ASGCT 2022 – Bigger than Ever

At this year’s annual meeting in Washington, DC, members of ASGCT finally had a chance to meet in person again. A larger venue and ever-growing exhibits were matched with a record attendance of >7,000 people, with the vast majority attending in person (albeit virtual attendance and talks were available as an option). The range of molecular and cellular therapeutics that are being developed continues to expand. Besides adeno-associated viral (AAV) gene transfer, cellular immunotherapy, and gene editing tools, just to name a few, lipid nanoparticle (LPN) delivery and extracellular vesicles were predominantly featured. Driven in part by the COVID-19 pandemic, LPN delivery of mRNA and other types of genetic vaccines against infectious disease and cancer were heavily featured. Safety and scalability are major advantages of mRNA therapeutics. In his George Stamatoyannopoulos Memorial Lecture, Dr. Drew Weissman explained how the chemistry of mRNA synthesis had to be empirically modified to reduce its innate immunogenicity, which otherwise would have prevented expression of the encoded pathogen antigen upon administration of the vaccine. Moreover, this has to be done without negatively impacting protein translation from the synthetic mRNA. Several recent articles in Molecular Therapy highlight similar challenges in the development of self-amplifying RNA vaccines. For example, generation of double-stranded RNA may trigger type 1 interferon production, which will limit antigen expression and therefore has to be minimized. Ironically, innate immune signals are critical to provide the activation signals to the immune system that are needed for successful vaccination. Having eliminated immunogenicity of the mRNA molecules, these signals needed to come from elsewhere. Interesting, the LPNs used to deliver the mRNA vaccines have adjuvant properties, which Weissman noted enhance the activation of the T helper cells needed to generate effective antibody and memory B cell responses. LNPs and viral vectors are seeing increased use for in vivo gene editing. The presidential symposium featured outstanding abstracts that showcase the potential of in vivo gene editing of cells in solid organs and of stem cells, such as hematopoietic stem cells for treatment of hematological disorders. As pointed out by Dr. Francis Collins, recipient of ASGCT’s inaugural Founder’s Award, development of technologies to specifically target organs and cell types in vivo will be key to more widely employ such approaches. Clinical gene therapy using AAV vectors continues to yield impressive successes in patients but also experiences setbacks. Dr. Katherine High, recipient of the Jerry Mendell Award for Translation Science, illustrated the winding journey that ultimately resulted in sustained correction of the bleeding disorder hemophilia B by hepatic AAV gene transfer. This pioneering effort paved the way for other success stories. For instance, AAV gene therapy enabled patients with glycogen storage disease 1a to substantially reduce intake of corn starch, which is normally required every 4 hours, even during the night, to keep the disease under control. Obviously, reduced dependency on corn starch and the ability to sleep through the night represents a major improvement in quality of life for these individuals. On the other hand, although gene therapy for muscular dystrophy has also yielded encouraging results, immunotoxicities are an impediment for treatment, which in this case relies on systemic administration of very large vector doses. Remarkably, several companies whose products are in advanced clinical testing have agreed to share their findings and, while formally being competitors, are working together to improve safety in the interest of patients. Besides viral and lipid-based delivery vehicles, extracellular vesicles are emerging as delivery platforms for various therapeutics, including immune stimulatory and suppressive molecules, non-coding RNA to regulate gene expression, viral vectors to enhance delivery and avoid neutralization by antibodies, and so on. Therefore, therapeutic applications are broad, as the Molecular Therapy family of journals will showcase in an upcoming joint special issue.¹ In conclusion, molecular technologies continue to evolve and shape modern medicine, as impressively illustrated at ASGCT’s annual meeting and in our journals.