Stanford Medicine teams awarded $18 million to improve kidney transplant and gene-editing techniques

Physician-scientists at Stanford Medicine have received about $18 million from the California Institute for Regenerative Medicine for two projects to advance cutting-edge treatments for children: a clinical trial to allow kidney transplantation without the need for long-term immunosuppression, and a study of a gene-editing treatment for a rare disease that progressively damages the brain, heart and other organs.

The principal investigators on the projects are Alice Bertaina, MD, PhD, associate professor of pediatrics, and Natalia Gomez-Ospina, MD, PhD, assistant professor of pediatrics.

Bertaina and her colleagues are receiving almost $12 million for a clinical trial of a treatment in which a child receives a stem cell transplant followed by a kidney transplant from the same donor, a parent. The treatment provides the recipient with the donor’s immune system, allowing the kidney to be accepted without the need for long-term immunosuppression.

The treatment relies on a method Bertaina pioneered to process donor stem cells before infusing them in the recipient, known as alpha-beta T cell depletion. The method greatly reduces the risk of complications such as graft-versus-host disease and enables stem cell transplants between donors and recipients who are matched on only half of their genetic markers, such as parents and children.

According to an early report by Bertaina’s team, which focused on three children with a rare condition called Schimke immuno-osseous dysplasia, providing stem cells and a matching kidney can free recipients from the need to take immune-suppressing medications, which have significant long-term risks. Schimke immune-osseous dysplasia is a genetic disease that causes bone marrow failure, meaning patients need a stem cell transplant, as well as kidney failure.

“With this CIRM funding, the primary diseases treated by our approach will increase to include cystinosis and systemic lupus erythematosus,” Bertaina said. Cystinosis is a genetic disease that interferes with metabolism of cystine, causing long-term kidney damage. Lupus is an autoimmune disease that causes kidney failure in some patients.

The researchers will also study the technique in patients who have rejected a previous kidney transplant due to focal segmental glomerulosclerosis, a form of scarring in the kidneys that is a common cause of transplant failure.

Cystinosis, lupus and focal segmental glomerulosclerosis — more common than Schimke immuno-osseous dysplasia — have not been previously treated with a stem cell transplant and matching kidney. If this trial succeeds, the number of patients who could benefit from this innovative approach will grow tremendously, she said. The CIRM funding will also support extensive studies of the immunological mechanisms that enable the new technique to work, possibly allowing it to improve transplant of other organs such as liver and intestine.

Gene editing to treat a rare disease

Gomez-Ospina and her team are receiving about $6 million to conduct a study of a gene-editing technique aimed at a rare, severe genetic disease known as mucopolysaccharidosis type 1, or Hurler syndrome.

Children with the disorder lack an enzyme that allows their cells to break down large, complex sugar molecules known as mucopolysaccharides or glycosaminoglycans. These sugars build up inside their cells, causing organ damage. Patients with the disorder have a life expectancy of around 10 years.

The Stanford Medicine team will genetically edit patients’ own blood-forming stem cells to restore the missing enzyme. The goal of the CIRM-funded trial is to show that the team can manufacture the cells and complete the safety studies needed to gain Food and Drug Administration authorization for a clinical trial.

“The funding will pave the way for trials in people to realize a more effective therapy for this devastating disease,” Gomez-Ospina said. “We will also generate safety and toxicity data that could facilitate the application of our genome editing platform to other genetic disorders for which a significant unmet need still exists.”