How gene editing therapies can go beyond rare diseases

Earlier this year, a group of scientists in the Netherlands used the gene editing tool CRISPR to eliminate HIV from immune cells in the laboratory, a striking approach that forms the basis of potentially curative therapies for the disease.

HIV is estimated to have an impact 39 million people around the world and although 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 attempts to eliminate the virus by cutting large parts of the genetic code – could finally provide a solution.

However, translating promising results in cells or animals to humans is always a big step, and earlier this month it was revealed that a landmark clinical trial conducted by San Francisco-based biotech company Excision BioTherapeutics had ended in relative failure. The company released interim data from five HIV patients who participated in the Phase 1 trial, showing that while using gene editing to make cuts in the HIV genome appeared relatively safe, it did not lead to meaningful suppression of the virus.

The company plans to refine the approach in a future clinical trial using a different method to deliver CRISPR to patients’ immune cells. Elena Herrera-Carrillo, an assistant professor at the University of Amsterdam who led the Dutch HIV study, remains hopeful that gene editing will provide a path to a cure.

She believes CRISPR could one day provide a new way to tackle a range of chronic viral infections, and not just HIV. “With its precise gene editing capabilities, CRISPR can target and disrupt potentially viral genomes, both DNA and RNA, providing new opportunities for the treatment and prevention of infectious diseases,” she says. “It has been used to target the SARS-CoV-2 genome, and it could be used to combat hepatitis B.”

The Excision BioTherapeutics study is a particularly big step because until now the majority of CRISPR applications have focused on rare diseases. In December, CRISPR Therapeutics and Vertex Pharmaceuticals made history when their gene-editing therapy Casgevy had been approved by the Food and Drug Administration as a treatment for the blood disorders beta-thalassemia and sickle cell disease. Although this was the first time a CRISPR-based therapy was given the green light by US regulators, it is believed that only 16,000 patients who are eligible for the treatment.

But with the next generation of gene editing tools also on the horizon, many patients could benefit from this emerging field in the long term. Metagenomi, a biotech company based in Emeryville, California that received an investment from Leaps in 2020 and went public earlier this year, has launched 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 first approval, and some other first-generation gene editing companies are doing exciting work, like Intellia Therapeutics and Verve Therapeutics, but it’s just getting started,” said Brian C. Thomas, former UC Berkeley. academic who is now CEO and founder of Metagenomi. “The coming years won’t just be about a single gene-editing tool, but a whole suite of tools that can be used to interact with the human genome to tackle a wide range of diseases. It is essential that we can tailor the right tool to a specific disease goal.”

Beyond Cas9

In recent years, scientists have used CRISPR-Cas9 to create new disease models to target neurodegenerative disorders such as Parkinson’s And Huntington’sand to discover gene targets essential for cancer growth and metastasis.

Several biotech companies and academic researchers are now exploring the next generation of gene-editing tools that may be safer and easier to deliver into the body. Over the past four years, several genome engineering studies have explored its potential applications Cas11, Cas12 even Cas13 enzymes, and companies like Caszyme, which was co-founded by Professor Virginijus Šikšnys, one of the original pioneers of CRISPR, are actively pursuing these new molecular tools.

“We are working to develop safer and smaller Cas nucleases that would be more compatible with various delivery technologies,” said Monika Paule, CEO of Caszyme.

At Metagenomi, Thomas predicts that second-generation gene-editing therapies will use CRISPR as a framework for other functions, such as CRISPR-associated transposases (CASTs) that allow scientists to effectively cut and paste a large stretch of DNA at a specific location. in the genome.

He suggests that this could ultimately provide a single way to tackle 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, it would take a huge number of therapies to treat all patients suffering from that disease using current gene editing technologies,” he says. “But with a CAST system you may be able to address all underlying mutations with a single treatment, by replacing the same piece of problematic DNA in each patient.”

The delivery challenge

Although CASTs are still far from the clinic, newer gene-editing nucleases may help solve some of the delivery problems that have contributed to the high costs of gene-editing therapies, along with existing safety concerns. Many of these new approaches were the subject of great excitement at the recent annual meeting of the American Society of Gene & Cell Therapy (ASGCT) in Baltimore, which brought together some of the leading experts in the field.

Currently, patients receiving the Casgevy therapy, which costs more than $1 million, must have stem cells extracted from their bone marrow, which are then modified outside their bodies and reinserted into the bone marrow, where they produce new blood cells. that reduce their symptoms. However, more tolerable methods of delivering CRISPR into the body could include 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 about the possibilities offered by nucleases that are smaller and more versatile than Cas9 and could allow them to penetrate further into the body. It is believed that such features will facilitate the delivery of genome editing tools to previously inaccessible tissue types and organ systems.

“It’s very simple 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 doesn’t cross the blood-brain barrier. Instead, you can use small viruses such as adeno-associated viruses (AAVs). They’re limited in what they can carry, but that’s where these smaller nucleases, which are a third the size of Cas9, really get exciting. You can easily get them wrapped in an AAV and think about jumping outside the liver and treating these other diseases.

As more clinical trials of CRISPR-based therapies take place and more gain regulatory approval, Thomas predicts that we will learn a tremendous amount about how to make these treatments effective and accessible to as many patients as possible.

The era of one-shot gene editing therapies is just beginning. Once science matures, I predict it will be nothing short of transformative.

Thanks to David Cox for additional research and reporting on this article.