Two Decades of Molecular Therapy and a 35-Year Personal View of Changes in Gene Therapy
Authors: David A. Williams
Journal: Molecular Therapy (2019)

I was pleased when Rob Frederickson asked me to provide a short editorial to mark the 20th year of Molecular Therapy. I served as Editor in Chief from 2005–2010 and, during that 5-year period, I wrote monthly editorials, so I have likely said most of what I could say about the field during that time. However, I started in the field in 1982 and thought I might be allowed to use this opportunity to offer some more personal remembrances to the readership, most of whom will have entered the field much later than I did and some of whom probably were not even born at that time. As an incoming hematology/oncology fellow at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, I was “instructed” in 1981 by my future (and still) boss, David G. Nathan, to interrupt my clinical training and go to the Massachusetts Institute of Technology to work with Richard Mulligan. Richard, who had just been recruited by David Baltimore from Paul Berg’s laboratory, was an emerging star in the development of recombinant retrovirus (RV) vectors for gene transfer (an interesting observation to put this era into context was that, when I searched for papers on the subject as a senior pediatric resident at Cincinnati Children’s Hospital Medical Center, I could find none!). My post-doctoral project was to exploit the advantages of retrovirus vectors and develop a protocol to transfer genes into hematopoietic stem cells (HSCs). Work in the 1960s and 1970 s (including infamous experiments in humans by Martin Cline) had attempted to do this by using transfection of plasmids, but the inefficiency of that methodology (1:10,000 cells on a good day) and the infrequency of HSCs (thought at the time to be 1 in 100,000 bone marrow cells) predetermined failure of this approach. Thus, the high efficiency with which RV vectors could transfer intact genomes into the chromosome of infected cells offered a real opportunity to tackle gene therapy for blood and immune disorders. We and others (including John Dick and Alan Bernstein) succeeded after much hard work, and the field more or less exploded with over-optimistic predictions of the application of these vectors to cure human genetic diseases. Those were heady days. For myself, oddly enough, I did not fall in love with vector technology or see gene therapy as a career, but I did fall in love with hematopoiesis, which I had to learn in some detail for the project. This became the basis for my subsequent and current NIH-funded research laboratory. Several hurdles slowed the predicted success in application of the mouse studies into human therapies. First, unrecognized initially, the efficiency with which genes could be transferred into reconstituting HSCs in the mouse and primitive blood forming cells in humans was significantly less than more mature primary cells and cell lines (more on this later). This led to a focus on diseases in which a small number of transduced primary cells might be selected for in vivo and to tinkering with culture and transduction conditions, with the subsequent discovery of the effects of fibronectin (Retronectin) by my own laboratory along the way as well as the current modifications using “transduction enhancers” to improve efficiency of gene transfer into primary HSCs by several other investigators. Second, as noted in Rob Frederickson’s and Seppo Yla-Herttuala’s editorial introducing this commemorative series,1Frederickson R.M. Ylä-Herttuala S. Two Decades of Molecular Therapy: The Journey Continues.Mol. Ther. 2019; 27: 1-2Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar leukemias developed in the severe combined immunodeficiency (SCID)-X1 trials in Paris and London. The theoretical risk of insertional mutagenesis had been predicted by some, but this risk was thought to be mitigated in the setting of helper-free recombinant RV vector stocks that practically eliminated the risk of widespread genome insertions. Li et al.2Li Z. Düllmann J. Schiedlmeier B. Schmidt M. von Kalle C. Meyer J. Forster M. Stocking C. Wahlers A. Frank O. et al.Murine leukemia induced by retroviral gene marking.Science. 2002; 296: 497Crossref PubMed Scopus (572) Google Scholar were prescient in this regard when they reported mouse leukemia was caused by insertional mutagenesis due to a helper-free recombinant vector, which predated the initial human adverse event. While a significant set-back for the field (ultimately 6/20 children in these two trials developed leukemia related to insertional mutagenesis), one result of these events was the formation of the Transatlantic Gene Therapy Consortium (TAGTC). A group of investigators formed the TAGTC coalition to work together to improve the safety of RV vectors and to collaboratively perform human trials. The direct result was demonstration of the safety of enhancer-deleted γ-RV vectors,3Hacein-Bey-Abina S. Pai S.Y. Gaspar H.B. Armant M. Berry C.C. Blanche S. Bleesing J. Blondeau J. de Boer H. Buckland K.F. et al.A modified γ-retrovirus vector for X-linked severe combined immunodeficiency.N. Engl. J. Med. 2014; 371: 1407-1417Crossref PubMed Scopus (296) Google Scholar but, perhaps more importantly, a highly productive long-term collaboration between multiple groups across the US and Europe that indirectly contributed to the formation of Orchard Therapeutics. The TAGTC has held recurring meetings, alternating between Europe and North America, devoted to this topic ever since. The 11th Stem Cell Clonality and Genome Stability Retreat meeting will be held in Barcelona, Spain in October 2019. Personally, the interactions with colleagues in London (Thrasher, Booth, and Gaspar), Hannover, Germany (Baum, Moritz, and Schambach), the NIH (Notarangelo and Malech), California (Kohn), as well as Boston (Pai and Biffi) have been some of the highest points of my career. The period after the tragic death of Jesse Gelsinger and the leukemias in the SCID-X1 trials was a clear nadir for the field, with both intellectual talent and investments in gene transfer technology fleeing the field. Fortunately, there were some investigators, including those mentioned above, who persisted and improved the gene delivery systems, leading to renewed investments and extraordinary talent energizing the field and, ultimately, the first gene therapy medicines gaining regulatory approval as medicines. The resulting innovations are also leading to wider applications in human diseases; as efficiencies of gene transfer improve, finely tuned regulation of transgene expression is possible, and the biology and molecular basis of human disease becomes better understood. We now can predict, safely, I think, that gene editing to correct mutations in humans will soon be successfully applied clinically. Interestingly, the issues of efficiency and safety are again front and center with regards to the clinical application of gene editing technologies. The investment of capital from biopharma companies, such as bluebird bio, has led to more robust manufacturing processes and, with that, increased safety and, one would hope, reduced overall costs (and hence prices). For me, I am still running an NIH-funded laboratory studying hematopoiesis and still running clinical trials, but, most importantly, still seeing children with devastating genetic blood diseases who need more therapeutic options. So, I am extraordinarily pleased to see the progress in the field and grateful for the opportunity to have been part of the history of this progress, and I look forward to much broader applications in the future. One last and important note, as this is an editorial series commemorating the journal. It should be clear to the readers that the success of Molecular Therapy as a journal is due in no small part to the leadership of Rob Frederickson, who has stewarded a fledging journal in a struggling scientific field to the most highly-rated journal in the field today. Rob, well done!