Two Gene Therapy Approvals Expand Options for Rare Immune Disorders as Access Challenges Persist

Two gene therapies for inherited immune disorders have received FDA approval within the past year, offering new treatment options while exposing a persistent challenge: successful genetic correction does not always translate into consistent clinical benefit or commercial availability.

At the 2026 American Society for Transplantation and Cellular Therapy Gene Therapy Summit in Boston, Sung-Yun Pai, MD, of the National Cancer Institute, reviewed the approvals alongside updates in gene editing and product safety. Her presentation traced how early treatment, manufacturing quality, and long-term monitoring influence whether promising advances reach patients.¹

New Approvals Bring Progress and New Questions

In December 2025, the FDA approved etuvetidigene autotemcel (etu-cel, Waskyra; Fondazione Telethon ETS) for patients aged 6 months and older with Wiskott-Aldrich syndrome (WAS) who are eligible for hematopoietic stem cell transplantation but lack a suitable human leukocyte antigen (HLA)-matched related donor. The approval also made Fondazione Telethon the first nonprofit applicant to secure FDA authorization for a cell and gene therapy.²

WAS causes immune dysfunction, thrombocytopenia, eczema, and recurrent infections. For children undergoing allogeneic transplantation, age and severe infection before treatment can influence outcomes. Pai emphasized the importance of intervening before complications can arise.

“It’s best to transplant these children when they’re young and before they have severe infection,” Pai said.¹

Etu-cel uses a patients’ own hematopoietic stem cells modified with a lentiviral vector expressing functional WAS protein. Among 27 treated patients, overall survival at 1 and 5 years was approximately 96%. Severe infections decreased from about 2.00 to 0.15 events per person-year when comparing the pretreatment year with the period beyond 6 through 18 months after infusion. Moderate or severe bleeding events also declined, from 2.00 to 0.80 events per person-year in the first year after treatment.³

“Only 1 patient died, and that patient died of a preexisting neurologic condition,” Pai said. “And there was reversal of the clinical symptoms, both the infection and the bleeding events and the eczema.“¹

The findings are especially meaningful for patients without a suitable transplant donor. Still, Pai emphasized that improving immune function does not always restore platelet counts to levels that allow unrestricted daily activities.

Why Manufacturing Matters to Patient Outcomes

“There was consistent correction of immune defects with variable platelet reconstitution,” Pai explained of earlier WAS gene therapy studies.¹ In the Boston experience she described, several patients had platelet counts of about 50,000/µL or lower years after treatment, while others approached the normal range. The difference correlated with vector copy number in modified stem cells.

“This vector, while very great, really ideally has to be transduced to a level of two to three copies per cell in the product because one copy appears to be insufficient,” Pai said.¹

That observation applies to the specific WAS vector studied. It is not a universal target for other gene therapies. It illustrates why the characteristics of each manufactured cell product can influence recovery across blood cell lineages.

These findings have operational implications for pharmacy teams. Treatment includes stem cell mobilization and collection, rituximab (Rituxan; Genetech) administration, reduced-intensity conditioning, and tightly coordinated product infusion.³ Pharmacists can help verify chemotherapy orders and exposure targets, manage infection prophylaxis and supportive medications, and coordinate toxicity monitoring. They must also account for product-specific preparation and administration requirements rather than assuming one gene therapy protocol applies to another.

A second approval followed in March 2026. Marnetegragene autotemcel (Kresladi; Rocket Pharmaceuticals) received accelerated FDA approval for pediatric patients with severe leukocyte adhesion deficiency type I (LAD-I) caused by biallelic ITGB2 variants who lack an available HLA-matched sibling donor.⁴

LAD-I impairs leukocyte movement into infected tissues, contributing to severe infections and impaired wound healing. Pai discussed a 9-patient study in which all participants achieved sustained engraftment and CD18 expression, with observed improvements in wounds and infection-related outcomes.

“100% survival, can’t beat that, and amazing efficacy,” she said.¹

The reported survival is encouraging, but accelerated approval rested on increased neutrophil CD18 and CD11a expression—surrogate markers considered reasonably likely to predict benefit. FDA reviewers found limitations in the infection-outcome data, and confirmatory evidence remains necessary.⁴

Expanded Eligibility Meets Long-Term Safety Concerns

In July 2026, the FDA expanded Exagamglogene autotemcel (Casgevy; Vertex Pharmaceuticals) to patients aged 2 years and older with sickle cell disease and recurrent vaso-occlusive crises or transfusion-dependent β-thalassemia, lowering the previous age threshold of 12 years.⁵ The decision allows treatment to be considered earlier, although stem cell collection, myeloablative conditioning, and prolonged follow-up remain significant clinical considerations.

Pai also reviewed Elivaldogene autotemcel (Skysona; bluebird bio, Inc), a lentiviral therapy for early, active cerebral adrenoleukodystrophy. In August 2025, the FDA strengthened its safety labeling after hematologic malignancies had been diagnosed in 10 of 67 trial participants (15%) as of July 2025.⁶ Reported diagnoses included myelodysplastic syndrome and acute myeloid leukemia.

The label calls for lifelong malignancy surveillance, complete blood counts at least every 3 months, assessments for clonal expansion, and bone marrow evaluation when indicated.⁶ These are product-specific risks, not evidence of equivalent malignancy rates with other therapies. For pharmacists, the changes reinforce the need for long-term laboratory follow-up and clear communication with patients and their care teams.

Scientific Advances Still Need a Route to Patients

Pai highlighted prime editing for p47phox-deficient chronic granulomatous disease. In an early report, 2 participants received the investigational product PM359 and achieved neutrophil and platelet engraftment, with NADPH oxidase activity detected after treatment. Follow-up was only 6 and 4 months, respectively, leaving durability uncertain.⁷

She also discussed investigational strategies to increase fetal hemoglobin in sickle cell disease and β-thalassemia. Yet, even promising results may not guarantee a commercial pathway, particularly for therapies developed for exceptionally small patient populations.

During the discussion, Pai returned to Fondazione Telethon’s achievement in bringing WAS gene therapy through regulatory review. She called the nonprofit-led approval a “huge, huge win.“ Acknowledging that “there are constraints that we have in the US” that may complicate similar development approaches, she added, “…the fact that they did it, I think, means a lot.“¹

The advances leave pharmacy teams with an expanding role in treatment preparation, long-term surveillance, and coordination across specialized centers. Their value will ultimately depend not only on molecular correction but on the clinical outcomes and access pathways that follow.

REFERENCES

1. Pai SY. Ex vivo gene therapy in 2026: updates from the past year. Presented at: ASTCT Gene Therapy Summit; November 4, 2026; Boston, MA.

2. FDA approves first gene therapy treatment for Wiskott-Aldrich syndrome. News release. FDA. December 9, 2025. Accessed November 4, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-wiskott-aldrich-syndrome

3. Ferrua F, Cenciarelli S, Giannelli S, et al. Etuvetidigene Autotemcel for the Treatment of Wiskott-Aldrich Syndrome. N Engl J Med. 2026;395(12):1193-1205. doi:10.1056/NEJMoa2515005

4. FDA approves first gene therapy for severe leukocyte adhesion deficiency type I. News release. FDA. March 26, 2026. Accessed November 4, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-severe-leukocyte-adhesion-deficiency-type-i

5. FDA approves first gene therapy for young children with sickle cell disease. News release. FDA. July 1, 2026. Accessed November 4, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-young-children-sickle-cell-disease

6. FDA approves required labeling changes for increased risk of hematologic malignancy following treatment with Skysona (elivaldogene autotemcel). News release. FDA. August 7, 2025. Accessed November 4, 2026. https://www.fda.gov/vaccines-blood-biologics/fda-approves-required-labeling-changes-increased-risk-hematologic-malignancy-following-treatment

7. Gori JL, Haddad E, Frangoul H, et al. Prime Editing for p47phox-Deficient Chronic Granulomatous Disease. N Engl J Med. 2026;394(12):1195-1203. doi:10.1056/NEJMoa2509807