Exploring Advances in ADA-SCID Gene Therapy: An Interview with Dr. Donald Kohn

Donald B. Kohn, M.D., is a Professor at UCLA in Microbiology, Immunology, and Molecular Genetics; Pediatrics, Hematology/Oncology; and Molecular and Medical Pharmacology. A pediatric bone marrow transplant physician, Dr. Kohn specializes in developing blood stem cell gene therapies for genetic disorders such as sickle cell disease and primary immunodeficiencies. His work focuses on advancing these therapies through clinical trials, improving their efficacy, and expanding their application to treat a wider range of diseases and reach more patients.

In this interview with OncoDaily, Dr. Donald Kohn shares insights from his work using lentiviral vectors to introduce normal ADA genes into autologous stem cells, highlighting long-term immune reconstitution and minimal conditioning. Dr. Kohn also discusses the challenges and future of gene therapy in treating ADA-SCID, offering a glimpse into how this approach is changing the treatment landscape for immunodeficiency disorders.

Given your background in bone marrow transplantation, how does gene therapy compare to traditional stem cell transplants in terms of long-term immune reconstitution for ADA-SCID patients?

In terms of long-term durability, gene therapy seems to be equally as good as an allogeneic HSCT. The data presented by Dr Masiuk at ASH showed data on patients out now 12 years from gene therapy and there has been no waning of the level of gene corrected cells, ADA enzyme expression in blood cells and protective immune function.

What do you think were the most critical factors that made this gene therapy so effective, and how has it changed the outlook for ADA-SCID patients who previously had no curative options?

The approach using lentiviral vectors to introduce the normal ADA cDNA into autologous hematopoietic stem cells has been under development for more than three decades, with steady improvement in efficacy.

What challenges did you face in terms of conditioning regimens, and how did the gene therapy approach, address or differ from traditional transplantation methods, especially in managing immune reconstitution?

Because only 10-20% of the stem cells need to carry the added normal ADA gene to completely reconstitute the immune system, we can use low dose conditioning before the cell reinfusion, minimizing acute toxicity. The children essentially remain fine in the post-transplant month, except for the intended transient neutropenia and mild thrombocytopenia. So only low dose, single agent busulfan is used for these autologous gene therapy transplants, Transplants from an allo donor, other than sibling, require pre and posttransplant immune suppression and higher doses of chemotherapy, and thus have potential for more side effects, as well as risks of graft versus host disease, which are completely absent in gene therapy.

What was the rationale behind using busulfan for reduced-intensity conditioning, and how did it impact patient recovery, both short-term and long-term, especially from a transplant physician’s perspective?

Busulfan is unique among chemotherapy drugs (also treosulphan) in specifically eliminating HSC, and not only progenitors as most other chemotherapy agents do. Again, with the relatively low dose we use, there is minimal if any acute toxicities, No nausea, vomiting, hair loss and patients have been growing normally after. Of course, there are potential late effects of decreased fertility, which most of the patients are still too young to know how often that will occur after low dose busulfan. We are looking forward to the development of effective antibody based conditioning regimens or direct in vivo gene therapy to eliminate the need for any
chemotherapy.

How long did it take for B cell function to recover after gene therapy, and what impact did that have on patients’ ability to maintain normal immune function without additional therapies?

B cell function is typically normal by one year after transplant. In the series presented at Ash 58/59 evaluable patients have stopped immunoglobulin replacement and all who have been tested ~50) have had normal antibody responses to tetanus vaccination.

What were some of the most important factors to consider when selecting patients for gene therapy, especially those who had previously undergone other treatments like enzyme replacement therapy or bone marrow transplants?

Most of the gene therapy patients had preceding ADA enzyme replacement therapy, which normalizes the toxic adenine metabolites and puts them in excellent clinical condition for the transplant. Patients who have a prior HSCT with conditioning are generally not considered good candidates for gene therapy that would use that marrow previously exposed to chemotherapy.

Could you walk us through a standard patient’s recovery timeline post-treatment? How long did it take for immune reconstitution to reach functional levels, and were there specific markers you used to track progress during recovery?

We follow immune reconstitution at 1,3,6,9,12,18, and 24 months per the study. B cells often reach normal levels within the first 6-12 months and T cells reach normal levels 1-2 years out. As mentioned above, once they have good numbers of B cells and their IgM or IgA levels are normal, we stop immunoglobulin replacement and if B cell numbers remain good, vaccinate with inactive vaccines like DPT and measure antibody responses. When those are documented as normal, we administer the pediatric live vaccines. We have not had any problems with this approach.

Were there any unexpected patient reactions, either positive or negative, following gene therapy? Did some patients experience faster or slower recovery in terms of immune function or overall health?

There is patient to patient variability in the rate of recovery of T and B cells within a range, but except for two patients who did not engraft the gene corrected cells, we have had no other surprises or unexpected reactions.

As gene therapy for immune disorders becomes more widely used, what do you see as the key challenges in making these therapies accessible to a broader patient population?

The key challenge is reaching FDA approval in the US (EMA and MHR in Europe/UK), to make it widely available. We have treated everyone so far under research studies, mostly funded by the California Institute for Regenerative medicine, but that is not sustainable one you’ve proven the efficacy. So, a company has been started, Rarity Public Benefit Corporation, to license the IP for the ADA gene therapy from UCLA and University College of London the co-developers and will work to get a BLA and marketing authorization. This requires development of commercial grade manufacturing of the lentiviral vector and the autologous cell product. Rarity will work with commercial drug manufacturing and clinical research organizations to do all this work and then ideally have it available.

Interview by Emma Ter-Azaryan