. (I remain a board member at Metagenomi.)
“We’ve just seen this initial approval, and some of the other first generation gene editing companies are doing exciting work, such as Intellia Therapeutics and Verve Therapeutics, but it’s just getting started,” says Brian C. Thomas, a former UC Berkeley academic who is now CEO and Founder of Metagenomi. “In the coming years it’s not just going to be about one single gene editing tool, but a whole variety of tools which can be used to interact with the human genome to address a broad range of diseases. Being able to match the right tool to a given disease target is essential to this.”
Beyond Cas9
In recent years, scientists have used CRISPR-Cas9 to create new disease models to study neurodegenerative conditions such as Parkinson’s and Huntington’s, as well to discover gene targets that are key to cancer growth and metastasis.
Various biotech companies and academic researchers are now looking into the next generation of gene editing tools which may be safer and easier to deliver into the body. In the last four years, various genome engineering studies have investigated the possible applications of Cas11, Cas12 and even Cas13 enzymes, and companies such as Caszyme, which was co-founded by Professor Virginijus Šikšnys, one of the original pioneers of CRISPR, are actively pursuing these new molecular tools.
“We’re working on developing safer and smaller Cas nucleases that would be more compatible with diverse delivery technologies,” says Monika Paule, CEO of Caszyme.
At Metagenomi, Thomas predicts that the second generation of gene editing therapies will use CRISPR as a framework for other functions such as CRISPR-associated transposases (CASTs) which allow scientists to effectively cut-and-paste a large piece of DNA at a particular site in the genome.
He suggests that this could ultimately provide a single way of tackling complex diseases such as the many different forms of muscular dystrophy, which can be caused by hundreds of possible variants in the dystrophin gene.
“Because there are so many different variants, a monumental number of therapies would be required to treat all patients that suffer from that disease using current gene editing technologies,” he says. “But with a CAST system, you might be able to go in and address all underlying mutations with a single treatment by replacing the same chunk of problematic DNA in every patient.”
The Delivery Challenge
While CASTs are still a long way from the clinic, newer gene editing nucleases may help solve some of the delivery challenges that have contributed to the high cost of gene editing therapies along with existing safety concerns. Many of these novel approaches were the subject of considerable excitement at the recent American Society of Gene & Cell Therapy (ASGCT) annual meeting in Baltimore, which brought together some of the leading experts in the field.
Right now, patients who receive the Casgevy therapy, which costs more than $1 million, need to have stem cells extracted from their bone marrow, which are then modified outside their body, and reinfused back into the bone marrow, where they produce new blood cells that reduce their symptoms. However, more tolerable methods of delivering CRISPR into the body may be lipid nanoparticles or modified lentiviruses.
Thomas says CRISPR therapies delivered via lipid nanoparticles will soon allow scientists to target metabolic disorders that occur in the liver. He is even more excited by the potential offered by nucleases that are smaller and more versatile than Cas9, which could make it possible to penetrate further into the body. It is believed that such features will facilitate delivery of genome editing tools to previously inaccessible tissue types and organ systems.
“It’s very straightforward to take a lipid nanoparticle and get that into the liver,” he says. “But you can’t use that method for neurodegenerative diseases because it won’t pass the blood-brain barrier. Instead, you can use small viruses such as adeno-associated viruses (AAVs). They are limited in what they can carry but that’s where these smaller nucleases, which are a third of the size of Cas9, become really exciting. You can comfortably get them packaged into an AAV and start thinking about jumping outside the liver and treating these other diseases.”
As more clinical trials of CRISPR-based therapies start to happen and more receive regulatory approval, Thomas predicts that we will learn a tremendous amount about how to make these treatments effective and accessible for as many patients as possible.
The era of one-and-done gene editing therapies is just beginning. Once the science matures, I predict it will be nothing short of transformational.
Thank you to David Cox for additional research and reporting on this article.
