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Gene Therapy Shows Durable Efficacy in Young Patients With ADA Severe Combined Immune Deficiency

December 30, 2021

Recent results published in Blood suggest gene therapy could offer an alternative to transplant for young patients with adenosine deaminase (ADA) severe combined immune deficiency (SCID). The treatment showed durable and long-lasting efficacy for up to 11 years in patients with ADA SCID.

"The ultimate life-long endurance of gene-corrected hematopoietic stem cells will require a decade to understand, but at least this first decade of observation is reassuring for the hoped-for permanence of the benefits of hematopoietic stem cell gene therapy," said corresponding study author Donald B. Kohn, MD, of the University of California, Los Angeles.

Dr. Kohn and colleagues enrolled 10 patients with ADA SCID between the ages of three months and 15 years who had received gene therapy in a phase II trial (NCT00794508) conducted between 2009 and 2012. The investigators transduced ex vivo autologous bone marrow CD34+ cells using the MND-ADA gamma-retroviral vector. Prior to the infusion of the gene-modified autologous cells, the researchers administered busulfan reduced intensity conditioning.

All patients were followed for up to two years, according to the original clinical trial protocol. After the initial two-year period, the participants could enroll in a longer-term safety follow-up study to further assess the gene marking blood cells and immune function. Overall, patients in the long-term follow-up study were monitored for between eight and 11 years.

The range of CD34+ cell/kg doses was 0.6 to 8.4 10e6/kg, while the range of vector copy number in the cell products was 0.6 to 2.7. Following a single fixed 90 mg/m2 dose of busulfan, the busulfan area under the curve ranged between 2,427 and 6,714 μM*min.
Nine out of 10 patients showed signs of sufficient immune reconstitution capable of offering protection against severe infections. These patients did not require resumption of enzyme replacement therapy (ERT) and did not need to receive secondary allogeneic hematopoietic cell transplantation.

The oldest patient who did not benefit from gene therapy resumed ERT after six months on gene therapy. Out of nine evaluable patients with the highest gene marking and B cell numbers, four remained free of immunoglobulin replacement therapy and responded to vaccinations.

According to the investigators, there were broad ranges of responses in regard to ADA enzyme activity normalization. All but two patients had ADA activity either within or above the normal range. Those who received gene therapy at the youngest ages showed high ADA enzyme activity levels were maintained throughout the long-term study.

There was a correlation between age at the start of gene therapy and median absolute lymphocyte count (ALC) during follow-up. Patients who started gene therapy at three months had ALCs reach >1,000/mm3, while those treated for between four and 20 months had ALCs reach >500 mm3. Patients treated with gene therapy for between eight and 15 years had ALCs that reached approximately 200/mm3.

The safety results were largely mixed. None of the patients experienced a clinically significant leukoproliferative event, despite the presence of frequent and abundant cell clones with vector integrants near proto-oncogenes, most notably MECOM. "These clones raise concerns about progression to leukoproliferation, but this hasn't occurred over the 10-year time scale and their frequency was remarkably stable in most of the patients where present," explained Dr. Kohn.

He added that ADA SCID appears to be relatively resistant to insertional oncogenesis from gamma-retroviral vectors compared with other conditions (e.g., X-linked severe combined immunodeficiency and X-linked chronic granulomatous disease), but the risks are still present.

Dr. Kohn noted that one of the major implications of the study relates to the finding that the common presence of cell clones with proto-oncogene adjacent integrants "reinforces the general move away from gamma-retroviral vectors with intact long terminal repeat enhancers for hematopoietic stem cell gene therapy and the adoption of lentiviral vectors with self-inactivating long terminal repeats for greater safety."

The depth of the immune function analysis in this study was limited by its retrospective nature. Additionally, the trial's small sample size warrants validation of these findings in larger long-term studies.


Reinhardt BC, Habib O, Shaw KL, et al. Long-term outcomes after gene therapy for adenosine deaminase severe combined immune deficiency (ADA SCID) [published online ahead of print, 2021 May 11]. Blood. doi: blood.2020010260.

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