Exploring the Efficacy of ASO Discovery Programs Through Animal Models: A Comprehensive Guide
In this interview with Dr. Susanne Back, Associate Director of Central Nervous System (CNS) Pharmacology at Charles River Laboratories, we delve into the growing significance of antisense oligonucleotides (ASOs) within neuroscience drug discovery for diseases like amyotrophic lateral sclerosis (ALS).
Dr. Back begins by introducing herself: “I am Susanne Back, currently serving as Associate Director of Central Nervous System Pharmacology at Charles River Labs. My academic journey started with a PhD in Pharmacology from the University of Helsinki in Finland, followed by 15 years dedicated to preclinical model development and research for neurological illnesses such as Parkinson’s disease and ALS.”
She elucidates on what ASOs are: “Antisense oligonucleotides (ASOs) consist of short synthetic sequences of single-stranded DNA that manipulate RNA expression or splicing during the translation process, where genetic code is converted into proteins. Depending on their design, ASOs can reduce, restore or modify protein expression. Although often described as gene therapy due to their impact on translation processes, their drug discovery and manufacturing are more akin to conventional small molecule drugs.”
Dr. Back discusses challenges in using ASOs: “The main obstacle with using ASOs is that they need direct access to the central nervous system (CNS), which often requires intrathecal injection into the spinal cord space as a method of administration. Other methods under investigation include conjugating ASOs with antibodies for easier passage through the blood-brain barrier or employing focused ultrasound techniques, similar to those used in clinical gene therapy.”
Assessment of ASO distribution and bioavailability is also covered: “Several methodologies are employed to evaluate ASO levels within living organisms. Tissue dissection combined with liquid chromatography-mass spectrometry (LC-MS), hybridization ELISA, or quantitative polymerase chain reaction (qPCR) enables us to quantify ASOs in various brain regions. Microdialysis is another valuable technique for measuring plasma and cerebrospinal fluid (CSF) concentrations of ASOs repeatedly over time.”
Regarding the half-life of ASOs: “The duration that therapeutic effects persist can vary significantly based on their chemical structure and backbone type. For instance, in experiments involving SOD1-ASO treatment, we observed sustained knockdown up to eight weeks after a single intrathecal injection. Similarly, with C9orf72 models treated with two injections of ASOs over time, significant effects were noted for approximately 24 weeks. These extended periods are advantageous as they reduce the frequency and burden on patients.”
Dr. Back provides an overview of Charles River’s capabilities: “At Charles River Labs, we’re committed to advancing neuroscience research by offering a full range of preclinical services including in vitro and in vivo model development for diseases affecting the central nervous system. Our expertise spans from foundational studies through regulatory processes, supporting our partners’ pursuit of innovative therapies that can ultimately transform patients’ lives.”
For further insights into ASOs or their application in treating ALS and other neurological conditions, readers are encouraged to explore Charles River’s cutting-edge research services and offerings.
