WHAT WE KNOW TODAY?
Being a newly discovered disease, the knowledge is still very limited. We know that the gene involved is called CECR1 and codes for the enzyme adenosine deaminase 2 (ADA2). The transmission of the disease is an autosomal recessive type: to show its symptoms, it is necessary to inherit a copy of the defective gene from each of the parents, who instead are healthy carriers (and therefore often unaware, since they are not symptomatic).
Some patients are homozygous, meaning they inherit from each parent the same mutation of the CECR1 gene. However, there are also cases of compound heterozygotes, which inherit two different mutations of the same gene. In some cases conventional genetic tests have been able to identify only a certain mutation. In both cases, patients are unable to produce the enzyme ADA2, which is essential for proper development of the immune system.
In particular, the data collected so far seem to indicate that the enzyme plays an important role in stabilizing the lining of blood vessels: this would seem to explain why people who do not have it can have serious problems in their vascular system. Furthermore, ADA2 appears to be involved in macrophage formation, a particular type of white blood cell that can cause or block inflammation.
A lack of ADA2 can “unbalance” the activity of macrophages towards inflammation, which through the release of specific cytokines such as IL-1, IL-6 and TNF alpha can cause generalized and unjustified inflammation, with damage to various organs.
GENE THERAPY IS RESOLUTIVE FOR A SIMILAR DISEASE CALLED BY A SCID OBTAINED AFTER 20 YEARS OF RESEARCH AT SR-TIGET: THE ST RAFFAELE TELETHON INSTITUTE FOR GENE THERAPY
What can we do for these patients today?
At the moment the only decisive treatment is represented by hematopoietic stem cell transplant, which however is limited by the availability of a compatible donor. Furthermore, due to the small number of transplanted DADA2 patients, disease organ damage and biology not yet fully known of the syndrome, there is a high probability of complications related to transplantation in patients with DADA2, often unpredictable (such as the vascular, autoimmune and infectious complications, transplant disease towards the host and rejection).
This is why marrow transplantation is currently performed only in very serious cases, including those with bone marrow failure, particularly severe neutropenia. Currently, 17 bone marrow transplants have been described in the literature, 16 with positive and one fatal outcome. All 17 transplant cases were affected by neutropenia. Several other transplants have been documented in international congresses and several of these have been ominous due to the complications mentioned above.
There is also no enzyme replacement therapy available for ADA2 deficiency. TNF-inhibiting drugs such as Enbrel® and Humira® have been shown to limit inflammation and stop the development of stroke; the data in this regard, however, are still very limited given the rarity of the disease, and are not sufficient to give long-term indications. Furthermore, the use of drugs for this disease is still off-label, as these are authorized for other therapeutic indications.
This makes it rather difficult to use in these patients (as experienced personally). It is the usual problem of all rare diseases that use “experimental” drugs which are used successfully but since there are not enough patients to validate them they remain without certification for use with this disease.
Gene therapy is the transfer of one or more healthy genes into a diseased cell in order to treat a disease caused by the absence or defect of one or more (mutated) genes.
Gene therapy unlike allogeneic transplantation does not require a donor because it uses the marrow of the patient with the correct gene. It also often requires a lower and less toxic dose of chemotherapy to “make room” for the correct cells. The risk of complications deriving from the donor-receiver immunological conflict, such as the disease of transplantation to the host and rejection, are non-existent in gene-therapy.The research group TIGET (Telethon Institute for Gene Therapy) of San Raffaele in Milan, coordinated by Prof. Alessandro Aiuti, has a long experience in gene therapy for the defect of ADA1, a disease with some affinity with the defect of ADA2. After a 20-year trial, this research group led to the commercialization of the first ex-vivo gene therapy drug in the world, called Strimvelis® for the treatment of ADA1 deficiency. The same group is currently working on the development of a gene therapy strategy to correct the ADA2 defect, with preclinical studies that, despite preliminary studies, put the group in a leading position at European and world level for the development of such an approach, given also the ten-year experience on gene therapy approaches on other diseases on a genetic basis (immune system deficit, haemoglobin diseases, metabolic diseases).
Gene Therapy is a promising strategy for the treatment of DADA2. Since DADA2 has many unresolved aspects of diagnosis, pathogenesis, prognosis and therapy, research is required for greater knowledge of the disease and for the development of safe and effective innovative strategies, which may be available to the majority of DADA2 patients possible.