Nucleic Acid Medicines Move Towards the Clinic
Authors: Robert M. Frederickson, Mike Dexter
Journal: Molecular Therapy (2005)

In its broadest sense, genetic therapy can be defined as any strategy that involves the manipulation of the function or content of the nucleic acid complement of a target cell or tissue for the purpose of treating a disease. The latest tool to appear in the gene therapist's arsenal is RNA interference (RNAi). In approximately five years, RNAi has moved from a newly discovered phenomenon in mammalian cells to a promising therapeutic strategy. The rapid trajectory of RNAi-based methods towards the clinic was well represented at the first annual meeting of the Oligonucleotide Therapeutics Society (OTS), held September 15-18, 2005 at the Rockefeller University in conjunction with the New York Academy of Sciences. Various presentations and posters covered the latest basic, preclinical and clinical results of RNAi-based strategies, in addition to nucleic acid medicines (NAMs) based on antisense DNA, CpG oligodeoxynucleotides (ODNs) and aptamers. Promising early results were presented describing studies in patients with age-related macular degeneration treated with a chemically modified inhibitory small RNA (siRNA) targeting VEGFR-1 (Sirna-027, Sirna Therapeutics). The drug was injected directly into the eyes of the patients and was well tolerated with some indication of efficacy. Interestingly, an antisense drug delivered orally to patients to treat myasthenia gravis (Monarsen, Ester Neurosciences) has shown efficacy. Targeted to the acetylcholinesterase gene, Monarsen appears to have the added benefit of not causing the intestinal side effects associated with the current treatment, pyridostygmine. Additional promising clinical results were presented for antisense drugs targeted to inflammatory and metabolic disorders (Isis Pharmaceuticals) and cancer (Lorus Therapeutics, Oncogenix). In addition to interaction with a target gene or mRNA, NAMs can bind to and affect the activity of cellular proteins. These interactions can have important effects upon the immune system of the recipient, which can be either beneficial or deleterious for the therapy depending on the disease being targeted. In this regard, data from two groups demonstrated that RNAs can contain immunostimulatory motifs, and that these motifs interact with cytosolic Toll-like Receptors (TLRs) 7 and 8 molecules to activate type I interferon responses. It will be of interest to determine whether the immunostimulatory activities of RNA could be used as vaccine adjuvants similarly to CpG ODN motifs. The latter are TLR9 agonists that can activate plasmacytoid dendritic cells to stimulate both the innate immune system and antigen-specific T-cell responses. Results were presented demonstrating a therapeutic effect of the CpG drug, PF-3512676 (Coley Pharmaceutical Group), against different cancers, either as monotherapy or in combination with chemotherapy. As is the case with small molecule drugs (SMDs), NAMs can give rise to off-target effects by affecting the activity of secondary targets. An interesting presentation suggested that Genasense, an antisense drug targeted to the Bcl-2 gene to treat cancer, might actually act not by inhibiting expression of its intended antiapoptotic target, but rather by inhibiting the function of a mitochondrial membrane channel resulting in hyperpolarization of the membrane and the induction of apoptosis. One possible explanation is that the drug might be acting through an aptameric mechanism completely unrelated to its antisense effect. Although intriguing, an important caveat is that these data have all been generated in cell lines and not in patients. Clinical data presented later by Genta, the developers of the drug, showed a modest positive effect of Genasense on the response of certain cancer patients who received the drug in combination with chemotherapy. Similarly to SMDs, other important issues for clinical utilization of NAMs comprise bioavailability, toxicity and stability. Several presentations discussed new chemical modifications to improve NAM stability and to enhance the capacity of these molecules to reach and bind their target sequence. The meeting concluded with a number of lively panel discussions. There was clearly strong interest in a comparison between RNA- and ODN-based technologies. The consensus that appeared to emerge was that both technologies have merits and drawbacks, many of which are overlapping. Although ODN-based medicines have had more clinical experience, RNAi has proven to be a powerful tool for gene silencing in vitro and in cultured cells. The “right” technology to use for a particular application will likely depend on the disease being targeted and will have to be tested empirically. Indeed, we have yet much to learn about how NAMs work. This was exemplified very well by Frank Bennett's presentation of a “top ten” list of what we still do not know about NAMs. Bennett cited many important issues, such as the difficulty in designing effective NAMs, and our incomplete understanding of how these agents are distributed and metabolized in cells. A further important unknown as NAMs enter the clinic is their long term toxicology. Clearly, we have much more to learn. Overall, the first annual meeting of the OTS provided an exciting overview of the promises and challenges of the rapidly evolving field of nucleic adic medicines. Molecular Therapy looks forward to publishing the exciting preclinical and clinical studies in this area, and encourages authors to contact us at [email protected] for rapid consideration of potential contributions. The untimely death of a colleague and friend always comes as a shock. Particularly so when the deceased was young and had so much more to offer his family, his friends and the biomedical research community. My first contact with Lez Fairbairn was when he wrote to me in 1987 enquiring about a post-doctoral position at the Paterson Institute in Manchester. His referees were unanimous in their appraisal: “bright, enthusiastic, likeable and cheerful.” Geoff Margison and I were interested in appointing someone to develop DNA repair gene transfer to hemopoietic stem cells in order to ameliorate the myelotoxic effects of chemotherapeutic agents, a major dose-limiting effect of treatment of cancer. I also wanted to encourage the establishment of an independent group to develop the general area of gene therapeutics within the Institute. Lez seemed like a good bet to grow into this role. His first few years in Manchester were barren in terms of publications since much basic ground work needed to be done. However, this was a long term project and we had the benefit of working within a funding environment that took a similar view. Notwithstanding this, we had to deliver, and although it took several years, Lez delivered in style. Papers in EMBO Journal and PNAS in 1992 documented the cytoprotective effects of DNA repair gene transfer. Various publications followed that set the scene for what was to become his major focus over the next decade: gene therapeutics for chemoprotection and for alleviation of congenitally acquired genetic disorders. In these areas, Lez made significant contributions, and it is a tragedy that he died just as his work was showing increased clinical promise and broad acceptance of efficacy. Lez had a range of personal qualities that made him distinctive. If Scotland beat England at anything (which did not happen very often!), we would never hear the last of it. A student from Saudi Arabia once asked me if Lez spoke English. Particularly after a drink or three, Lez' Scottish ancestry came to the fore and much of what he said was incomprehensible. Lez also fancied himself as a singer, an endeavor with which he tried to compete with me on numerous occasions. Fortunately, he always deferred to my seniority. He is missed not only by his wife Andrea (who he met in my Department) and his children, but also by the many staff, students, post-docs and collaborators who have passed through his group. His efforts on behalf of the gene therapy community, particularly the British Society for Gene Therapy, were very much appreciated.