Gene and Cell Therapy: Tearing Down Walls

This year's 26th Annual Congress of the European Society of Gene and Cell Therapy (ESGCT) is being organized jointly with the International Society for Stem Cell Research (ISSCR) and will be held in Lausanne, Switzerland. Many of us are looking forward to this recurrent yearly event that traditionally showcases some of most exciting advances in this multidisciplinary field. The format of this joint ESGCT–ISSCR meeting is particularly appealing, as it promotes cross-fertilization between the gene therapy field sensu stricto and the stem-cell field, fostering interactions between various stakeholders who may otherwise not readily interact, and hopefully planting the seeds for new ideas and joint projects. The field of gene therapy would not be where it stands today without the stem-cell field and vice versa. Indeed, historically, the ability to deliver genes efficiently into hematopoietic stem cells, initially by using γ-retroviral vectors ¹ and later lentiviral vectors, ^2,3 essentially jump-started the gene therapy field. Conversely, the discovery of induced pluripotent stem cells as a platform for regenerative medicine and many other applications benefited from the gene therapy technology, allowing de novo expression of reprogramming factors. ⁴

“Tearing down walls” always promotes mutual understanding and has proven to be a successful modus operandi not only in the field of gene therapy and regenerative medicine but in any other medical or scientific discipline. Bringing together the complementary expertise of all stakeholders in these fields, including researchers and clinicians, business developers, and representatives from industry, regulatory authorities, and funding agencies, will bring this community closer toward reaching our common goals and hopefully alleviate human suffering and combat disease more effectively. This philosophy is diametrically opposed to the divisive and polarizing ideas being exploited by the current generation of populists for their own political gain. International collaborations have been a powerful driving force contributing to the increased momentum in the field of gene and cell therapy. Funding by the European Commission through the different successive Framework Programs, ⁵ including the latest EU Horizon 2020 initiative and beyond, fostered intra-EU and EU–United States international collaborations and has been an essential catalyst to stimulate collaboration across borders, ultimately resulting in the first gene therapy products on the market, first in the EU and more recently also in the United States. These developments helped to trigger the increased momentum in the field that we are now all witnessing. For those of us being fortunate to have been in the field for the past 25 years, it has been particularly rewarding now finally to see the benefits emerge of these medical innovations that will forever change the face of modern medicine. In particular, over the past year, we have witnessed the first gene therapy products being approved by the U.S. Food and Drug Administration (FDA) for the treatment of a genetic disorder resulting in congenital blindness, Leber congenital amaurosis. ⁶ In addition, after the initial clinical successes in gene therapy for hemophilia B resulting in stable therapeutic 2–5% factor IX levels, ⁷ normalization of clotting factor VIII levels and correction of the bleeding phenotype has recently been achieved after gene therapy in patients suffering from hemophilia A, obviating the need for prophylaxis by repeated clotting factor infusions. ⁸ This represents another milestone in the field, since it has historically been much more challenging to express high factor VIII levels compared to factor IX after gene therapy. Meanwhile, the overall efficacy of gene therapy for hemophilia B continues to improve, ⁹ thanks largely to the use of hyperactive synthetic transgenes. ¹⁰ I believe that we are reaching the stage now where we are truly pushing the boundaries of what can be accomplished with gene and cell therapy. We are even beginning to treat some of the notoriously challenging disease targets with gene therapy resulting, for the first time, in encouraging results in Phase I clinical trials. In particular, therapeutic effects have been achieved recently after gene therapy in patients suffering from spinal muscular atrophy, ¹¹ Fanconi anemia, ¹² or hemoglobinopathies. ^{13 –15}

The very principle of “tearing down walls” also applies to the gene therapy technology itself, since advances in treatment for one particular disease will likely benefit gene therapy treatments for other diseases. Indeed, the historic trials based on the use of gene-modified T cells to treat hereditary severe combined immune deficiencies ¹⁶ serve as a compelling example and ultimately constituted the basis of the now successful and FDA-approved immunotherapy for cancer based on chimeric antigen receptor T cells. ¹⁷ Similarly, the search for the ideal adeno-associated virus capsid or the most optimal expression cassette is still very much a work in progress, but any substantial improvement at the level of gene delivery or expression will likely have a broad impact on the field and not be restricted to one particular disease. The gene therapy field is also well positioned to benefit from the recent advances in gene editing technology and vice versa. Since gene editing is very much again a challenge related to safe and efficient gene delivery, translating discoveries in the CRISPR field ^18,19 into safe and effective therapies inevitably relies on the lessons learnt in gene therapy. Again, it will be essential to tear down the walls between the gene editing and gene therapy field ultimately to maximize the benefit for the patients. The earlier setbacks in the field due to insertional oncogenesis ²⁰ had prompted intense research efforts to minimize this risk. Gene editing technologies offered a way to get around this by specifically modifying the DNA at a unique locus, now offering unique and novel opportunities to start testing this in the clinic. ²¹ Nevertheless, one should also proceed cautiously to ensure off-target effects ²² are thoroughly investigated and that translational studies are conducted in large animals ²³ to assess efficacy and safety better prior to moving forward into the clinic. Despite the prevailing atmosphere of cautious optimism, as a community, we have to continue to strive toward making better and safer vectors and improving our understanding of the exact consequences of gene therapy at the molecular, cellular, and physiological level. Though it is likely that setbacks will be encountered in the future, this should never discourage us to continue our quest for finding cures for otherwise incurable diseases, which, like a sword of Damocles, hang over the heads of patients and their families that are blighted by these diseases.