22nd Annual Meeting Recap

I always feel a combination of excitement and nervousness leading up to conferences, especially if I’m speaking. I’m excited for all I’ll learn, but I’ve never really managed to avoid feeling anxious about standing up and presenting in front of an audience. Will I remember to say what I meant to? Will I get questions that I can’t answer? Will I fall on my face on the way to the podium? (That has never happened to me, but still I worry). Now that the ASGCT 22nd Annual Meeting is over, I feel comfortable calling the event a success.  I’ve only been attending for a few years, but even in that short time, I feel like there has been a clear shift toward more advanced pre-clinical and clinical programs. This is exciting because it means that gene therapies are getting to people who need them. Meanwhile there were still a good number of innovative new approaches which I look forward to following in the future.

Monday morning featured abstract sessions and a session on pricing and access. This session brought together different perspectives to continue a discussion that I became aware of with the release by ASGCT last year of the white paper, Addressing the Value of Gene Therapy: Enhancing Patient Access to Transformative Treatments. As gene therapy continues to advance to the clinic, many more people are becoming interested in and have a stake in these issues, so it is nice to see the discussion continuing.

The “Gene Silencing Approaches” session featured different approaches to gene silencing including Zinc Finger proteins to reduce Tau and to achieve allele-specific reductions in mutant Huntingtin as well as AAV gene therapy to deliver RNAi to various regions of the CNS. Dr. Ornit Chiba-Falek presented an interesting talk on epigenomic targeting of α-synuclein (SNCA) in Parkinson’s disease (PD). Her group has developed a lentiviral vector to deliver dCas9 fused to DNA (cytosine-5)-methyltransferase 3A (DNMT3A) and a guide RNA targeting a CpG island in intron 1 of the α-synuclein gene. Hypomethylation of this CpG island has been shown in the brains of patients with PD and Lewy body dementia, and its demethylation upregulates SNCA expression. Using their targeted DNMT3A, they were able to show increased methylation within the intron 1 CpG region and a 30% reduction in SNCA mRNA and protein.

On Tuesday in a session entitled "How-to" - Design, Delivery, and Application of RNA Therapeutics, Dr. Christopher Alabi presented a beautiful talk explaining design considerations, synthesis and potential of antibody nucleic acid conjugates, focusing on the delivery of RNAi via antibody-siRNA conjugates.

Dr. Michel Sadelain delivered the George Stamatoyannopoulos Memorial Lecture, elucidating the history, mechanisms and challenges of CAR T cell therapy. Why and how do some cancer cells escape engineered CAR-T cells and what causes T cell exhaustion?

In the Outstanding New Investigator session, Dr. Steven Gray described his effort to bring gene therapy for giant axonal neuropathy to pediatric patients and how the activity of patient advocacy groups which led to its fruition. Dr. Anna Kajaste-Rudnitski presented work on engineering of human hematopoietic stem cells focusing on how Cyclosporine H (CsH) can improve lentiviral gene transfer by inhibiting interferon-induced transmembrane protein 3 (IFITM3) and limiting the innate immune response.

On Wednesday, the Sonia Skarlatos public achievement award was presented to the Muscular Dystrophy association, acknowledging the important role that patients and patient advocacy groups play in our work. The outstanding achievement lecture was presented for Dr. John J. Rossi by his son. Before the discovery of RNAi, Dr. Rossi was developing antiviral ribozymes and antisense oligonucleotides targeting HIV. He pioneered the practice of expressing RNA molecules such as antisense RNAs and hairpins in the nucleus. He described his extensive studies using both chemically synthesized and expressed siRNA to induce RNAi.  Finally, he touched on the recent discovery and development of activating small RNAs (RNAa), which extends the RNA toolkit, allowing both positive and negative regulation of genes.

The Presidential symposium featured Dr. George Church, who was funny and engaging. He described methods for limiting the immune response to viral vectors. Although the immune response to AAVs is generally believed to be minimal, he made the case that limiting the immune response could simultaneously improve the safety and effectiveness of gene therapy vectors. He described an oligonucleotide sequence, “io2”, derived from telomeres, which appears to limit the TLR9-mediated response to AAV and improves transduction efficiency. In addition, Dr. Church described a machine learning platform for AAV engineering and the detection, using this platform of a previously unidentified gene that is conserved in multiple AAV serotypes.

Finally, the presentation of top abstracts featured the presentation by Dr. Perry Shieh on Audentes Therapeutics’ ASPIRO Phase I/II clinical trial of gene therapy for X-linked Myotubular Myopathy (XLMTM). The clinical vector in this study is an rAAV8 designed to deliver functional copy of the myotubularin gene to muscle. In what I’m sure was a highlight of the meeting for many of us, he showed videos of boys who before treatment could not sit or breathe on their own sitting up, smiling and laughing. I will admit that I was brought to tears by his presentation. He reported that 3 out of the 8 patients who received the treatment were completely off the ventilator and all had improved respiratory function. In contrast to what would be expected given the natural history of the disease, all patients were sitting without support and 3 patients were crawling or standing with support.

Thursday the meeting wrapped up with a few more abstract sessions. I stayed until the end, as my presentation was in the last session. After a last-minute panic correction of my slides, I managed to convince myself that I was excited, rather than nervous and celebrated the talks of a few colleagues who were also scheduled on the last day, wrapping up what was an enjoyable and informative meeting.

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