Gene Therapy Offers Promise in Treating Inborn Errors of Immunity

A new report says early evidence of using gene therapy to treat monogenic diseases offers reason for optimism.

Gene therapy (GT) holds significant potential to help correct monogenic diseases, although more evidence is needed to better understand the long-term effects of the therapies, according to a new report.

In JAMA Pediatrics, investigators outlined the latest research about GT and explained why they believe it is a “promising” alternative to hematopoietic stem cell transplantation (HSCT) for patients with inborn errors of immunity.1

Abstract luminous DNA molecule  | Image Credit:

There are 2 primary approaches to gene therapy: gene addition and gene editing | Image Credit:

They said that HSCT “carries risks, such as graft-vs-host disease and decreased survival rates in the absence of an HLA-matched donor.” Alternatively, GT offers a more targeted approach to correcting gene mutations, adding that GT can be conducted ex vivo by genetically modifying cells like CD34-positive (CD34+) hematopoietic stem and progenitor cells and then transplanting them into patients. It can also be performed in vivo by delivering genetic material to target cells within the body.

“Corrected stem cells then regenerate and promote the expansion of progenitor cells and the blood and immune system,” they wrote.

They then described the 2 primary approaches to GT. Gene addition (GA) entails delivering a desired gene into the genome, and gene editing (GE) involves correcting a specific mutated gene.

The first human trial of GA was conducted in 2 patients with adenosine deaminase (ADA)-associated severe combined immunodeficiency (SCID), the investigators said. The 2 patients received gene-modified autologous T cells, but scientists were later able to use γRv vectors to target CD34+ hematopoietic stem and progenitor cells in patients with X-linked SCID (SCID-X1). In 2016, the European Medicines Agency authorized a γRv vector–based GT called Strimvelis to treat patients with ADA-associated SCID. GA is also being studied in other inborn errors of immunity, such as Wiskott-Aldrich syndrome, chronic granulomatous disease, and leukocyte adhesion defect, the authors said.

Yet, the authors noted that some patients treated with GA develop T-cell–malignant neoplasms as a result of gene integration near oncogenes. Other genotoxic effects have also been reported, they said. The development of self-inactivating viral vectors has helped to improve the safety of GA therapies.

“Overall, during the past 3 decades, more than 200 patients with inborn errors of immunity received treatment with GT using GA approaches, with a 5-year overall survival rate higher than 94%,” the authors said.

Still, they said GE may be the superior approach, as it is more targeted and, unlike GA, has the ability to address gain-of-function disorders, the investigators said.

By far, the most prominent GE platform is the CRISPR platform using the CRISPR-associated protein 9 (Cas9).

The study authors explained how CRISPR works.

“The RNA-guided DNA endonuclease targets a particular location, where the Cas9 enzymatic machinery induces a double-stranded DNA break (DSB),” they said. “The correct DNA sequence is then inserted, and the DSB is repaired either using the cell’s natural repair mechanism, nonhomologous end joining, or by using a template DNA in homology-directed repair, enabling the precise repair of the DSB using a homologous DNA sequence as a template.”

They said adenoassociated virus type 6 is a commonly used delivery vector for donor-template DNA.

The investigators said CRISPR gene editing has been used successfully in SCID-X1 and in RAG2-associated SCID using distinct approaches. Both approaches appear to be promising, the authors said, but they added that maintaining physiological regulation will offer longer-term benefits, and there is not yet sufficient evidence to say whether the current approaches can achieve those long-term results.

There is, however, reason for optimism. In the SCID-X1 study, published back in 2019, investigators said they successfully achieved their gene-editing goal without finding evidence of significant adverse effects.2

“As measures of the lack of toxicity, we observe no evidence of abnormal hematopoiesis following transplantation and no evidence of off-target mutations using a high-fidelity Cas9 as a ribonucleoprotein complex,” they wrote.

The present study’s authors said more research is needed to confirm the safety of GT, and they added that another major hurdle is the high cost to develop, manufacture, and administer these therapies. They said it would be beneficial if such costs could be lowered, although they also noted that the therapies might be cost-effective even at a high price point due to their ability to lower longer-term health care utilization among patients whose conditions are cured by the therapies.

“Ongoing advancements in the field hold the potential to ensure safety and efficacy while mitigating current challenges,” they concluded.


1. Somekh I, Hendel A, Somech R. Evolution of gene therapy for inborn errors of immunity. JAMA Pediatr. Published online May 20, 2024. doi:10.1001.jamapediatrics/2024.1116

2. Pavel-Dinu M, Wiebking V, Dejene BT, et al. Gene correction for SCID-X1 in long-term hematopoietic stem cells. Nat Commun. 2019;10(1):1634. doi:10.1038/s41467-019-09614-y

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