Unlocking The Potential Of Oligonucleotide Therapeutics

Oligonucleotide therapeutics treat disease by using short, synthetic nucleic acids to induce specific gene expression modulation. Antisense oligonucleotides (ASOs) are engineered to interact with cellular RNA by binding to their target sequences through Watson-Crick-Franklin base pairing. This binding mechanism allows them to suppress disease-causing genes, correct splicing anomalies, or block protein translation._[1]

Oligonucleotide therapeutics offer advantages over traditional small molecule drugs, including broader target accessibility, high specificity through base pairing, and potential for personalized medicine. These characteristics enable oligonucleotide therapeutics to address diseases previously considered undruggable, tackle a variety of genetic irregularities, and adjust to changing disease profiles effectively. Additionally, they require less screening and optimization, making development faster and more efficient._[2]

The development of oligonucleotide therapeutics faces significant challenges, primarily in delivering these molecules effectively to target tissues beyond the liver. Off-target interactions, sequence-dependent toxicity, and the risk of saturating RNA processing pathways add additional layers of complexity to their development._[2]

Elsie Biotechnologies aims to unlock the full potential of oligonucleotide therapeutics to bring safer and more efficacious therapeutics to the market to treat the most intractable human diseases.

Altering even a single atom in an antisense oligonucleotide (ASO) sequence can significantly impact its efficacy. Leveraging this knowledge, Elsie's advanced oligonucleotide platform explores the full range of 3D structural possibilities, enabling the synthesis, deconvolution, optimization, and precise delivery of homogeneous oligonucleotide therapeutics.

How Latch supports and accelerates Elsie’s design process

LatchBio plays a pivotal role in Elsie's platform, functioning as a bioinformatics engine that is accessible and enabling to scientists. It equips Elsie’s scientists with the necessary bioinformatics orchestration, robust cloud computing resources, and comprehensive computational expertise needed to advance their work in oligonucleotide therapeutics.

Additionally, LatchBio not only provides the computation that Elsie’s platform runs on, but it also puts data back into the hands of the scientists, ultimately shortening the design, test, and analyze cycle.

Discovery Process

Elsie's Discovery Engine is a state-of-the-art approach to the discovery and optimization of nucleic acid therapeutics. Embracing a completely agnostic methodology, the engine is designed to tailor oligonucleotide pools to the specific research questions being addressed. The process is an iterative DNA encoding technology that relies on ultra-high throughput screening of antisense oligonucleotides (ASOs) coupled with next generation sequencing and advanced bioinformatics on LatchBio’s platform.

Designing Antisense Oligonucleotide Libraries

The process begins by first choosing a transcript of interest. A Latch Workflow is then utilized to design a library of antisense oligonucleotides (ASOs) to target this transcript. LatchBio’s platform allows for every design to be archived, formatted, and recorded in a way that enables Elsie to maintain a single source of truth and seamlessly integrate data into downstream pipeline tools. 

Testing Therapeutic ASO Candidates

Next, the oligonucleotide library undergoes testing in biologically relevant substrates, a crucial step for pinpointing accessible hot spots on the transcript of interest. These sites indicate high affinity, activity, and molecular selectivity potential for ASOs. 

Following this, next generation sequencing data is generated and imported into Latch Data, from where it undergoes analysis through a proprietary workflow designed to deconvolute accessibility of ASOs in the library. 

Validation of Therapeutic Candidates Through Transcriptomic Analysis

RNA-seq is an integral assay used in the validation process of the discovery pipeline. It accurately measures the changes in gene expression caused by therapeutic candidates. This is crucial for confirming specific on-target effects or identifying potential off-target biological effects in order to guide initial discovery efforts.

To first understand the differential gene expression, a Deseq2 tool on Latch is used to compare RNAseq data between potential candidate sequences. This provides a high-level overview of the variations in the direct effects of the therapeutics on gene expression.

Pathway analysis is then conducted on Latch to gain deeper insights into the functional impacts and potential side effects of these candidate ASOs, further informing the selection process.

Overall, the ability for various types of disparate data to be archived and linked together on Latch (specifically RNAseq and transcript accessibility data for ASO libraries) enable the rapid intuitive deconvolution of data that is integral to efficient scientific program decision making.

Oligonucleotide Optimization

The discovery process on Latch generates ASO sequences that are then optimized and investigated further. These optimizations are a core part of the Elsie process and involve various chemical and molecular biology techniques. _{[3] [4] [5]}

One such process involves refining the most effective sequences from the initial discovery process through thorough exploration of the chemical modification pattern. This stage includes conducting parallel selections aimed at enhancing affinity and stability, while focusing on minimizing toxicity.

Next, even though the sequences have been optimized with specific chemical modifications, maintaining properties such as the cellular uptake of the therapeutic remains a challenge. To tackle this, the focus shifts to further refining their linkages and stereochemical identities. The goal is to achieve a balance between potency, safety, and drug-like characteristics, ultimately resulting in the development of advanced oligonucleotide therapeutic sequence candidates.

Elsie leverages proprietary PSI chemistry technology to enhance oligonucleotide properties by integrating novel linkages, with precisely controlled stereochemistry into a candidate to fine tune therapeutic design. This method, characterized by atomic-level precision, also leads to consistent chemical structures, improving the safety and reliability of the therapeutics. Elsie believes that this holistic approach to chemical optimization of oligonucleotide therapeutics will overcome historical challenges in the field and lead to the creation of life changing drugs. 

Streamlining Cutting-edge Oligonucleotide Therapeutic Development

Latch has bridged the gap between informatics and scientists at Elsie, leading to faster screening, improved experimental iteration, and impressive cost reductions. The computational accessibility and streamlined experimental design process that Latch provides has enabled Elsie to rapidly develop oligonucleotide therapeutics that are capable of targeting and combating the most devastating diseases.

Sources

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2. Roberts TC, Langer R, Wood MJA. Advances in oligonucleotide drug delivery. Nat Rev Drug Discov. 2020 Oct;19(10):673-694. doi: 10.1038/s41573-020-0075-7. Epub 2020 Aug 11. PMID: 32782413; PMCID: PMC7419031.
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