UCLA's CRISPR Sickle Cell Therapy Enters Human Trials Directly Fixing the Mutation, Not Just Working Around It

Most approved gene therapies for sickle cell disease work around the problem rather than fixing it. One adds a modified anti-sickling gene; another boosts fetal hemoglobin to prevent sickling. UCLA's approach does something different: it uses CRISPR-Cas9 to directly correct the exact mutation in the beta-globin gene that causes the disease .

The challenge was scale. Laboratory experiments involve a few hundred thousand cells; treating one patient requires editing hundreds of millions . The UCLA team developed a manufacturing process where blood-forming stem cells are cultured for two days, then exposed to electrical pulses that open temporary pores in their membranes, allowing CRISPR-Cas9 and a short corrective DNA strand to enter without using a viral vector 

The team completed seven manufacturing runs four at full clinical scale using cells from sickle cell patients and healthy donors. All large-scale runs met quality requirements, yielding cell products with high stem cell purity and viability . When edited cells were grown into red blood cells in the lab, they produced substantially less sickle hemoglobin and higher levels of healthy adult and fetal hemoglobin .

In mice, the edited human cells engrafted successfully, and the proportion of corrected gene copies remained stable over 16 weeks a crucial sign that the correction could persist long-term. No noteworthy treatment-related toxicity or abnormal tissue changes were found .

The manufacturing process has been implemented at UCLA to produce cell products for two participants in an ongoing Phase 1 trial led by Dr. Mark Walters at UCSF Benioff Children's Hospital Oakland . The trial will assess safety and efficacy, including whether corrected cells persist in patients over time.

If enough long-lasting corrected stem cells engraft, the therapy could offer a one-time treatment with curative potential allowing those cells to continuously produce red blood cells containing normal adult hemoglobin . The approach also provides a framework for moving other gene-editing therapies for inherited blood disorders from the lab to the clinic.

The study was published in Molecular Therapy .