Two clinical studies have shown the long-term success of hematopoietic autologous stem cell (HSC) gene therapy in correction of ADA-SCID. 7, 8 In both cases, the use of chemotherapy (either busulfan 4 mg/kg or melphalan 140 mg/kg) was thought to remove autologous ADA-deficient HSCs and thereby promote the engraftment of gene-modified cells.
How does ADA gene therapy work?
Feb 03, 2020 · Ex vivo retrovirally mediated gene therapy has been shown within the last 20 yr to correct the T cell immunodeficiency caused by γc-deficiency (SCID X1) and adenosine deaminase (ADA) deficiency. The rationale was brought up by the observation of the revertant of SCIDX1 and ADA deficiency as a kind of natural gene therapy.
Is gene therapy a viable treatment for ADA SCID?
Abstract. Twenty-five years have passed since first attempts of gene therapy (GT) in children affected by severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) defect, also known by the general public as bubble babies. ADA-SCID is fatal early in life if untreated. Unconditioned hematopoietic stem cell (HSC) transplant from matched sibling …
What is ADA deficiency and how is it treated?
Nov 01, 2012 · In the 1990s, clinical trials for ADA-deficient SCID were performed in Europe and in the United States with the use of γ-retroviral vector–mediated transfer of the human ADA cDNA into bone marrow or cord blood CD34 + HSC. 8 –10 Unfortunately, these studies achieved only low numbers of ADA-gene corrected blood cells. On the basis of ethical ...
Can Gene Therapy treat adenosine deaminase-deficient severe combined immunodeficiency?
Gene and cell therapy research recently reached a fundamental milestone toward the goal to deliver new medicines for orphan diseases. In 2016, the European Commission granted market approval to GlaxoSmithKline (GSK) for ex vivo hematopoietic stem cell (HSC) gene therapy for the treatment of adenosine deaminase (ADA)‐deficient severe combined immunodeficiency …
What type of gene therapy is used for SCID?
Investigators led by Harry Malech, MD, of the National Institute of Health, use the St. Jude SCID-X1 gene therapy vector to restore complete immune function in adolescents with SCID-X1 who were not cured by bone marrow transplantation.
Which cells is used to treat ADA deficiency?
The long-standing treatment of choice for ADA-deficient SCID is a hematopoietic stem cell (HSC) transplantation from an unaffected, HLA-matched sibling.
Which treatments would be appropriate for ADA deficient SCID?
What Are the Treatments for ADA-SCID? Various treatment options are currently available for ADA deficiency, as shown in Figure 2, including enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT, sometimes referred to as bone marrow transplantation), and more recently gene therapy (GT) (10).Aug 16, 2016
How is ADA cured by gene therapy?
Treatment includes gene therapy. In this, lymphocytes from the blood of the patient are grown in a culture in vitro. A functional ADA cDNA is introduced into these lymphocytes using a retroviral vector. These lymphocytes are introduced back into the patient.
What is SCID ADA?
A rare, inherited disorder in which the immune system is damaged, causing a person to have a complete lack of B lymphocytes and T lymphocytes (types of white blood cells that help the body fight infection).
What is SCID due to?
The best-known form of autosomal recessive SCID is caused by adenosine deaminase (ADA) deficiency, in which infants lack the ADA enzyme necessary for T-cell survival. X-linked SCID, which is caused by mutations in a gene on the X chromosome, primarily affects male infants.
How ADA deficiency leads to SCID?
Adenosine deaminase (ADA) deficiency is an inherited disorder that damages the immune system and causes severe combined immunodeficiency (SCID). People with SCID lack virtually all immune protection from bacteria, viruses, and fungi.
How does ADA deficiency cause SCID?
ADA-deficient SCID is characterized by severe lymphocytopaenia affecting T-and B-lymphocytes and NK cells, but, because of the ubiquitous nature of the enzyme, non-immunological manifestations are also observed, including neurodevelopmental deficits, sensorineural deafness and skeletal abnormalities.Apr 24, 2018
What type of mutation causes ADA-SCID?
Adenosine deaminase deficiency SCID, commonly called ADA SCID, is a very rare genetic disorder. It is caused by a mutation in the gene that encodes a protein called adenosine deaminase (ADA). This ADA protein is an essential enzyme needed by all body cells to produce new DNA.Jun 2, 2014
What is the ADA gene?
The ADA gene provides instructions for producing the enzyme adenosine deaminase. This enzyme is produced in all cells, but the highest levels of adenosine deaminase occur in immune system cells called lymphocytes, which develop in lymphoid tissues.
What is the underlying defect of ADA-SCID?
The underlying defect is an enzyme deficiency that leads to the buildup of toxic metabolites, which in turn have an effect on different organ systems, most notably the immune system.
What is ADA deficiency?
Adenosine deaminase (ADA) deficiency is a rare inherited disorder of purine metabolism characterized by the accumulation of metabolic substrates that lead to abnormalities of immune system development and function and a variety of systemic defects. The initial and most devastating presentation of the disease is the result of the immune defects;
What is HSCT in transplant?
HSCT is the treatment choice that is most widely available to most physicians and transplantation centers. To date, there have been no formal data on the outcome of transplantation for ADA-SCID alone. The most notable SCID transplantation outcome papers have reported survival figures for all forms of SCID, and extensive data on ADA-SCID transplantation outcome and completeness of immune recovery have not been readily available. For instance, in the largest series of 475 SCID patients form the European SCETIDE database reported by Antoine et al, 20 51 ADA patients were included and the study documented a 3-year survival of 81% for human leukocyte antigen (HLA)–matched transplantations and 29% for HLA-mismatched transplantations with no further information on the degree of immune recovery. 20 Only 4 unrelated donor transplantations were reported in this series, and no outcome data on these patients were presented. Similarly in a 2-center study documenting outcome on 94 SCID patients, 6 ADA-SCID patients were included. 21 The deficiency in formal outcome data has limited the ability to make informed choices regarding transplantation. This is further compounded by anecdotal physician experience that ADA patients have more difficulty with transplants, especially from unrelated and haploidentical donors, possibly because of the need for conditioning and the underlying metabolic nature of the condition.
What is the function of ADA?
ADA is a purine salvage enzyme expressed in all tissues of the body and catalyzes the deamination of deoxydenosine (dAdo) and adenosine (Ado) to deoxyinosine and inosine, respectively . 3 The absence of ADA results in accumulation of dAdo in both intracellular and extracellular compartments.
What are the molecular defects that cause SCID?
SCID arises from a variety of molecular defects that have profound effects on lymphocyte development and function, including defects in the lymphocyte-specific signaling molecules (common γ chain, JAK-3, and IL-7 receptor α) and in molecules that control rearrangement of the T-cell receptor and immunoglobulin genes (RAG-1/2, Artemis, DNA ligase IV, DNA-PKcs, Cernunnos/XLF) or signaling through the pre-T-cell receptor (CD3δ, CD3ϵ, CD3ζ, and CD45). 1 ADA-deficient SCID accounts for approximately 10% to 20% of all cases of SCID and was the first form of SCID in which the underlying defect was identified. 2
Is ADA-SCID fatal?
Allogeneic hematopoietic stem cell transplantation (HSCT) has long been considered the mainstay of treatment of ADA-SCID.
Is ADA a monogenic disease?
As a severe monogenic disease, ADA deficiency is a compelling candidate for treatment with GT. 32 Several clinical studies have investigated the safety and efficacy of ADA gene transfer into autologous hematopoietic cells using retroviral vectors. In initial trials conducted in the early 1990s, 19 patients received infusions of transduced lymphocytes 33-35 or hematopoietic progenitor cells while continuing ERT. 34, 36 No toxicity was observed, and in most patients gene-modified T cells persisted in the circulation several years after infusion. 37-39 However, the relatively low gene transfer efficiency and engraftment level of transduced cells observed in these patients did not lead to substantial immunologic improvement and clinical benefit.
How is ADA gene therapy done?
This gene therapy involves inserting a normal copy of the ADA gene into the patient’s own blood-forming stem cells. First, stem cells are collected from the patient’s bone marrow or peripheral blood. Next, a harmless virus is used as a “vector,” or carrier, to deliver the normal ADA gene to these cells in the laboratory.
What causes ADA-SCID?
ADA-SCID, which is estimated to occur in approximately 1 in 200,000 to 1,000,000 newborns worldwide, is caused by mutations in the ADA gene that impair the activity of the adenosine deaminase enzyme needed for healthy immune system function .
What is the NIH?
NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov. NIH…Turning Discovery Into Health®.
Where are stem cells collected?
Stem cells were collected from bone marrow in the U.S. trials and from peripheral blood in the U.K. trial. In one of the U.S. trials, 10 children were treated with genetically corrected stem cells that had been frozen and later thawed.
What is a DNA double helix?
Darryl Leja, NHGRI. An investigational gene therapy can safely restore the immune systems of infants and children who have a rare, life-threatening inherited immunodeficiency disorder, according to research supported in part by the National Institutes of Health.
Why is ERT important after chemo?
These are important data especially because, as the authors state, the use of ERT for a short time period after gene therapy may not only protect patients in the period of lymphopaenia after chemotherapy, but may also promote engraftment of gene-corrected cells.
Does ERT blunt gene engraftment?
The first finding was that continued use of ERT did not blunt gene-modified cell engraftment. However, the most striking results were seen in experiments that most accurately represent the clinical scenario, which is the use of gene-modified lin-ve progenitor cells in nonmyeloablated (200 cGy) hosts.
Introduction
Defects in adenosine deaminase (ADA), a crucial enzyme in the purine salvage pathway, result in autosomal recessive severe combined immunodeficiency (SCID).
Results
The characteristics of the patients and detailed information about the clinical trials have been reported previously.
Discussion
The patients in this study did not receive busulfan conditioning, and, therefore, full engraftment of gene-corrected cells was not successful. Several factors, including the disease background, influence the complex engraftment pattern of gene-corrected cells.
Materials and methods
All study protocols involving the participation of the patients were approved by the Ethics Committee of the National Center for Child Health and Development. PB and BM samples were obtained from both patients. The patients and their parents provided written, informed consent to comply with standard ethical procedures.
Acknowledgments
We thank both patients and their families for their cooperation. We are also grateful to the medical staff who cared for the patients. We thank the laboratory staff at the Department of Human Genetics, National Research Institute for Child Health and Development, for excellent support.
Why is GVHD not a problem after gene therapy?
In contrast, GVHD is not a problem after gene therapy because the individual is transplanted with their own Hematopoietic Stem Cells (HSC), negating the need for a HSC donor. ...
Can PIs be treated with gene therapy?
Gene therapy may provide an alternative for those individuals with severe forms of PIs, who may be treated with Hematopoietic Stem Cell Transplantation (HSCT) from a haplo-identical parent or unrelated donor.
Is gene therapy needed for transplants?
Most gene therapy has used chemotherapy to support the engraftment of the corrected stem cells, but generally less chemotherapy is necessary for gene therapy than is needed for transplants from another donor. Until now, gene therapy has been used to treat individuals with Severe Combined Immunodeficiency (SCID) secondary to adenosine deaminase ...