Can Graphite Bio Realize the Promise of CRISPR Gene Editing to Develop One-time Cures?

One dose, one cure. Countless researchers with this dream have worked for decades toward developing life-saving medicines for genetic diseases. That’s gene therapy’s goal: to fix DNA errors and see a pathological condition halted or reversed with just a single shot.

Graphite Bio is pioneering a precision gene editing approach that has the potential to transform health by achieving one of medicine’s most elusive goals: to precisely “find & replace” any gene in the genome. Graphite Bio’s UltraHDR gene editing platform takes CRISPR beyond cutting and harnesses the power of high-efficiency precision DNA repair.

Using an adeno-associated virus called AAV6 as a delivery vehicle, Graphite Bio uses a DNA template to correct genetic mutations, replacing entire defective genes with functional genes or inserting new genes into predetermined, safe locations in stem cells. The company was co-founded by academic pioneers in gene editing and gene therapy, including Maria Grazia Roncarolo, MD, and Matthew Porteus, MD, PhD.

Graphite Bio’s platform is being used to develop genetic medicines targeting several blood diseases. Nula-cel, formerly GPH101, is Graphite Bio’s lead investigational therapy that will be evaluated as a potential cure for sickle cell disease (SCD) patients. Nula-cel uses the UltraHDR platform to directly correct the point mutation in the beta-globin gene that causes SCD, changing sickle hemoglobin (HbS) to normal adult hemoglobin (HbA).

Graphite Bio claims to be one of the first companies advancing a genetic therapy with the potential to change a disease-causing gene back to normal for any indication. The multi-center, open-label clinical study called CEDAR is designed to evaluate the safety, preliminary efficacy, and pharmacodynamics of GPH101 in adult and adolescent patients with severe SCD. In August 2022, Graphite Bio dosed the first patient in the CEDAR trial, with initial proof-of-concept data from the Phase I/II CEDAR trial anticipated in mid-2023.

Graphite also has a research program for treating beta-thalassemia, one of the most common autosomal recessive disorders. This genetic blood disorder is characterized by reduced production of beta-globin, a protein that forms oxygen-carrying hemoglobin with alpha-globin. Graphite seeks to replace the mutated beta-globin gene with a functional gene and restore adult hemoglobin (HbA) expression. In addition, Graphite has an early-stage research program for treating alpha-1 antitrypsin (AAT) deficiency, a severe inherited genetic disorder that can cause progressive lung and liver disease. The program leverages the company’s targeted gene insertion approach to increase AAT protein production permanently.

GEN Edge talked through Graphite Bio’s underlying strategy to develop several genetic cures with CEO Josh Lehrer, MD, MPhil, FACC.

GEN Edge: Josh, how did you end up joining Graphite Bio?

Lehrer: Before joining Graphite Bio, I was the chief medical officer at Global Blood Therapeutics (GBT) and worked for many years on developing Oxbryta, the first approved mechanism-based therapy for sickle cell disease (SCD). We had our co-founder, Matthew Porteus, come to give a seminar at GBT to talk about his groundbreaking work. When I heard what he was doing, I was floored. He had figured out how to make a decades-long dream in the field of genome engineering a reality. He showed us edited cells from a patient with SCD that had been corrected, indistinguishable from the cells of a patient’s unaffected siblings or parents. This was simply incredible. I saw an amazing opportunity to take what I had learned and join with Matt to both build a company around this platform and also rapidly move into the clinic to hopefully transform the lives of people living with SCD.

We started the company at the beginning of the COVID-19 pandemic, in April 2020, and have grown to over 100 employees. We became a public company just over a year ago and are fortunate to have the resources we need to advance our sickle-cell program and, in parallel, several other genetic therapies.

We’ve also thought about not just the technology, the platform, and the cell engineering, but how we can get these genetic therapies to be more than a headline, more than an exciting publication, more than a handful of patients treated to really impact large numbers of people in need. We realized that the conditioning treatment—how a patient’s bone marrow is treated to make room for the gene-edited stem cell therapies—is as critical as the editing technology. We have used our experience in stem cell biology and immunology to begin research on a new approach to conditioning. We are now developing what we hope will become a best-in-class, non-toxic antibody targeting approach, ultimately enabling a one-time cure that wouldn’t require a hospital stay or have chemotherapeutic conditioning risk—a very different paradigm than what we can currently offer patients.

GEN Edge: What is Graphite’s strategy to move these therapies quickly through approval?

Lehrer: Since our founding, our focus has been on advancing our programs with a sense of urgency, and ultimately getting our potentially curative therapies to as many patients as possible.

We are planning to move quickly through our clinical trials, leveraging the experience of other clinical trials in SCD. But we are also thinking about this end-to-end. We’re trying to think of what success means with a long-term view—not just how we get this technology to the initial clinical data readout, but how we generate data to demonstrate the unique advantages of a definitive gene correction approach. This means designing our clinical trials with new endpoints that can measure the benefit of a complete cure versus an indirect approach, and these endpoints could ultimately translate into an approval for a greater number of patients with sickle cell disease.

We are also thinking holistically, beyond our clinical trials for Nula-cel, about the barriers we need to overcome to impact more patients. If the science tells us we should be developing a new antibody to improve conditioning and remove a barrier to access, then it makes sense to do that, even if that wasn’t part of our initial focus or strategy. This also means investing early in advancing how we manufacture our therapies, making the process more scalable and reducing costs. We should invest in these strategic priorities to ensure that our programs have the most extensive potential patient benefit. They may be much more important than adding a third or fourth program to our pipeline.

GEN Edge: Does Graphite Bio consider partnerships to expand the platform’s reach?

Lehrer: We think about partnerships if others can bring unique expertise or resources that help us leverage our gene editing platform in additional directions. We are starting to turn to those conversations a little more, where we think we have the best tools for efficiently integrating DNA in virtually any cell type ex vivo. And that is applicable outside of hematopoietic stem cells—to engineering T cells, NK cells, iPS cells, or other types of cells that could be therapies in other areas. For example, we’re probably not going to identify new cancer targets ourselves. These would be perfect opportunities to collaborate with other companies, where we can do the editing more efficiently and other companies can provide biological or developmental expertise in different therapeutic areas.

GEN Edge: What drove the decision for Graphite Bio to become a public company?

Lehrer: We wanted to leverage a platform broadly and have the opportunity to broadly consider what’s required to cure SCD patients, beyond just one clinical trial and one data readout. If we were focused on creating value as a private company, we’d stay private a company, get the first few patients of data in our SCD program, increase value, and then figure out what’s next. We would be moving forward in serial.

But we needed more resources and a bigger team because we have bigger ambitions. For example, in SCD or any cell therapy, you must think about the commercial manufacturing process from the beginning. If not, you end up with what we’ve seen happen with other companies—making many changes along the way and getting delayed for years. That requires a significant upfront investment, a big team, and a public company’s resources. We were fortunate that the market was very receptive when we decided to go public.

GEN Edge: What milestones has Graphite Bio set for the next five years?

Lehrer: If we’re having this conversation in five years, bringing this technology to people living with SCD and realizing its full potential is a big part of what’s driving us. We are moving that forward, validating the platform, showing that clinically we are different, and then translating that into endpoints demonstrating that we can impact all aspects of the disease and treat all severely affected patients who need a cure. We want to go beyond what others have shown, which is a reduction in pain, to show that our approach can be a definitive cure by producing normal red blood cells, preventing strokes in kids, preventing organ damage, and essentially phenocopying what is the gold standard for cure inSCD: allogeneic transplants.

In five years, if we have a best-in-class antibody conditioning therapy that can be administered in the outpatient setting to create room in the bone marrow niche for engraftment of our stem cell-based cure, then we can bring this therapy to kids with SCD who aren’t yet experiencing complications and stop the disease before the damage begins. That would transform how we think about SCD—every child born with the disease could have a chance to live a completely normal life. And we’re thinking about manufacturing cell therapies as an engineering problem to where we can get costs down from where they are now to make this accessible broadly and see a significant impact from a public health standpoint.

We’d hope to take the same approach to other severe genetic diseases. We have a program in beta-thalassemia that would synergize with our approach in SCD. It was even more technically challenging because we need to use our gene editing technology to replace an entire gene.

Our gene editing technology can also precisely insert genes into stem cells to give them new functions, potentially bringing one-time cures to many other types of genetic diseases using our platform. These cells can repopulate brain microglia within the central nervous system (CNS) and permanently deliver proteins across the blood-brain barrier to fight neurodegenerative diseases, for example. We could also engineer stem cells to produce red cell precursors as protein factories to make enzymes and proteins to treat diseases like alpha 1 anti-trypsin deficiency or to produce clotting factors for hemophilia. Having some of these programs in the clinic to show the broader potential of our platform is something else we’d like to see in a five-year timeframe.

Beyond that, we’re starting discussions about how to leverage our platform outside of hematopoietic stem cells. We want to pursue new programs where we think we can solve a different need or have a differentiated therapy. An example would be if there’s a strong hypothesis around a better CAR T that requires multiplex editing, or insertion of several different transgenes. We have a highly efficient way of doing this, and this could be a productive collaboration with a company that brings cancer biology expertise.

GEN Edge: What are the rate-limiting factors to getting Graphite Bio to these milestones?

Lehrer: The rate-limiting factor in demonstrating clinical data and clinical translation with these therapies is manufacturing—the CMC (chemistry, manufacturing, and controls). I’ve previously worked in small molecules and biologics; the difference here with gene editing is that there’s no target risk. If you can do what you’re trying to do, you can cure a patient because you’re changing a dysfunctional gene back to a functional one. You can also get to proof of concept in the lab or even animal models. A postdoc project can lead to a development candidate. So, that part is fast, and that’s exciting.

But where things can be slower, because the steps are not as efficient and the standards are still evolving, is going from that to the clinical material and then commercial supply. This requires strict controls and analytics. And this is a new field, so to some extent, the testing required by the FDA is a moving target. Regarding manufacturing, there’s a lot of experimentation, continued investigation, and learning that has to happen in tandem with your clinical experience. That isn’t true if you make an antibody or a small molecule.

Initially, we’re using a GMP facility built at Stanford, where we did our initial work to support our IND. But we also are prepared to move beyond the academic facility to one that can scale with us. One of the ways to prevent these bottlenecks is to move as early as possible to a manufacturing facility that can also supply us and scale all the way to a commercial product. We’ve decided that we aren’t going to build a $200-million plant for commercial supply ourselves. We have great partners that can start working with us now and then scale with us over time.

GEN Edge: Where does the company name originate?

Lehrer: It has a lot of meaning for us internally. One connection people make, which was part of the reason for the name, is that of a graphite pencil rewriting genes. There’s also the idea of graphite being made from carbon—the element of life.

But the company name comes from Rosalind Franklin’s story. Rosalind Franklin took the famous X-ray fraction photograph that Watson and Crick used to solve the structure of DNA. She didn’t get much credit and was largely written out of the history of this discovery. Rosalind Franklin was a woman in science who didn’t get her fair shake. The crystal structure she solved before working on DNA was the atomic structure of graphite. So, it’s a connection to the origin story of DNA and a reference to Rosalind Franklin’s contributions, which have historically been neglected—much like SCD and many of the patient communities that we serve.

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