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Doudna, Urnov-led Center Creating 'Cookbook' for Rare Disease CRISPR Cures

Double-stranded DNA with mutation in a gene, conceptual illustration

NEW YORK – Researchers leading a new center based at the University of California, Berkeley, are hoping that insights from their work to create two new CRISPR treatments will help others develop gene-editing therapies more efficiently.

At the center, dubbed the Danaher-IGI Beacon for CRISPR Cures, the aim is to create a research, development, and regulatory framework for treatments that use CRISPR, a gene-editing technique based on the immune system of bacteria and the backbone of a newly approved treatment for sickle cell disease. Collaborators at the center believe that such a model will help others in the field streamline their preclinical and clinical development of CRISPR treatments for rare diseases.

They hope to create a "cookbook" that lays out the science, technology, and processes needed to take a CRISPR therapy from conception to patients, said Fyodor Urnov, a professor in the molecular and cell biology department at UC Berkeley and director of technology and translation at the Innovative Genomics Institute (IGI), a collaboration between UC Berkeley and UC San Francisco (UCSF). 

While the Danaher-IGI Beacon is based at UC Berkeley, it's a partnership among the life sciences firm Danaher, the IGI, and the University of California, Los Angeles. Urnov is leading work at the new center with Jennifer Doudna, the IGI founder and a professor in the chemistry department and the molecular and cell biology department at UC Berkeley. The program is funded by Danaher.

"We are making a substantial financial contribution to cofound the center," a Danaher spokesperson said, but declined to disclose the funding amount. 

In recent years, drug development leveraging CRISPR has been a hot topic in the biotech sector, spurred by Doudna's discoveries. Doudna, in 2012, developed the CRISPR gene-editing technique with Emmanuelle Charpentier, earning them the Nobel Prize in chemistry in 2020. In 2013, researchers at the Broad Institute led by Feng Zhang published the first example of using CRISPR to edit genes in mouse and human cells.

Now, just over a decade later, the technology's clinical use is beginning to take hold. Last year, Vertex Pharmaceuticals and CRISPR Therapeutics' Casgevy (exagamglogene autotemcel) was approved in the US and UK, representing the first ever CRISPR gene-edited therapy to be commercialized. Multiple other gene-editing drugs are in development at companies like Editas Medicine, Excision BioTherapeutics, and Intellia Therapeutics.

Urnov, who consulted with Vertex on the Casgevy development program, said he believes CRISPR-based therapies could one day be the "standard of care" for many illnesses. "We want to expand the footprint of gene editing into a broad range of diseases," Urnov said.

The joint effort from the IGI and Danaher specifically focuses on creating resources to cut the time and expense needed to develop therapies for rare diseases that struggle to attract funding. These sorts of efforts have cropped up in recent years as a growing number of cell and gene therapies enter the market.

A public-private consortium led by the Foundation for the National Institutes of Health, for example, earlier this month published the first version of a "playbook" for drugmakers on how to shepherd gene therapies for rare diseases from preclinical research into clinical trials. The US Food and Drug Administration last year launched a pilot program to explore whether increasing communication between drugmakers and the agency would speed up development of gene and cell therapies for rare diseases.

At the Danaher-IGI Beacon, researchers will develop CRISPR therapies for two severe, rare immune disorders caused by germline variants known as inborn errors of immunity (IEIs). The development programs build on researchers' efforts at UCSF to treat patients with Artemis-deficient severe combined immunodeficiency (ART-SCID) using a lentivirus-based gene therapy that delivers a functional version of the DCLRE1C gene. ART-SCID is a disorder caused by mutations in that gene, which encodes for a protein called Artemis that is involved in DNA repair. The Artemis deficiency results in T and B cells that fail to mature, leaving infants susceptible to infection.

With CRISPR, researchers believe they can more precisely target genetic fixes and avoid toxicities. Manufacturing lentiviruses for a gene therapy is also extremely expensive, Urnov added, and there's the potential for manufacturing CRISPR therapies to be less so, when done within the sort of plug-and-play framework the Danaher-IGI Beacon is working toward.

The second CRISPR therapy that the center plans to advance into human trials is for treating familial hemophagocytic lymphohistiocytosis (HLH), a disease in which tissues and organs are damaged due to overactive immune cells caused by mutations in several genes, including PRF1 and UNC13D.

These two programs will serve as models for researchers at the center to advance a "platform approach" to CRISPR drug development. Although each IEI disease comprises a distinct patient population, there are about 500 such diseases that collectively affect more than 112,000 patients globally. The Danaher-IGI Beacon's vision is that, rather than starting from scratch each time to create an individual gene-editing therapy for each disease — which can take a massive investment of time and money — researchers will instead be able to develop treatments by tweaking their platform for new diseases. 

The CRISPR component, for example, can be reprogrammed to target other gene mutations, opening the door for developing treatments for many diseases caused by a single-gene mutation. Additionally, researchers may be able to create standardized preclinical and manufacturing pipelines for successfully steering CRISPR therapies through the FDA and getting them to patients faster.

As researchers develop these resources, they plan to disseminate them not only to industry but also to the academic and nonprofit sectors that are often involved in creating rare disease cures, especially at the early stages, but that lack the funding of traditional drugmakers.

"Our goal is not only to treat patients … with two severe inborn errors of immunity," Urnov said, but also to create technologies and approaches that could be "rapidly used for disease number three, disease number four, disease number five."

The Danaher-IGI Beacon is a collaborative program, involving researchers from multiple University of California institutions and industry partners from Danaher. Researchers at the UCLA Human Gene and Cell Therapy Facility will work on clinical cell manufacturing, for example. And as part of the collaboration with Danaher, researchers at the center will be able to use the company's reagents, technologies, and other resources to manufacture the CRISPR therapies.

Danaher doesn't develop drugs but operates multiple companies in the life sciences space that sell tools used by drugmakers, including Integrated DNA Technologies (IDT), which manufactures products used in diagnostic tests; Aldevron, which manufactures nucleic acids and proteins used in gene and cell therapies; and Leica Microsystems, which manufactures microscopes and other scientific instruments. These firms are involved in work underway at the Danaher-IGI Beacon, according to a Danaher spokesperson.

"Academia can't take on a challenge like this alone," the spokesperson wrote in an email. Researchers at the center also will be able to work with Danaher to develop new technologies and establish standards for safety and efficacy in preclinical and clinical development. Together, "these Danaher technologies could be used to build a 'stacked' manufacturing platform for gene-editing therapies, first for rare diseases and ultimately for a broader range of diseases," the spokesperson added.

The Danaher-IGI Beacon for CRISPR Cures is part of a broader Beacon program that Danaher runs, through which it partners with universities and funds academic research that it believes can underpin the development of new technologies. In addition to this center focused on CRISPR-based treatments, Danaher has several other Beacons it is funding under the program, including one focused on preclinical drug safety at Cincinnati Children's Hospital Medical Center; a second center on cell therapy manufacturing at the University of Pennsylvania; a third on gene therapy innovation at Duke University; and a fourth on precision medicine for sepsis at the University of Oxford.

The Danaher-IGI collaboration is initially set for four years; however, the Danaher spokesperson said the firm wants to foster a "long-term relationship."

Urnov said the Danaher-IGI Beacon expects to advance the two gene-editing therapies into clinical trials within three years. If the investigational therapies demonstrate strong efficacy and safety in clinical trials, Urnov hopes that an industry partner will take over regulatory and commercialization efforts, so the center can keep focusing on refining and distributing resources and tools on CRISPR gene therapy development.

"Ultimately, the for-profit sector has to take this on," he said. As a public academic institution, "our overarching goal is to make the cookbook, and the toolbox, and the solutions broadly available."