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.
Full Answer
Does gene therapy work for severe combined immunodeficiency due to lack of Ada?
Adenosine deaminase deficiency is a disorder of purine metabolism leading to severe combined immunodeficiency (ADA-SCID). Without treatment, the condition is fatal and requires early intervention. Haematopoietic stem cell transplantation is the major treatment for ADA-SCID, although survival following different donor sources varies considerably.
How is SCID treated in ADA deficiency?
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 gene therapy for SCID?
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.
What are the FDA-approved medications for ADA deficiency?
Oct 22, 2009 · Allogeneic hematopoietic stem cell transplantation (HSCT) has long been considered the mainstay of treatment of ADA-SCID. However, unlike other SCID forms, 2 other treatment options are available for ADA-SCID, namely, enzyme replacement therapy (ERT) with pegylated bovine ADA (Pegadamase, Adagen, or PEG-ADA) and autologous HSC gene therapy …
Which of the following cells are 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.
How does gene therapy treat ADA-SCID?
The treatment supplies the patient with hematopoietic stem cells that pass a functional ADA gene to all their progeny. Of the 10 patients with SCID due to ADA deficiency who were treated in this manner, there was restoration of immune function and protection against severe infection in 9.Jan 29, 2009
Which treatments would be appropriate for ADA deficient SCID?
The only way to cure ADA-SCID is with a stem cell transplant. Doctors will put healthy stem cells into your body to try to rebuild your immune system. It's most successful in infants, and when the donor stem cells come from a close relative.Oct 14, 2020
What is ADA gene therapy?
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 (SCID), a very rare congenital disorder of the immune system.Apr 10, 2017
What is ADA deficiency?
Collapse Section. 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.
Can SCID be treated?
The most common treatment for SCID is an allogeneic bone marrow transplant, which will introduce normal infection-fighting cells into your child's body. Allogeneic transplants use stem cells from a relative or an unrelated donor from the National Marrow Donor Program.
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 role of ADA in purine metabolism?
The enzyme ADA is involved in purine metabolism. A lack of ADA activity leads to the accumulation of toxic deoxyadenosine and dATP (within the cell ), and thus the premature death of lymphocyte progenitor cells (Kohn et al., 2019).
Why is genome editing important?
This is important for both safety and efficacy.
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 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
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.
Background
We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency.
Methods
We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells.
Results
All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%).
Conclusions
Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481#N#. opens in new tab#N#and NCT00599781#N#. opens in new tab#N#.)
Gene Therapy
Before gene therapy, a central venous catheter was implanted, and bone marrow specimens were obtained and cryopreserved for possible later use.
Laboratory Studies
Blood and marrow samples were obtained from patients with SCID due to ADA deficiency, and blood samples were obtained from healthy children and adults as controls, with approval from the San Raffaele Scientific Institute's Ethics Committee and the Hadassah University Hospital Ethics Committee, according to standard ethical procedures.
Statistical Analysis
Mean or median values are reported, as appropriate. Clinical follow-up (including safety) data were updated as of August 31, 2008; analyses regarding molecular, biochemical, and immunologic variables were performed on data as of November 2007.
What is ADA deficiency?
Adenosine deaminase deficiency (ADA deficiency) is an inherited condition that damages the immune system and is a common cause of severe combined immunodeficiency (SCID). People with SCID due to ADA deficiency are unable to fight off most types of infections, including bacterial, viral and fungal infections.
What are the symptoms of ADA deficiency?
In children and adults with the mild form of ADA deficiency, the diagnosis is made based on symptoms which include frequent unusual infections, low WBCs in the blood, absent tonsils or lymph nodes, and low levels of the adenosine deaminase enzyme.
How do you know if you have adenosine deaminase?
They have trouble gaining weight and do not grow very well. Other symptoms include skin rashes, absent tonsils and lymph nodes, bone abnormalities, and developmental delay. [2] [4] Approximately 10-15% of people with ADA deficiency do not develop symptoms until later in childhood, often between ages 1 and 10, or even into adulthood. In these cases, people are usually diagnosed with "combined immunodeficiency (CID)", since symptoms are initially milder than those seen in SCID. However, over time, people with the milder form of ADA deficiency may develop chronic lung damage, malnutrition, and other health problems. [1] [2]
What is a combined immunodeficiency?
In these cases, people are usually diagnosed with "combined immunodeficiency (CID)", since symptoms are initially milder than those seen in SCID. However, over time, people with the milder form of ADA deficiency may develop chronic lung damage, malnutrition, and other health problems.
How many people have ADA?
Adenosine deaminase deficiency (ADA deficiency) affects about 1 in 200,000 – 1 in 1,000,000 people worldwide. [2] About 15% of all cases of severe combined immune deficiency are caused by ADA deficiency. [1]
What is the treatment for a scid?
The primary treatment is transplantation of blood-forming stem cells from the bone marrow of a healthy brother or sister (allogenic bone marrow transplant /stem cell transplant or BMT/SCT). This therapy is effective in approximately 70% or more of people with severe combined immunodeficiency (SCID), including SCID caused by ADA deficiency. [5]
What is gene therapy?
Gene therapy involves replacing a copy of the non-working ADA gene with a working copy, so that a person can make the ADA enzyme on his or her own. Gene therapy for SCID due to ADA deficiency has been approved in Europe [7], but is still considered experimental in the US. Last updated: 11/28/2018.