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 (BMT). 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 (SCID), 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 (GvHD), 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 Adenosine Deaminase Severe Combined Immunodeficiency (ADA-SCID), it is close to being the recommended route of treatment when a well-matched bone marrow donor cannot be found.
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’, a different type of vector, may be more effective, so future trials will use these.
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 in humans.
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.
The results from 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) treated with gene therapy (GT) were published in the New England Journal of Medicine in 2021. 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.
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.
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.
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 USA at the National Institute of Health 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 these sites.
The company CSL Behring and Seattle Children’s 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.
Developing gene therapy depends on an in-depth understanding of the genes causing the PID. For example, knowledge is needed on the precise genetic fault (mutation), where it is in the DNA make-up of a cell, what controls the gene involved and in what cells the protein product of the gene is expressed. Unfortunately, for some PIDs this information is not known at present or the tools we have at present cannot fix the defect. Newer techniques such as gene editing may provide an answer for other PIDs in future.
Over 100 people have had gene therapy for PID. The work is taking place all over the world with groups working together and sharing gene therapy tools and methods. There are currently collaborative trials and the major PIDs being targeted are X-SCID, ADA-SCID, WAS, X-CGD, XLP1 and XLA.
No, gene therapy only corrects the defect in the cells of the bone marrow of the person and not the reproductive cells such as sperm that will still carry the faulty gene causing the PID. For example, a boy who had received gene therapy for an X-linked disorder will have daughters who will carry the condition but will not have affected sons. It is important to consider family planning issues at the appropriate time and your health team will help with this.
In some cases not all the immune cells are completely corrected by gene therapy. If B cells are not fully corrected (the cells that make immunoglobulin) then the individual may have to continue on immunoglobulin therapy.
This page was reviewed by the Medical Advisory Panel, July 2014 and updated August 2022.
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