CHEMISTRY & TRANSLATION
7:00 am Check-In & Coffee
7:30 am Workshop A: Navigating Complexity of Conjugated Oligonucleotide Formulation to Ensure Efficient Brain Delivery
Synopsis
Synthesis and formulation of conjugated oligonucleotides can be very different to naked oligonucleotides and require a proper control strategy to be set in place prior. How can we leverage experience from protein and biologic formulation development to better navigate conjugate formulation for siRNAs, ASOs & RNA aptamers in the CNS
- Sharing case studies in formulating more complicated modifications to the backbone using new starting material to
- gain insights into customized synthesis
- Understanding the changes in biophysical properties of oligonucleotides with conjugation
- Exploring use cases of more challenging modifications and conjugations e.g. formulating oligonucleotides with 2’ sugar positioning
- Developing and validating analytical methods capable of determining impurities in complex modified and conjugated oligonucleotides
- Optimizing formulation to avoid aggregation of oligonucleotides and protecting safety
NEW DELIVERY TECHNOLOGY
7:00 am Check-In & Coffee
7:30 am Workshop B: Beyond Intrathecal Administration, What is the Next Step in Less-Invasive Oligonucleotide Delivery?
Synopsis
While intrathecal delivery has offered an opportunity for oligonucleotides to be administered directly to the CNS, the technique remains highly invasive with a significant risk of postoperative infections and a need for multiple doses per year. This will inherently limit treatment uptake and clinical utility especially for large scale patient demographics. Alternative non-invasive routes of administration for oligonucleotide therapeutics are under investigation, including receptor mediated systemic delivery and the promising nose-to-brain delivery that offers clinically translatable and safer alternatives.
Join this workshop to:
- Learn of the different modalities for invasive and non-invasive oligonucleotide delivery to the CNS, including preclinical and clinical examples.
- Understand nose-to-brain delivery of oligonucleotides using an innovative Minimally Invasive Nasal Depot (MIND) approach pioneered by the workshop presenters.
- Evaluate different oligonucleotide therapeutic delivery examples in naïve and disease-specific rodent models.
- Appreciate the pathways to clinical translation of MIND for treatment of neurological diseases.
10:30 am Morning Break & Refreshments
10:45 am Workshop C: Optimizing Conjugate-Oligonucleotide Structure-Activity Relationship for Streamlined Brain Shuttle Delivery
Synopsis
Balancing between optimizing PK/PD across the blood-brain barrier while maintaining high receptor binding affinity has been a significant bottleneck in the development of efficacious oligonucleotides for CNS diseases. Perfecting the charge, polarization and chemical structure of the therapeutic is critical to drug development success.
Join this workshop to:
- Explore innovations in LNP conjugation to alter surface charge and improve transport into the CNS and more even distribution throughout the brain
- Delving into chemistry of intranasal delivery for oligonucleotides to cross the cribriform plate
- Assessing optimal binding site positioning of conjugates on oligonucleotide: exploiting opportunities across FAB and Fc antibody regions and more
2:15 pm Short Refreshment Break
CHEMISTRY & TRANSLATION
2:30 pm Workshop D: Prioritizing Genetically Closer Preclinical Models for Testing Oligonucleotides for Animal Use & In-Vitro
Synopsis
While finding accurate preclinical models is crucial for drug development of any modality, it is particularly crucial for
developing oligonucleotides, which require a near perfect match in sequence alignment to allow targeting. Current nonclinical GLP studies require rodent and large animal data to assess safety data in humans, however transcriptomic rodent sequences, and to a lesser degree even NHPs, are largely divergent from human, misleading perceived translational safety.
Join this workshop to understand:
- Exploring regulatory complexities of generating tox data and minimal translational relevance to humans
- Evaluating alternate seed sequences in the human transcriptome & genome that appear safe in rats but not in humans.
- Strategizing on how to prevent the wrong toxic dose from being chosen in non-clinical safety studies
- Redefining the regulatory route to selecting translationally relevant preclinical species in toxicity study
- Evaluating the need for rodent vs NHP assessments within GLP toxicity package
NEW DELIVERY TECHNOLOGY
2:30 pm Workshop E: Evaluating Toxicity in Preclinical Models: Reviewing Distribution & Safety of Delivery Methodology to Produce More Effective & Tolerable Therapeutics
Synopsis
This workshop provides an in-depth exploration of key considerations in intrathecal and conjugate delivery techniques, aiming to achieve optimal distribution and penetrance while addressing factors such as affinity, efficacy, and specificity for efficient oligonucleotide delivery to the brain.
Participants will gain insights into:
- Quantifying and mitigating acute neurotoxicity induced by ASOs and siRNAs in the central nervous system
- Maximizing therapeutic impact by assessing dose frequency, optimizing distribution profiles, and enhancing efficacy while minimizing drug toxicity
- Understanding the importance of even distribution and penetrance in intrathecal delivery
- Balancing affinity, efficacy, and specificity to optimize delivery efficiency
- Determining preclinical efficacy, safety, and PK/PD correlation to prioritize ASOs and siRNAs of interest
- Exploring innovative approaches and technologies for improving intrathecal delivery outcomes