Leap of Faith
Authors: Rick Morgan
Journal: Molecular Therapy (2014)

When I started in this field some 25 years ago, most of us young Turks thought that we would have successful treatments for a variety of genetic diseases within five years. Five years quickly passed, and many of us were still arrogant enough to use the same slide saying that gene therapies for many monogenic diseases would be a reality in another five years. But by this time (the mid-1990s) it was hard to look a mother of a hemophiliac son in the eye and make this statement, when we ourselves doubted it was true. Although I will never make another five-year prediction, 2014 brings with it a variety of new genetic tools, such as the potential for site-specific viral vector integration that will have a significant impact on the treatment of monogenic diseases. To achieve such a long-sought-after goal as specific vector integration requires the combination of diverse technologies—a feat that I believe can most effectively be accomplished in a commercial environment rather than an academic one. So, what has made 2014 different from the previous years? I would say that the two most important developments have been the industrialization of viral vector platforms (primarily adeno-associated viral and lentiviral vectors) and the development of several robust and complementary gene-editing technologies. Both of these key technological advances have been driven to a great extent by the biotechnology companies, which have access to the capital and resources to develop robust, scalable manufacturing processes that generate high-quality reproducible products. When I recently made the jump (or as, some of my friends call it, a leap of faith) from an academic position to one in industry, I did so with the full knowledge of not only what I was leaving behind but also what I was potentially gaining. In the past couple of years, we have seen US or EU approval of the first commercial cell therapy product (Provenge, manufactured by Dendreon) and the first viral vector–based therapy (Glybera, manufactured by uniQure). Although the long-term commercial success of these products has yet to be determined, they prove that commercial cell and gene therapy products are a reality and that the ability to treat large numbers of patients, a goal beyond the reach of academic centers, is now possible. Centralized manufacturing of patient-specific cell therapy products and large-scale high-titer, high-purity viral vectors are largely industry-driven innovations. In addition, adeno-associated viral vector-based treatments for certain forms of blindness and hemophilia are well on their way to becoming products, and industrial-quality lentiviral vectors are having similar early success in the treatment of hematopoietic stem cell–based genetic diseases. You can't read a journal these days without using the new vocabulary of gene editing: zinc fingers, TALEN, CRISPR/Cas9, homing endonuclease, and MegaTALs. Although CRISPR/Cas9 is all the rage, the only gene-editing technology currently reduced to clinical practice is the zinc finger–based approaches being commercialized by Sangamo. We take a lot of things for granted in our field, but consider that there are now dozens of patients who are walking around with somatic cells in their bodies that have had specific chromosomal loci deliberately altered by a gene-editing enzyme! If you don't think this is fantastic, please check your pulse. Even more fantastic are some of the potential combinations that could be afforded by the marriage of industrial-quality viral vectors and gene-editing technologies. Beyond the obvious possibility of highly efficient delivery of the nucleases, some of these enzyme platforms have the ability to facilitate site-specific vector integration and, potentially, homologous recombination. While not a new concept, site-specific integration and homologous recombination are now approaching efficiencies that make their clinical application possible. The malignant transformation of hematopoietic cells associated with gamma-retroviral vector insertions in the context of ex vivo treatments for patients with certain inherited immune deficiencies could in the future be eliminated by highly specific vector integration. Further investment in the development of these technologies can potentially greatly expand the safety of integrating viral vectors and push these technologies as therapies for less severe chronic diseases. Biotech companies have an inherent advantage in the combined application of these new technologies, by being able to acquire, license, or partner with stakeholders (academic or commercial) with access to diverse technologies. Consider the complexities needed to assemble such diverse technologies as high-titer, high-purity viral vectors; a nuclease gene-editing platform; and a high-efficiency, high-viability transient RNA or protein delivery system, and now contemplate how you're going to use this to treat thousands of patients a year. In the development phase alone, these are multimillion-dollar endeavors and require long-range planning and financial commitments that are not possible in a standard grant-driven academic environment. Faith in its best manifestation results from the accumulation of knowledge. It is a choice, not a command. Those of us who have made that leap of faith from academia to industry do so with the belief that the large-scale implementation of highly diverse technologies can be the next big step for our field and make transformative gene therapies a reality. The author is an employee of and owns stock in bluebird bio Inc. bluebird bio is a biotechnology company potentially interested in the development of one or more of the technologies described in this Editorial.