Gene therapy restores immunity in Artemis-deficient severe combined immunodeficiency

Artemis-deficient infants with severe combined immunodeficiency improved after their stem cell genes were corrected, allowing them to expand their own T and B cells, according to a published study. , of New England Journal of Medicine.

Mutation 1C in DNA cross-link repair (DCLRE1C) gene causes Artemis deficiency severe combined immunodeficiency (ART-SCID). It is characterized by the absence of B lymphocytes or the absence of T lymphocytes with non-functionality.

ART-SCID responds poorly to the classic SCID treatment, allogeneic hematopoietic stem cell transplantation (HSCT). Human leukocyte antigen matching (HLA), according to researchers.

This DNA defect makes them more sensitive to chemotherapy and radiation than other patients. Morton J. Cowan, MD A pediatric immunologist at UCSF Benioff Children’s Hospital told Healio.

Morton J. Cowan

“These patients are more likely to reject bone marrow grafts from others, have a higher incidence and severity of graft-versus-host disease, and can be lethal when donor T cells react with recipient or host tissue. and cannot fully reconstitute T- and B-cell immunity.” Cowan said.

“Gene therapy, which uses the patient’s own bone marrow stem cells to modify, eliminates many of these key problems associated with standard bone marrow transplantation,” Cowan continued.

Without treatments that provide a new and durable immune system, patients with SCID will die from infections in infancy. Jennifer Pack, M.D. A pediatric immunologist at UCSF Benioff Children’s Hospital told Healio.

jennifer pack

“Gene therapy, achieved by adding the correct copy of the Artemis gene to the patient’s own hematopoietic stem cells taken from the bone marrow, could circumvent the complications of rejection and graft-versus-host disease, giving ART-SCID patients a chance. For a long and healthy life,” Puck said.

research design

This study included 10 infants (60% boys) without HLA-matched siblings enrolled and treated at UCSF Benioff Children’s Hospital. Newly diagnosed ART-SCID From June 2018 to September 2021.

Clinicians performed manufacturing, cryopreservation, and quality control testing of the patient’s transfected autologous CD34+ cells. DCLRE1C gene.

Patients were then given busulfan containing these cells intravenously for two days. Her median age at the time of transgenic cell injection was 2.7 months (range, 2.3–13.3 months).

The researchers began measuring patient immune reconstitution and gene marking 4 weeks after injection, and T cell receptor (TCR) diversity and vector insertion site analysis 12 weeks after injection. The patient was evaluated monthly until her 6th month, after which she was evaluated every 3 months until her 24th month.

result

Median follow-up was 31.2 months (range, 10–48.9 months).

The researchers detected gene-marked CD3+ cells at a median of 12 weeks (range 6–16 weeks) in all 10 infants. Five of her six patients followed for at least 24 months experienced reconstitution of cell-mediated immunity at a median of 12 months (range 6–24).

Also, the levels of CD3+, CD4+, and CD8+ T cells, naive CD4+ T cells, and regulatory T cells increased 9 months after infusion. Three to six months after injection, researchers detected increased TCR excision circles in parallel with naive T cells.

All patients, except those with ongoing cytomegalovirus infection, showed normal lymphoproliferation in response to phytohemagglutinin by 9 months. The researchers observed levels similar to healthy adults and also reported improved TCR beta diversity.

Flow cytometry and gene marking detected B cells in all 10 patients at a median of 6 weeks (range 4–10), but levels declined thereafter in 1 patient. Twenty-four months after infusion, three patients had normal her IgM levels and immune responses, and the fourth patient had initiated immunization.

Investigators observed 40 non-serious adverse events possibly, probable or probable related to treatment, including 23 grade 1 or 2 and 17 grade 3 or 4 events Did.

AIHA is a complication of HSCT, so it is not unique to gene therapy, Dr. Cowan said.

Overall, four patients developed AIHA and recovered following reconstitution of T-cell immunity between 4 and 11 months after infusion, the researchers said; He added that he was in good health and was leading a normal life at home.

Conclusion, next steps

Cowan called the treatment’s ability to reconstitute T-cell immunity in all patients and B-cell immunity in many patients “very satisfying and important” without the side effects of low-dose chemotherapy. I called.

“We expected T-lymphocyte recovery, but were surprised and pleased to find that all 10 treated patients had gene-corrected B-lymphocytes. and stopped relying on antibody injections,” Puck added.

Puck also notes that the successful use of the native human Artemis promoter sequence in a vector to achieve the right amount of Artemis protein at the right time for proper T- and B-cell development is one of the benefits of this treatment. said that it is an important aspect of the law.

“Other gene therapies to date have used common promoters,” Puck said.

Precisely targeted, very low doses of busulfan also proved sufficient to make room in the patient’s bone marrow for the transplantation of gene-corrected cells.

“So far, despite known difficulties in repairing DNA damage in Artemis SCID patients, we have not seen adverse side effects from this,” Puck said. rice field.

In addition, Puck noted that the researchers expected to enroll infants with Navajo and Apache Native American backgrounds, noting that the founder mutations found in these populations , their study population is highly diverse and includes Navajo and Apache Native Americans, as well as White, Hispanic, Japanese, Vietnamese, and Middle Eastern backgrounds.

“Thus, although considered to be extremely rare, Artemis-deficient SCID occurs in different populations around the world,” said Puck.

To get FDA approval, researchers will have to continue with the trial, Cowan said.

“Meanwhile, the next generation of gene therapy, such as targeting specific safe sites in the genomic DNA of stem cells, specifically editing mutations, and identifying non-chemotherapeutic approaches to create bone marrow space. We’re investigating approaches,” said Cowan.

Ultimately, Cowan said the researchers hope to be able to administer this treatment in vivo by injecting the vector into a vein.

And because the treatment is new, patients need to be followed longer to determine whether it’s safe and has lasting effects, Puck said, adding that the researchers had 15 years of follow-up. They also plan to expand the trial to enroll more patients and hope to offer treatment at other sites.

“We are also enrolling elderly Artemis SCID patients who lack adequate immunity despite previous transplants from healthy donors,” said Puck.

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For more information:

Morton J. Cowan, MD, You can contact him at [email protected].

Jennifer Pack, M.D., You can contact me at [email protected].