CRISPR for Rare Diseases: UCSF’s Mission to Cure Immune Disorders in Children
For over 40 years, UCSF has led the transformation of severe combined immunodeficiency (SCID) from a disease that would kill children within the first years of life to a curable condition.
Today, this success is serving as the foundation for something even more ambitious: a CRISPR platform that could treat more than 500 inherited immune diseases affecting tens of thousands of children.
Matthew Kan, MD, PhD, and the UCSF Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation are developing this next generation of treatments, leveraging UCSF’s clinical expertise by starting with Artemis-SCID, the most serious and difficult-to-treat variant of SCID.
The Initial Gene Therapy Breakthrough
Children with SCID lack the immune cells that coordinate memory responses to infections, leaving them vulnerable to illnesses that healthy children easily survive. Even with a bone marrow transplant – the current standard treatment – some children fail to develop a normal immune system and require repeated donor cell infusions. Others don’t have a viable donor for transplant or are ineligible to receive one.
UCSF became the epicenter of saving children's lives with SCID through Morton Cowan, MD, a pioneer of SCID transplant treatment, and Jennifer Puck, MD, who developed universal newborn screening for SCID. Their dedication led to a landmark lentiviral gene therapy trial for Artemis-SCID.
Their approach requires less chemotherapy and forgoes the need for a matched donor by using a modified virus to add a healthy copy of the missing Artemis gene into a patient’s own blood stem cells.
The results were revolutionary: all infants in the trial survived and developed a functioning immune system that responded normally to vaccinations. Watch the story of HT, the first child to receive this life-saving therapy at UCSF.
The Next Frontier: CRISPR
Lentiviral gene therapy has saved lives, but its complexity makes it difficult to scale. “Viral gene therapy randomly inserts genes into the genome, which can cause unpredictable effects,” says Kan. “Furthermore, the manufacturing process is so complex and expensive that these therapies remain out of reach for many families. CRISPR offers a more precise, scalable solution."
Instead of random insertion, Kan's non-viral CRISPR technique integrates a healthy copy of the gene into a neutral "safe harbor" zone of DNA. This ensures the gene is placed in a secure location and bypasses the need to create individual therapies for each of the 50+ unique mutations observed in patients with Artemis-SCID.
A Platform for Hundreds of Diseases
The implications extend far beyond Artemis-SCID. Over 20,000 unique genetic mutations underlie more than 500 inherited diseases of the immune system. Creating 20,000 distinct therapies is not feasible — but a CRISPR platform that doesn’t need to be adapted to specific mutations could change that equation entirely.
"Our hope is that if the therapy is successful and safe for Artemis-SCID, we could quickly develop therapies for other inherited blood diseases," says Kan. "Only the DNA template of the corrected gene sequence would need to be unique for each condition. The rest of the platform remains the same."
UCSF's Unique Ecosystem for Genome Editing
Few institutions can match the combination of capabilities that makes this work possible at UCSF. Kan's research represents a bridge between UCSF's clinical legacy in SCID treatment and the world's most advanced genomic engineering at the Innovative Genomics Institute (IGI), a partnership among UCSF, UC Berkeley, and UC Davis. His mentorship team includes both Puck and Jennifer Doudna, PhD, the Nobel laureate who co-discovered CRISPR.
The transformative potential of genome-editing was recently demonstrated when teams at IGI and the Children's Hospital of Philadelphia successfully treated an infant with a life-threatening metabolic disorder using the first "personalized" genome-editing therapy. Building on this breakthrough, the Chan Zuckerberg Initiative and IGI launched the Center for Pediatric CRISPR Cures to develop "on-demand" CRISPR treatments for children with inherited immune and metabolic diseases.
Kan will help develop the therapies for immune disorders, collaborating with Fyodor Urnov, PhD, center director, Chris Dvorak, MD, chief of the UCSF Division of Pediatric Allergy, Immunology, and BMT, and other leaders across UCSF and UC Berkeley.
"Bringing these innovative therapies to patients requires scientific innovation, clinical excellence, and manufacturing capabilities working together," says Kan. "Between UC Berkeley and UCSF, we've assembled one of the best teams in the world to create potentially transformative treatments."
From One Disease to Thousands
For decades, UCSF transformed SCID from fatal to curable through pioneering transplants, universal newborn screening, and breakthrough gene therapy. Now, Kan aims to create multiple CRISPR platforms that could be adapted to treat any of the 20,000 genetic mutations underlying more than 500 inherited diseases of the immune system.
For families who once faced impossible diagnoses, this research represents the difference between a devastating prognosis and a future where their child can build a healthy, thriving life. That's the promise UCSF is working to deliver.
Consider a gift to support Kan’s research to advance CRISPR therapies for rare diseases and help us accelerate groundbreaking discoveries that bring hope to families.