In 1990, a four-year old girl with adenosine deaminase deficiency, a form of severe combined immunodeficiency (SCID), became the first patient to receive gene therapy. Revolutionary for its time, her treatment involved ex vivo viral delivery of a corrected gene to her leukocytes. Fast forward nearly three decades, the promise of gene therapy still captivates both researchers and clinicians alike.

This morning’s symposium, “Correcting Nature’s Mistakes and Beyond: The Promise of Gene Therapy,” will showcase research tools that are at the cusp of accomplishing astonishing feats in cell and gene therapy.  What’s more, many of these applications will be moving into clinical practice in the next year or so, according to Michael Milone, MD, PhD, the session moderator. Milone will summarize the technological landscape and clinical implications behind immunotherapy.

The chimeric antigen receptor (CAR) approach consists of genetically engineering a patient’s own T cells to specifically and permanently eliminate harmful populations of B cells.  Truly a disruptive technology, it has changed treatment for certain diseases, such as leukemias and lymphomas, and there are multiple others on the horizon.  “The ability to customize therapies by constructing them to target the patient’s own tumor represents the ultimate form of precision medicine,” says Milone.  But the treatment is not without its limitations.  In fact, a major patient safety concern associated with CAR T cell therapy is the “cytokine storm,” a potentially life-threatening side-effect lacking biomarkers and methods to measure them routinely in the clinical laboratory. Milone will give insights into how the laboratory medicine community can play a critical role in meeting immunotherapy’s very unique needs.

Valder Arruda, MD, PhD, will then bring the audience up to speed on the current state of gene therapy for hemophilia. He will cover pre-clinical studies and ongoing clinical trials for hemophilia B (factor IX deficiency), along with encouraging data for hemophilia A (factor VIII deficiency). At present, adeno-associated viral (AAV) vectors are the most promising for in vivo gene therapy.  Current protein prophylaxis regimens consist of multiple injections every week, whereas AAV-based approaches are greatly simplified, delivering the benefits of prophylaxis with just a single injection.  Interestingly, just 1% of normal factor activity is needed to prevent someone with hemophilia from developing the phenotype.

Arruda, a hematologist, has always been eager to test the hypothesis that a major benefit could arise from an imperfectly performing tool.  The tool continues to be improved.  For example, designing AAV vector serotypes with varying tissue tropisms has generated therapeutics with delivery-associated advantages, making them highly translatable to humans.  Furthermore, exploring the effects of different mutations on transgene activity directly addresses a primary patient safety concern: the cellular immune response to the vector capsid. Arruda is optimistic that, because of the applicability of the AAV-based tools developed for hemophilia, other diseases will follow hemophilia’s lead and, in time, also enjoy the promise of gene therapy.

The session will conclude with a presentation by Matthew Porteus, MD, PhD, a pioneer in gene editing, on the use of correcting mutations to cure childhood diseases such as sickle cell disease.  The toolbox of nucleases engineered for gene editing is expanding, allowing gene editing to be performed quicker and cheaper than ever before. Porteus will explain how hematopoietic stem and progenitor cells can now be modified with extremely high efficiencies (20-50%) by homologous recombination, and contemplate the clinical implications of such technology. Given the technological maturation observed over the past three decades, the next 30 years of gene-based therapeutics are looking even brighter.