Significant progress achieved over the past decade has turned gene therapy into a tangible and effective approach for treating and curing primary immunodeficiencies (PIDs).

What is Gene Therapy?

Gene therapy, akin to a ‘mini gene transplant,’ involves extracting stem cells from patients with primary immunodeficiency (PID), replacing the defective genes within these cells with healthy and fully functional genes, and reintroducing the gene-corrected cells back into the patient’s body. This process enables the cells to generate the necessary cells or proteins essential for combating infections.

The procedure is comparable to a bone marrow transplant (BMT), where patients might undergo chemotherapy beforehand, known as ‘conditioning,’ to eliminate cells carrying the genetic defect. While some forms of severe combined immunodeficiency (SCID) may require minimal or no conditioning for gene therapy, most other PIDs necessitate chemotherapy similar to that used in BMT.

Gene therapy boasts a significant advantage as it employs the patient’s own cells, mitigating the risk of rejection associated with donor-derived cells in bone marrow transplants. Furthermore, gene therapy avoids graft-versus-host disease (GvHD), a major concern in traditional bone marrow transplants.

Despite its potential, gene therapy is not without risks and may entail serious side effects. Currently categorized as an experimental treatment for certain conditions, it is emerging as a preferred option, especially in cases like Adenosine Deaminase Severe Combined Immunodeficiency (ADA-SCID) when finding a well-matched bone marrow donor proves challenging. Ongoing research and advancements in gene therapy hold promise for expanding its applications in treating various PIDs.

How Does Gene Therapy Work?

Scientists initiate the gene therapy process by affixing the desired normal and healthy gene to a benign virus known as a vector. This vector, typically a harmless virus, undergoes modification wherein its genetic material is replaced with instructions to create a healthy version of the patient’s missing or mutated gene.

Subsequently, the vector, now carrying the normal gene, is combined with the patient’s bone marrow. The vector infiltrates the stem cells within the patient’s bone marrow, displacing the defective gene with the healthy counterpart. The corrected cells are then cultivated in an incubator, and once a sufficient quantity is obtained, they are reintroduced into the patient. Over time, the bone marrow assimilates these corrected cells, enabling them to produce healthy white blood cells capable of combating infections.

Traditionally, gene therapy trials for various immunodeficiencies utilized ‘retroviral’ vectors. However, scientists are increasingly considering ‘lentiviruses,’ a distinct type of vector, as potentially more effective. Consequently, upcoming trials are anticipated to explore the use of lentiviruses, reflecting advancements in refining gene therapy techniques.

Are Vectors Safe?

Extensive research is conducted by scientists to identify the safest and most efficient vectors for gene therapy, involving the deactivation of vector viruses to render them harmless.

Prior to human trials, vectors undergo thorough examination using ‘cell models’ and animal testing. These evaluations assess potential damage to animal organs and the effectiveness of the vectors. Determining the optimal quantity of a specific vector for efficacy is also a crucial aspect of this testing phase.

Patient trials follow animal and laboratory assessments, as human trials are essential for confirming the safety and efficacy of the treatment. The transition to patient trials underscores the limitations of animal and lab tests in ensuring the safety of the treatment for humans.

The production and testing of vectors occur under stringent conditions in specialized laboratories. This meticulous approach aims to guarantee the highest quality of vectors, ensuring their compliance with regulatory authority standards. The stringent testing and production processes are essential to secure approval for vector use in patients.

ADA-SCID Gene Therapy Trials

The findings of a study involving 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) who underwent gene therapy (GT) were reported in the New England Journal of Medicine in 2021. The results strongly support the efficacy of GT in treating this rare condition. The overall survival rate reached 100% throughout the follow-up period (two years for U.S. study patients and three years for UK study patients). Notably, at one year, event-free survival was 97% for U.S. study patients and 100% for UK study patients. The study also demonstrated sustained ADA gene expression, metabolic correction of the disorder, and functional reconstitution of the immune system in 48 out of the 50 patients.

X-SCID Gene Therapy Trials

A collaborative trial spearheaded by Boston Children’s Hospital and Great Ormond Street Hospital, aimed at treating children with X-SCID, has been broadened to encompass several additional U.S. centers. The trial is actively seeking participants, and the initial data from the first patients treated shows promising outcomes.

Leukocyte Adhesion Deficiency (LAD-1) Gene Therapy Trials

LAD-I is a rare genetic disorder that impacts the immune system, leading to life-threatening infections due to white blood cells being unable to exit the bloodstream for defense. Severe LAD-I can prove fatal within the first two years of life without a successful bone marrow transplant.

Rocket Pharma is actively developing a gene therapy, RP-L201, to address LAD-1. Currently in Phase 2 clinical trials, this stage focuses on evaluating the safety and efficacy of the therapy in pediatric patients with severe LAD-I. The trial is set to include nine participants across three sites, including Great Ormond Street Hospital in the UK and two sites in the USA. Early results from the initial seven treated patients have shown promise, as presented at international meetings. Read more at Leukocyte Adhesion Deficiency-I | Rocket Pharmaceuticals.

Autosomal Recessive Chronic Granulomatous Disease (p47-CGD) Gene Therapy Trials

After successful early-phase clinical trials for X-linked chronic granulomatous disease (X-CGD), a new clinical trial is set to commence in both the UK at Great Ormond Street Hospital and in the USA at the National Institute of Health. This trial aims to assess the safety and efficacy of applying the same approach to treat an autosomal recessive form of CGD (p47-CGD). The recruitment goal for this trial is up to 10 patients across these participating sites.

Gene Therapy for Other Conditions

CSL Behring and Seattle Children’s Research Institute have joined forces in a strategic partnership to propel the development of gene therapy for Primary Immunodeficiency (PID). The collaboration will primarily focus on advancing therapies for Wiskott-Aldrich Syndrome (WAS) and X-linked Agammaglobulinemia (XLA). Further details about their partnership can be found in their official announcement, accessible here.

Why is Gene Therapy not developed for other conditions but some PIDs?

The progress of gene therapy hinges on a comprehensive comprehension of the genes responsible for Primary Immunodeficiency (PID). This involves acquiring knowledge about the specific genetic anomaly (mutation), its location within the DNA structure of a cell, the regulatory mechanisms governing the involved gene, and the types of cells expressing the gene’s protein product. Regrettably, for certain PIDs, this information is presently unknown, or the existing tools lack the capability to rectify the defect. Emerging technologies like gene editing may offer potential solutions for addressing other PIDs in the future.

How many people have gotten Gene Therapy to treat PID?

Gene therapy for Primary Immunodeficiency (PID) has been administered to more than 100 individuals. This global initiative involves collaborative efforts with teams worldwide, pooling resources and exchanging tools and techniques for gene therapy. Ongoing collaborative trials are addressing key PIDs, including X-SCID, ADA-SCID, WAS, X-CGD, XLP1, and XLA.

If my child has gotten Gene Therapy to treat his PID, will he pass it on to his children?

No, Gene therapy solely addresses the cellular defects within the bone marrow of an individual and does not rectify issues in reproductive cells like sperm, which may still carry the flawed gene responsible for the PID. For instance, if a boy undergoes gene therapy for an X-linked disorder, his daughters may carry the condition, but there won’t be affected sons. It is crucial to discuss family planning considerations at the appropriate time, and your healthcare team will provide assistance in navigating these decisions.

Why do some children still have to get immunoglobulin therapy after getting Gene therapy to treat their SCID?

In certain instances, gene therapy may not entirely correct all immune cells. If B cells, responsible for producing immunoglobulin, are not fully corrected, the individual might need to maintain immunoglobulin therapy.

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