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Original Papers: Candotti, F. et al. 2012. Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: Clinical comparison of retroviral vectors and treatment plans. Blood 120: 3635−3646.

Gaspar, H. B., A. Alessandro, P. Fulvio, C. Fabio, M. S. Hershfield and L. D. Notarangelo. 2009. How I treat ADA deficiency. Blood 114: 3524−3532.

Hershfield, M. S. et al. 1987. Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase. New England Journal of Medicine 316: 589−596.

Severe combined immunodeficiency (SCID) is a very rare inherited condition in which individuals show high susceptibility to viral, fungal, and bacterial infection. Left untreated, it is fatal. SCID can be caused by mutations in any of several genes, one of which codes for the enzyme adenosine deaminase (ADA). ADA is produced in all cells, but the highest levels are found in lymphocytes.

Inside lymphocytes, when DNA is metabolized, toxic deoxyadenosine is produced. When ADA is present, deoxyadenosine is converted to a nontoxic molecule. When ADA is not present, deoxyadenosine accumulates and causes cell death, especially of T cells.

There are currently three treatments for ADA-SCID. In enzyme replacement therapy (ERT), patients are injected with ADA, usually weekly. This restores normal levels of ADA (6−12 µmol/h/mL) and deoxyadenosine (less than 10 percent of adenine nucleotides) in blood and immune function. The table below shows the results of ERT in one patient.

The second treatment method is hematopoietic stem cell transplantation (HSCT), in which stem cells from a donor give rise to lymphocytes that carry the normal ADA gene. These are transplanted into the patient. The greatest obstacle in HSCT is finding a donor whose cell surface markers (in this case, human leukocyte antigens, a type of MHC protein) are similar to those of the patient. To understand the significance of the matching process, 87 patients underwent HSCT with donors having various levels of “matching,” and were studied for long-term survival (Figure A).

The third treatment for ADA-SCID, gene therapy, can be used when a matching stem cell donor is not available. Blood stem cells are removed from an ADA patient and then exposed in the lab to a viral vector that inserts the correct gene sequence for ADA into the cells. These modified cells are then returned to the patient. Figure B shows the results for one patient. The normal range of ADA activity is at least 60 nmol/10⁸ cells/min.

Questions

Question 1

By 3 weeks after the initial treatment, ADA and deoxyadenosine levels were normal. Weekly injections were probably needed because ADA gets broken down in blood serum.

Question 2

Matched sibling and matched family donors had almost the same survival percentage: 87% and 88%, respectively. Matched unrelated donors were not nearly as successful, with only 67% survival. However, even this was better than the mismatched family donors, which had only 43% survival. The lowest survival of all was shown by mismatched unrelated donors: 29%. The survivorship of untreated patients might be similar to that with mismatched unrelated donors, but perhaps with even lower survival.

Question 3

In gene therapy, hematopoietic stem cells are the cells that receive the genetic modification. Thus they are the only cells that will be able to produce and maintain normal levels of ADA. However, all cells produce ADA, because all cells undergo a certain level of DNA metabolism. ERT could keep other body cells from reaching dangerously high levels of deoxyadenosine.