CRISPR cures on the horizon: Breakthrough center aims to heal rare, deadly genetic diseases

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Children and adults with rare, deadly genetic diseases have fresh hope for curative therapies, thanks to a new collaboration between the Innovative Genomics Institute (IGI) and Danaher Corporation, a global life sciences and diagnostics innovator.

The new Danaher-IGI Beacon for CRISPR Cures Center will use genome editing to address potentially hundreds of diseases, including rare genetic disorders that have no cure. The goal is to ensure treatments can be developed and brought to patients more quickly and efficiently.

The IGI comprises genetics researchers and clinician experts from three University of California campuses: UCSF, UCLA and UC Berkeley, where the institute is housed, as well as other research institutions. Danaher will provide tools, reagents, resources and expertise to accelerate preclinical and clinical development and establish new standards for safety and efficacy.

The center will work first on CRISPR treatments for two genetic defects of the immune system: familial hemophagocytic lymphohistiocytosis (HLH), which causes immune cells to become overactive, damaging tissues and organs throughout the body; and Artemis-deficient severe combined immunodeficiency (ART-SCID), in which T and B lymphocytes fail to mature, making infants vulnerable to fatal infections.

The standard treatment for both conditions, a bone marrow transplant, is inadequate due to frequent complications.

"With CRISPR, we can speed up the development of improved therapies that can reach all the patients who need them," said Jennifer Puck, MD, a pediatrics professor who directs the UCSF Jeffrey Modell Diagnostic Center for Primary Immunodeficiencies. "All patients deserve a sense of urgency – including those with rare diseases, many of whom are children."

Since the CRISPR platform being created at IGI could, in theory, be reprogrammed to address any gene mutation, the goal is to use treatments for HLH and ART-SCID as models to develop a scalable approach from which new medicine for other genetic diseases can be rapidly developed.

"The unique nature of CRISPR makes it ideal for developing and deploying a platform capability for CRISPR cures on demand," said Fyodor Urnov, IGI's Director of Technology and Translation, who is overseeing the project along with Doudna and IGI Executive Director Brad Ringeisen. "Danaher and the IGI are in a unique position to potentially create a first-of-its-kind CRISPR cures 'cookbook' that could be used by any team wishing to take on other diseases."

ART-SCID and HLH are typical of many rare diseases in that they have small patient populations, making drug development challenging and cost prohibitive. On average, it takes 10 years for a single clinical trial.

HLH and ART-SCID are two examples of a class known as inborn errors of immunity or IEIs. Each IEI is very rare, but collectively there are about 500 such diseases affecting more than 112,000 patients.

"We can develop CRISPR cures in a laboratory, but at the end of the day we need a way to turn those into clinical products for thousands of patients," says IGI founder Jennifer Doudna, PhD, a UC Berkeley biochemist who won the Nobel Prize for co-developing CRISPR.

Currently there are only a few hundred patients in clinical trials for CRISPR-based therapies; the IGI hopes its work will allow that number to ramp up ten-fold over the next decade.

After decades of research, Puck and UCSF Pediatrics Professor Mort Cowan, MD, successfully treated 14 children with ART-SCID, known colloquially as Bubble Baby Disease, by inserting a corrected version of the Artemis gene into the children's own bone marrow stem cells using a delivery system known as a lentivirus. A CRISPR-based version of this treatment could more precisely target where the gene copies go, avoiding possible toxicity from lentiviral interference with genes near sites of insertion in the genome.

Both ART-SCID and HLH have extensive patient registries to facilitate enrollment in future clinical trials. Since both are diseases of blood-forming bone marrow stem cells that renew the immune system throughout the life span, targeting these cells can bypass challenges in delivering CRISPR molecules to tissues in other disorders.

We know how to deliver the CRISPR molecules into the cells to fix them. We also know how to reach patients, because there is an existing registry and network of expert physicians. By focusing on ART-SCID and HLH first, we aim to create a roadmap through pre-clinical and clinical development and lead the way for other indications, whether they are rare or not."

Mort Cowan, MD, UCSF Pediatrics Professor

The IGI team includes UCSF physician-scientists Matthew Kan, MD, PhD, Puck and Cowan focusing on ART-SCID; and David Nguyen, MD, PhD, Michelle Hermiston, MD, PhD and Bryan Shy, MD, PhD, focusing on HLH. Petros Giannikopoulos, MD, director of IGI's Clinical Laboratory, will be the center's diagnostic and analytical lead. Donald Kohn, MD, of UCLA will be involved in translating the gene editing approaches developed at UCSF and UC Berkeley to clinical cell manufacturing in the UCLA Human Gene and Cell Therapy Facility.

Cowan, Kan, Kohn and Puck are recipients of grants from the California Institute of Regenerative Medicine, CIRM, which have enabled them to reach the current stage of their work with the Beacon center.

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