The importance of understanding mutation-specific biology, exemplified by JIP3

This study highlights the importance of understanding mutation-specific biology, exemplified by a toxic gain-of-function mutation in JIP3 (R578C) that disrupts axonal transport, signaling pathways, and overall neuronal function. By elucidating the molecular proximal pathological mechanisms associated with this mutation, we have successfully identified allele-selective ASOs as the optimal therapeutic strategy.

Understanding and reducing the risk of innate immune activation

Phosphorothioate antisense oligonucleotides (PS-ASOs) can activate the innate immune response via toll-like receptor 9 (TRL9), creating safety challenges in the clinic. Our research has uncovered how the PS-ASO-induced innate immune response is terminated. This work significantly advances our understanding of PS-ASOs, enabling the development of drugs that are better tolerated to improve outcomes for patients.

DYRK1A, a Discovery case’s evolution from research to high-throughput scalability

The current DYRK1A program has evolved from designing a small number of candidate ASOs to leveraging n-Lorem’s high-throughput n-of-1 Discovery pipeline. This work has enabled us to conduct rapid, rigorous and high-quality screening combined with functional studies to specifically target the pathogenic mechanism of this nano-rare disorder.

iPSC strategies to reduce time and cost in disease modeling

This work describes the establishment of an optimized iPSC-derived neuronal differentiation platform to streamline disease modeling for ASO screening. By utilizing patient-specific iPSCs, this approach offers a scalable, robust, and cost-effective solution for high-throughput ASO screening, significantly reducing timelines and costs in the preclinical discovery pipeline.

Progress in creating agonist-like ASOs for patients with LOF mutations

Building on foundational work from the Crooke lab and integrating our own AI-driven algorithm, we have developed a platform to identify and validate genomic regulatory elements that can be targeted by ASOs to upregulate protein expression. This therapeutic strategy has now established proof of concept protein upregulation and addresses haploinsufficiency and loss-of-function diseases through a mutation-independent approach, broadening its applicability across diverse patient populations.

Tackling RNA-caused diseases: A focus on RNU4-2

Mutations in U-rich RNAs are increasingly recognized as drivers of neurodevelopmental disorders. Although their short length and structured nature presents challenges, ASO technology offers a unique therapeutic opportunity. This work focuses on a recently identified mutation in RNU4-2, highlighting its functional characterization and n-Lorem’s therapeutic strategy to address its toxic effects.

Using ‘omics’ data to inform and refine ASO design

This study illustrates how we apply our experience and deep expertise to harness insights from large-scale public genomic and transcriptomic datasets to inform multiple stages of ASO discovery; from feasibility assessment to design and optimization. We will also discuss the critical importance of selecting appropriate datasets to support informed and effective decision-making throughout this process.

Robust safety monitoring in n=1 trials: A scalable approach from REDCap to PowerBI for data safety monitoring board oversight

We present a scalable data lifecycle framework for n=1 trials, designed to support robust safety monitoring and Data Safety Monitoring Board (DSMB) review. Beginning with individualized protocol development, the workflow moves to custom REDCap electronic data capture (EDC) builds, remote data monitoring and cleaning, and direct export of cleaned data into PowerBI. Our PowerBI dashboards enable real-time, visualized safety review across adverse events, concomitant medications, labs, and other key safety measures.

From sequence to safety: Preclinical assessment of tolerability and toxicology profiles of ASOs

At n-Lorem, patient safety is the foundation of our discovery and development process. The development of optimal experimental ASOs depends on achieving excellent safety profiles, guided by rigorous tolerability and toxicology assessments throughout. This poster outlines n-Lorem’s comprehensive preclinical development approach for creating well-tolerated ASOs with favorable toxicological profiles. It will detail standard class-related in vivo findings, the primary types of toxicities encountered, and key safety considerations at each stage of preclinical development.

Ensuring quality at every step in our ASO manufacturing and formulation

Our approach to antisense oligonucleotide (ASO) manufacturing ensures rigorous quality control from lead identification through GMP production. This poster outlines how, once a lead ASO is selected, we assess key development risks and timelines to inform the strategy for GMP drug substance manufacturing—either in parallel with or following toxicology batch production. The selected sequence is transferred to the drug substance CMO, and documentation preparation begins.  The GMP process involves several steps: amidite preparation, solid-phase synthesis, cleavage and deprotection, purification, ultrafiltration, and lyophilization. GMP drug substance is then transferred to the drug product CMO where it is further processed through formulation, sterile filtration, and filling into ready for dosing vials. Quality is ensured through comprehensive analytical testing, including HPLC purity/impurity profiling, sterility assessment and annual stability testing. These activities are executed in close partnership with trusted CDMOs to ensure consistency and compliance with regulatory standards.