Two Decades of Molecular Therapy: The Journey Continues
Authors: Robert M. Frederickson, Seppo Ylä-Herttuala
Journal: Molecular Therapy (2018)

This issue of Molecular Therapy marks the first issue of its 20th year of publication, and this editorial is the first of several commemorative editorials and commentaries highlighting key events of the first two decades of the journal. The concept of gene therapy dates back to the early 1970s, and early trials took place in the early 1990s. However, the first issue of Molecular Therapy appeared just as the cloud of the Gelsinger affair had settled over the field. As most readers will know, American patient Jesse Gelsinger died in 1999 following an experimental gene therapy using a recombinant adenoviral vector, setting the field back several years as US regulators put some key studies on hold with a view to reevaluating the review and approval process for gene therapy trials. Even as the dust was settling on this event, the field was elated as the first reports of success with ex vivo retroviral vector-based gene therapy to cure genetic immunodeficiency appeared in the early 2000s, but, again, the issue of the safety of the technology was brought into question as cases of leukemia subsequently developed in a couple of the treated patients. Although investment shrank and public perception of the technology took a hit, the field circled its wagons and tackled the scientific issues underlying these events head on. These tragic events, in a way, proved beneficial to the development of the journal as the relevant ethical, regulatory, and scientific issues were rigorously debated in our pages—the flagship journal of an only recently-formed society. We subsequently published many of the studies undertaken to better understand and address the oncogenic events initiated by the retroviral vector used to cure the genetic immunodeficiency—and new terms entered the gene therapy lexicon: genotoxicity and insertional mutagenesis. The end result was a better understanding of how these vectors worked, and this ultimately led to important improvements to their safety. In addition, lentivirus vectors were developed and adenoviruses had become a workhorse for gene therapy experiments. All the while, the profile of another vector, based on adenovirus-associated virus, or AAV, was quickly rising. Based on a small endemic and nonpathogenic virus, AAV vectors proved quite efficient and useful to target a variety of different non-dividing differentiated cells and tissues owing to exploitation of the natural diversity of available serotypes. By the mid-2000s these vectors had been shown to correct genetic blindness and hemophilia in animal models and subsequently in human patients. Immune-related issues remain to be solved, but the future looks particularly bright for this vector class as various animal models of genetic disease have been successfully treated with them (many such studies appearing in our pages) and numerous companies have been formed with the aim of bringing these treatments to the marketplace. In fact, an AAV gene therapy for the treatment of Leber congenital amaurosis, a rare genetic retinal disease, was approved by the US Food and Drug Administration (FDA) in late 2017. Fundamentally, technology development has always underpinned the American Socity of Gene and Cell Therapy, and this is clearly reflected throughout the journal’s development. In the early 2000s, we find the first papers in our pages referring to small inhibitory RNA (siRNA) or RNA interference (RNAi), protein transduction domains, and Sleeping Beauty transposons. By the mid-2000s we see reports of genetic modification by zinc-finger nucleases, documentation of the therapeutic potential of exosomes, and studies showing that RNA itself could serve as a gene transfer vector. The current star of the field of genome editing—CRISPR/Cas technology—made its first appearance in our pages a mere 4 years ago and, since this time, a whopping 132 papers making use of this technology have appeared in Molecular Therapy or its sibling journals. Importantly, this technology has already reached clinical testing, although concerns remain with regard to the potential for missuse of this powerful technology, highlighted by very recent lay media reports of the birth of gene-edited twins in China. We also published numerous papers over the years describing various types of “oncolytic virotherapy,” which is technology that exploits the inherent susceptibility of certain cancer cells to infection and destruction by various types of attenuated or genetically “armed” viruses. In fact, the first gene therapy to be approved worldwide is Gendecine, a p53-expressing adenovirus vector developed by Shenzhen SiBiono GeneTech Co., Ltd. It was approved in 2003 by the China FDA as a first-in-class gene therapy product to treat head and neck cancer. More recently, a herpesvirus-based treatment of melanoma was approved in the US. More oncolytic viruses are currently in clinical trials, and it appears likely that we will see a few reach the market before too long, either as single agents or as part of combination therapies that include checkpoint inhibitors or, of course, T cell-based therapies, such as those based on “chimeric antigen receptors” or CARs. Regular readers of this journal would be quite familiar with CAR T cell therapy, which has shown remarkable success treating hematological cancers and is under intense study to tackle solid tumors as well. Several of our most highly cited papers over the last decade report clinical findings using this technology. In addition, various other cell therapy applications have been published during the last decade. It is impossible in a short editorial to highlight all the salient events of two decades of a very fast-moving and forward-looking field. For example, while the near-term clinical prospects for the field mostly involve viral vectors, the advances in nonviral gene therapy and nanoparticle research has been impressive—and the trajectory will ultimately lead to the clinic. Indeed, the outlook is promising for the field, possibly greater than any time in its history, but challenges remain, and we look forward to providing the venue for discussions aimed at finding the right solutions. A key issue for the field continues to include access to therapies, whether owing to cost or geographic limitations. Gene therapy is expensive and will require innovation in how health care is provided. The issue highlights very clearly not only the divide between the developing and developed world, but how the two might work together to solve the cost and accessibility problem.