ATMP Use Case - Severe Combined Immunodeficiency (ADA-SCID)
Adenosine Deaminase Deficiency - Severe Combined Immunodeficiency (ADA-SCID) is a genetic disorder that belongs to a group of severe combined immunodeficiencies. Children with ADA-SCID suffer from a purine metabolism disorder, resulting in the accumulation of toxic metabolites that prevent the development of lymphocytes, essential cells for a functional immune system. As a result, these children have a deficiency of T cells, B cells, and natural killer (NK) cells, leading to severe, recurrent infections, such as middle ear infections, bronchitis, and pneumonia. ADA-SCID can also cause non-immunological symptoms, including growth retardation, chronic diarrhea, skeletal dysplasia, motor and cognitive impairments, deafness, and liver dysfunction.
The frequency of ADA-SCID is estimated to be 1 in 50,000 to 1 in 100,000 live births, or about 15 children annually across Europe. The disease primarily manifests early (85-90% of cases), though some individuals may have a delayed onset of symptoms after the first year of life (10-15%), and rarely, later onset cases are observed. Since August 2019, ADA-SCID has been included in the expanded newborn screening in Germany, and the diagnosis is confirmed through complex immunological and molecular genetic tests, including the absence of adenosine deaminase activity.
Treatment Options
Patients with ADA-SCID require protection from infections caused by viruses, bacteria, and fungi, as even mild infections in healthy individuals can be life-threatening for those with ADA-SCID. Therefore, treatments like immunoglobulins, antibiotics, antifungals, and antivirals are used to manage infections. Newborns with ADA-SCID are also not allowed live vaccines and can only be breastfed if the mother has never had a cytomegalovirus (CMV) infection. While these measures can prevent or mitigate infections, they do not offer a cure.
To effectively combat recurring infections, a functional immune system is necessary, which can be restored through various treatments:
- Stem Cell Transplantation: Prior to the approval of ADA-SCID gene therapy, allogeneic stem cell transplantation was the only potential cure, though it required a suitable donor and carried risks of severe complications. The mortality rate from bone marrow transplantation, before newborn screening was implemented, was approximately 1 in 10.
- Enzyme Replacement Therapy (ERT): In this treatment, the missing ADA enzyme is injected into the muscles once or twice a week. However, ERT does not provide a long-term solution and is not considered a satisfactory long-term treatment for ADA-SCID.
- Gene Therapy: A gene therapy to treat ADA-SCID is Strimvelis®, which was approved in Europe in 2016. This ATMP involves extracting stem cells from the patient’s bone marrow, modifying them via genetic modification to deliver the functional ADA gene before the modified stem cells are reintroduced back into the patient. The corrected stem cells produce functioning lymphocytes, restoring a functional immune system.
Conclusion: Gene therapy has emerged as a transformative treatment for ADA-SCID, offering patients the opportunity for a functional immune system without the risks associated with allogeneic stem cell transplants. The availability of gene therapy and other advanced treatments has dramatically improved the outlook for children with ADA-SCID.