Stem cell-based Gene Therapy Successfully Treats 6 Patients with Rare Hematological Diseases

Chronic granulomatous disease (CGD) is a very rare, life-threatening primary immunodeficiency with the most common type of it being X-linked chronic granulomatous disease (X-CGD), which accounts for 60% - 65% of all types.

Patients with the disease often have a family history, and their parents are mostly married to close relatives. X-CGDmostly affects men, and women are usually carriers of the mutated gene. The main clinical symptom is juvenile onset (mostly within 2 years old, a few can be as late as 10 years old), often manifested by repeated attacks of fatal bacterial or fungal infections, which mainly occur in lymph nodes, subcutaneous tissues, lungs, liver, and gastrointestinal tract. Excessive inflammatory reactions gradually form granulomas, leading to enteritis, obstruction of the genital tract, and chronic wound healing.

X-CGD is caused by a mutation in CYBB gene, leading to difficulty in encoding the gp91phox protein, an important component of the NADPH oxidase complex. And this complex is necessary to respiratory bursts that can effectively kill ingested microorganisms. Due to this kind of mutations, specific white blood cells, including neutrophils, cannot effectively remove bacteria and fungi, so patients are unable to survive severe chronic bacterial and fungal infections.

So, can it be cured? Prophylactic antibiotics and antifungal drugs in current treatment schemes cannot prevent disease progression, and the only curative method at present is allogeneic hematopoietic stem cell transplantation. Although after transplantation from donors compatible with human leukocyte antigen (HLA), the long-term survival rate of patients can reach more than 90%, identifying healthy matched bone marrow donors is difficult, and recovery from transplantation can present complications such as graft-versus-host disease, risk of infection, and transplant rejection.

On January 27, 2020, Donald Kohn‘s team from the University of California, Los Angeles,, published a research paper titled Lentiviral gene therapy for X-linked chronic granulomatous disease in the Nature Medicine.

The study performed stem cell editing therapy on 9 patients with X-CGD. 6 of these patients have now recovered and have been able to stop other antibiotic treatments, which indicates that autologous gene therapy is a very promising treatment for chronic granulomatous disease.

The researchers removed hematopoietic stem cells from patients with X-CGD and modified the cells to correct genetic mutations. The patients' own genetically modified stem cells were then transplanted back into their own bodies. These stem cells are now capable of producing white blood cells, which in turn produce chemicals that enhance immunity.

"With this gene therapy, you can use the patient's own stem cells instead of donor cells for transplantation." Commented by a specialist in Creative Biolabs, a company providing top-notch service for stem cell therapy development, "This means that these cells match the patient perfectly and should be a safer transplant without the risk of immune rejection."

The 9 patients in the study ranged in age from 2 to 27 years. 4 of them were treated at Great Ormond Street Children's Hospital in London, and 5 were treated in the United States. In this study, 2 people died of severe infections within three months of receiving treatment because they had severe infections before they received gene therapy. 7 surviving patients were followed up for 12 to 36 months after receiving stem cell-based gene therapy. No new infections associated with chronic granulomatosis have occurred in all, and 6 of 7 have been able to stop prophylactic antibiotics that are commonly used.

Since the publication of the paper, 4 more patients have been treated. All patients are currently free of new infections and complications associated with chronic granulomas.

It is reported that Donald Kohn's team will work with US and European regulators to conduct larger clinical trials to further study the effectiveness of this innovative therapy. They also plan similar treatments for other types of chronic granulomatous disease caused by leukocyte protein deficiency.