DUBLIN – Versant Ventures, the founding investor of Crispr Therapeutics AG, is teaming up with one of the academic founders of that company, Stanford University’s Matt Porteus, to start a new gene editing firm, Graphite Bio Inc., which is focused on targeted integration of DNA to achieve a therapeutic benefit.
Graphite Bio, of South San Francisco, has raised $45 million in a series A round that also brought in Samsara Biocapital. It is already prepping a first IND filing, in sickle cell disease (SCD). “This is a relatively mature company for a series A financing. We’ll be treating patients in the first half of 2021,” Jerel Davis, managing director of San-Diego-based Versant told BioWorld. Data could start to flow about a year after that.
It is by no means a one-program company either. “There are probably eight to 10 behind that, at different stages of validation,” Davis said. “This is a high-momentum company, with a huge amount of ambition.”
In addition to Porteus, the company’s other scientific founder is Maria Grazia Roncarlo, professor of stem cell and regenerative medicine at Stanford, who is one of Europe’s gene therapy pioneers. Among her many scientific and clinical achievements, she led the development of the gene therapy Strimvelis, an autologous ex vivo engineered CD34+ cell therapy, which is approved for treating severe combined immunodeficiency due to adenosine deaminase deficiency.
Graphite Bio’s approach to gene editing is based on a lengthy and painstaking research effort to optimize the many steps involved in delivering a genetic payload to a specific site within a gene and ensuring it is expressed at appropriate levels. That includes working with high fidelity and engineered CAS nucleases to achieve targeted DNA strand breaks; innovations in the design of the DNA templates that facilitate homology-directed repair of DNA and allow for the site-specific insertion of genetic payloads; the development of an efficient adeno-associated virus vector gene therapy process to deliver those donor templates; and the accumulation of knowledge about cell handling and cell culturing conditions that ensure cell survival.
“Because it’s such an inefficient process, it hasn’t been therapeutically tractable,” Versant partner Carlo Rizzuto told BioWorld. “When Matt Porteus started work on this, efficiencies were below 1%,” he said. Porteus and his lab scientist, Danny Dever – who has transitioned to the new company as head of translational science – have pushed that efficiency to more than 50%, across many different cell types, including CD34+ hematopoietic stem cells. “This is something that a lot of people have been trying to achieve,” he said. It brings the original promise of gene editing within reach.
The early clinical applications of gene editing that are now undergoing clinical trials mainly involved targeted deletions and gene knockouts rather than insertions. In SCD, for example, gene editing programs in development at Zug, Switzerland-based Crispr Therapeutics and at Brisbane, Calif.-based zinc finger nuclease specialist Sangamo Therapeutics Inc. do not involve the correction of the disease-causing mutation in the beta-globin gene but disruption of the gene encoding BCL11A, a transcriptional repressor of fetal hemoglobin production.
Cambridge, Mass.-based Bluebird Bio Inc. is further advanced with a genetically modified autologous cell therapy in the same indication. It is in phase I/II in SCD with Lentiglobin, which employs a lentiviral vector to deliver the betaA-T78Q-globin gene. The same product has already received European Union approval in beta-thalassemia, marketed under the brand Zynteglo (betibeglogene autotemcel). Graphite Bio’s program also involves the ex vivo engineering of patients’ hematopoietic stem cells, but the crucial difference is it is inserting a functional DNA sequence within the original, damaged gene. Lentiviral vectors, in contrast, integrate randomly within the genome, which may give rise to unpredictable effects.
Graphite Bio’s CEO, Josh Lehrer, is a veteran of drug development in SCD. As chief medical officer at South San Francisco-based Global Blood Therapeutics Inc., he led the effort that culminated in the approval last year of Oxbryta (voxelotor). “It’s sort of hard not to get super excited about the rate at which these newer therapeutic approaches are evolving,” he told BioWorld. “There is exciting data from these programs. There is no doubt there is benefit to patients.” At the same time, the medical need is still urgent. “Mortality hasn’t improved for adults,” he said. “They’re still dying in their forties.”
Graphite Bio’s ambition is to change patients’ genotypes to normal. In SCD, that does not mean achieving 100% efficiency. Because cells that express wild-type hemoglobin have a survival advantage over sickle cells, even a 20% repopulation of the bone marrow with healthy hematopoietic stem cells results in about 90% of the red blood cell population carrying the correct gene. “If it wasn’t for that, the bar for curing this would be very high,” Lehrer said. The company will initially recruit adult patients and those in their late teens. Infants stand to gain the most benefit from curative therapy, but the safety profile first needs to be established in an older patient population.
The company is not yet disclosing the specific indications it is working on in addition to SCD, but it will be guided by clinical need. “We have an exciting platform, but I don’t think of this as a platform company,” Lehrer said. Its initial focus will be on ex vivo engineering of patient cells, but it also plans to develop in vivo applications.
Jerel Davis and Abe Bassan, vice president at Samsara Biocapital, have joined Graphite Bio’s board in conjunction with the financing.
The company’s name is intended to evoke several associations, the most obvious being that most basic of writing instruments, the pencil. But it also contains a disguised reference to Rosalind Franklin, whose crystallographic studies contributed so much to the discovery of DNA’s structure. In addition to that towering achievement, Franklin also solved the crystal structure of graphite.