Gene therapy

Great advances made in the last ten years mean that the use of gene therapy to treat and cure primary immunodeficiencies (PID) is a reality.

What is gene therapy?

Gene therapy is a ‘mini gene transplant’. Doctors remove stem cells from the patient with a PID, replace the defective genes inside the cells with new, healthy, fully functioning genes and then give the gene-corrected cells back to the patient. The cells can then go on to produce the cells or proteins needed to fight infection.

Having gene therapy is similar to having a bone marrow transplant. Patients may need chemotherapy beforehand to get rid of as many cells with the genetic defect as possible. This is called ‘conditioning’. In some forms of severe combined immunodeficiency, gene therapy can be undertaken with little or no conditioning. In most other forms of PID, chemotherapy that is similar to what is used for a bone marrow transplant is needed.

A big advantage of gene therapy is that it uses the patient’s own cells, so rejection is not a problem like it can be with bone marrow transplants, where the cells come from another person. Also, because it uses the patient’s own cells, gene therapy avoids graft-versus-host disease, which is one of the major problems associated with a bone marrow transplant.

Gene therapy is not without risk and can have serious side effects. It is still considered an experimental medicine for some conditions but for others, such as ADA-SCID, it is close to being the recommended route of treatment when a well-matched bone marrow donor cannot be found.

How does gene therapy work?

Scientists start by attaching the normal, healthy gene they want to give the patient to a harmless virus called a vector.

They remove genetic material from the vector and replace it with genetic instructions to make a healthy copy of the person’s missing or mutated gene.

They then mix the vector and new gene with bone marrow from the patient.

The vector carrying the normal gene will penetrate the stem cells in the patient’s bone marrow and replace the defective gene with the healthy gene.

Doctors then grow these corrected cells in an incubator. Once they have enough, they put them back into the patient. The bone marrow will gradually absorb them. The new cells can then start making healthy white blood cells able to fight infection.

Until now, gene therapy trials for many immunodeficiencies have used ‘retroviral’ vectors. However, scientists now believe ‘lentiviruses’ may be more effective, so future trials will use these.

How safe are vectors?

Scientists spend a long time researching what the safest and most effective vectors are to use for gene therapy. They always ‘inactivate’ the vector viruses, making them harmless.

They test vectors on ‘cell models’ and animals. They will check if the vector damages animals’ organs and whether it works on them. They will also work out how much of a particular vector is needed to make it effective.

Scientists may then do patient trials, as animal and lab tests cannot guarantee the safety of any treatment.

Scientists test and make vectors under stringent conditions in special laboratories to make sure what they produce is of the highest quality possible and will pass regulatory authority tests so the vectors can be used in patients.

Here we summarise recent developments:

Gene therapy trials for ADA-SCID

The results from 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) treated with gene therapy (GT) have been published in the New England Journal of Medicine.  The results are compelling for the use of GT to treat this rare condition.  Overall survival was 100% through the end of follow-up (two years for U.S. study patients and three years for UK study patients).  At one year, event-free survival was 97% in U.S. study patients and 100% in UK study patients.  The results also showed sustained ADA gene expression, metabolic correction of the disorder, and functional reconstitution of the immune system in 48 out of the 50 patients. Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency | NEJM

Susan, CEO of Immunodeficiency UK says, 'The impact of having a child affected by ADA-SCID is massive for families. Parents live in constant fear and anxiety of their child getting a life-threatening infection, with all aspects of life, for both child and family, affected in a negative way, so we welcome the extremely positive data from this ADA-SCID gene therapy trial.  We know, first-hand, from families that having gene therapy can be life-saving and life-changing and these results will be hugely reassuring and informative for newly diagnosed families who are considering this treatment option. The results are timely we accelerate towards to the start of England's SCID new born screening programme in September.' 

Gene therapy trials for X-SCID

A collaborative trial led by Boston Children's Hospital and Great Ormond Street Hospital treating children with X-SCID has been expanded to include several other US centres.  The trial is still actively recruiting with promising early data from the first patients treated.

Gene therapy trials for Leukocyte Adhesion Deficiency (LAD-1)

LAD-I is a rare genetic disorder affecting the immune system. Those affected can develop life-threatening infections because their white blood cells are unable to leave the bloodstream to fight them.  Without a successful bone marrow transplant, severe LAD-I can often be fatal during the first 2 years of life.

The company Rocket Pharma is developing a gene therapy treatment known as RP-L201 to treat LAD-1 with a Phase 2 clinical trial currently underway. This part of the trial is designed to assess the therapeutic safety and efficacy in paediatric patients with severe LAD-I. The trial will enrol nine patients across three sites including Great Ormond Street Hospital, in the UK, and two sites in the USA.  Read more at Leukocyte Adhesion Deficiency-I | Rocket Pharmaceuticals.  Promising early results of the first 7 patients treated have been presented at International meetings over the past few months.

Gene therapy trials for autosomal recessive CGD (p47-CGD)

Following on from early phase clinical trials to treat X-linked chronic granulomatous disease (X-CGD), a clinical trial is due to open in the UK at Great Ormond Street Hospital and in the US at NIH to investigate the safety and efficacy of the same approach to treat an autosomal recessive form of CGD (p47-CGD).  Up to 10 patients will be recruited across sites and the trial is due to open later this year.

Gene therapy for XLA, WAS, ADA-SCID and X-CGD

The company CSL Behring and Seattle Children‚Äôs Research Institute have formed a partnership to help advance gene therapy for PID. The alliance will initially work on therapies for Wiskott-Aldrich Syndrome (WAS) and X-linked Agammaglobulinemia (XLA).  You can read their announcement here.

The company Orchard Therapeutics Focus - Orchard Therapeutics is also developing gene therapy for WAS, ADA-SCID and X-linked Chronic Granulomatous Disease (X-CGD).    


This page was reviewed by the Medical Advisory Panel, July 2014 and updated June 2021.