Sixfold Biosciences aims to capitalise on the potential of RNA interference in oligonucleotide therapeutics. Reeta Daswani, Senior Scientist at Sixfold Biosciences, noted that the biggest bottleneck is delivery. She explained that current delivery modalities target less than 1% of all human cell types. Therefore, there is a huge gap and opportunity in the delivery space that Sixfold Biosciences aims to exploit.
Daswani is working on conjugate-based delivery, with a focus on enhancing the conjugate itself to unlock new cell types. The first generation of conjugate-based delivery was mainly driven by having prior knowledge of the receptor and uncovering a ligand that would bind to the receptor. The second generation examined a narrow chemical space that investigated how ligands behave sometimes without fully understanding the receptor mechanism. Finally, the third generation leverages unbiased ML, agnostic, and data-driven processes to select conjugates.
One of the key obstacles linked to the third-generation discovery of conjugates is giving the ML experts the appropriate data to make an accurate predictive model based on in vivo data. Daswani mentioned that even with adequate in silico and in vitro evaluation the issue of translatability to in vivo testing can still arise.
In order to tackle this problem, Daswani encouraged the use of computational methods to efficiently map and explore the chemical space. With high-throughput conjugations, one can screen and test the PKPD properties of these conjugates directly in animal models. She described their innovative pipeline that allows for the detection of multiple conjugates within the same animal, reducing the number of animals needed, bypassing intra-animal variability, and improving cost-effectiveness.
Next, Daswani presented a case study on local injection for intrathecal CNS delivery. The CNS is notoriously difficult to reach. Fortunately, there are two FDA-approved antisense therapeutics for CNS. However, these approved drugs target the more external region of the brain rather than the deep internal regions. So, Daswani and her team prepared 15 different conjugates with unique chemistries. They were co-formulated and injected into the same animals to perform a multiplex iteration of computationally selected conjugations. The team observed that the way a ligand distributes to different regions of the brain varies depending on their chemistries, with some conjugates outperforming the control group (Alnylam C16 Linker).
In summary, this study aimed to create better RNA conjugates for deep brain regions. The pipeline developed by Sixfold Biosciences creates a strong foundation for screening multiple conjugates in vivo and provides useful data for optimising drug delivery strategies.