In collaboration with Ionis and Biogen, we previously developed nusinersen (Spinraza), an antisense oligonucleotide (ASO) that modulates alternative splicing of SMN2 exon 7, restoring normal levels of functional SMN protein in the context of spinal muscular atrophy (SMA). The long duration of action of CNS-administered ASOs like Spinraza allows infrequent dosing by lumbar puncture, providing a feasible and effective approach to treat neurological disorders. Consequently, many ASOs are being developed against relevant targets in neurology and neuro-oncology. Splice-switching ASOs, in particular, are highly versatile, because of the pervasiveness of pre-mRNA splicing. I will describe selected applications of this powerful technology.

Therapeutic cells exhibit distinct transcriptomic profiles in on-tumor versus off-tumor immune responses, independent of receptor clonality. To deliberately modulate these states, we integrate RNAi therapies into adoptive cell therapy manufacturing, achieving durable effects in proliferating cells. In an allogeneic stem cell transplant and CAR T cell models, we are exploring multiplex siRNA cocktails and miRNA mimics that selectively reduce off-tumor activity while preserving anti-tumor responses through transcriptomic reprogramming of T cells.

It has been 46 years since ZATA’s co-founder, Dr. Paul Zamecnik (1911–2009), pioneered the field of oligotherapy (ASO on 1978). And yet, despite decades of research and investment, oligotherapy has not reached anything close to its full potential. The reason? The chemistry toolbox we use to build oligonucleotides is still too limited. Current synthesis platforms lack the versatility needed to design and fine-tune truly effective ON-based drugs.

Prion disease is a rapidly progressive neurodegenerative disease that is universally fatal and currently untreatable. Pathogenesis is driven by the misfolding of a single causal protein, the prion protein (PrP), into a self-propagating conformer. This talk will describe the academic-led advancement of a PrP-lowering divalent siRNA through preclinical and IND enabling studies, as well as regulatory and clinical strategy.

Wave’s PRISM platform enables the generation of chimeric phosphoryl guanidine (PN) backbone-containing stereopure oligonucleotides with position-controlled chemistry and stereochemical configuration. We will show examples where stereopure design and incorporation of PN linkages improve the pharmacological properties of oligonucleotides designed for distinct genetic targets, modalities, and tissues. Data from our ongoing clinical trials suggests that the improved pharmacological properties of investigational PN-containing oligonucleotides are translating into the clinic.

The importance of miRNAs for basic science has always been clear, but the application to therapy has lagged far behind. Now, however, our understanding of the mechanism of action for miRNAs and tools for identifying miRNA has advanced. Together, these advances provide the foundation for understanding how miRNAs affect disease and improve drug development.

• Strategic collaboration models between pharma, biotech, and academia: New academic modalities, models for technology transfer university to pharma and your interface with the university and pharma
• Exploring RNA as a potential therapeutic
• Criteria for developing new oligonucleotide therapeutics
  

• Developing new modalities with platform technologies
• Balancing new biology with technology advances
• Choosing delivery platforms 
• Portfolio development and filling the therapeutic pipeline
  

RNA-based vaccines and immunotherapies offer powerful opportunities for treating infectious diseases and cancer. Their efficacy depends on both the mRNA payload and the lipid nanoparticles (LNPs) that deliver it. In this talk, I will describe how engineering these components enhances immune activation and therapeutic benefit. Using combinatorial and medicinal chemistry, we developed ionizable lipids that drive strong antibody and T-cell responses, achieving protection comparable to FDA-approved vaccines at 100-fold lower doses. We also created adjuvant-like mRNAs (ADJ-mRNAs) that directly reprogram innate immune pathways, yielding durable anti-tumor immunity and improved responses against influenza and SARS-CoV-2. Together, these strategies advance next-generation personalized vaccines and immunotherapies.

Prime editors have shown limited tolerance to sugar modification in synthetic templates. Here, we show that evolved and engineered polymerases can efficiently read 2'-O-Me-modified editing templates in both traditional fused-PE and split PE formats. Using these polymerases to carry out PE with modified templates, we show significantly improved editing efficiency when compared to MMLV RT and unmodified templates. We also show that the inclusion of non-nucleotide blockers into editing templates can improve editing purity by reducing readthrough into the scaffold.

Intellia is developing potentially curative gene editing treatments to transform the lives of patients. Cas9 mRNA has been applied to our pipelines of in vivo and ex vivo CRISPR-based therapies for life-threatening diseases with high unmet need. Our lead clinical programs, NTLA-2001 for ATTR amyloidosis and NTLA-2002 for hereditary angioedema, have entered Phase 3 trials.

Wave’s AIMers are short, chemically modified oligonucleotides that direct A-to-I RNA editing via endogenous ADAR enzymes. Our optimized AIMer design supports efficient RNA editing in extrahepatic tissues including the central nervous system, kidney, and lung. We will show that AIMers support RNA editing and functional protein restoration of disease-relevant targets in multiple tissues.