Exploring the Efficacy of ASO Discovery Programs in Animal Models: A Comprehensive Analysis

Insights from industry: Susanne Back, Associate Director of Central Nervous System (CNS) Pharmacology at Charles River Laboratories.

In this interview, Dr. Susanne Back explains the growing role of antisense oligonucleotides (ASOs) in neuroscience drug discovery. She discusses their benefits, challenges related to administration and in vivo modeling, as well as methods for assessing bioavailability in CNS disorders like ALS.

Could you please introduce yourself?

I am Susanne Back, Associate Director of Central Nervous System (CNS) Pharmacology at Charles River Labs. I earned my PhD in Pharmacology from the University of Helsinki in Finland and have spent the last 15 years developing and working with preclinical models for neurological illnesses such as Parkinson’s disease and amyotrophic lateral sclerosis (ALS). In my current role, I lead and oversee preclinical studies for our clients, employing in vivo models to assist drug development programs in neuroscience, rare diseases, cardiovascular disorders, and oncology.

Can you tell us a bit about what ASOs are, and why they are a trending modality in neurological disease treatment?

Antisense oligonucleotides (ASOs) are short strands of DNA or RNA that bind to specific messenger RNA molecules, preventing the translation of certain proteins. They have emerged as promising treatments for genetic disorders by targeting underlying pathogenic mechanisms without affecting healthy cells. ASOs offer several advantages in neurological disease treatment due to their precise and often long-lasting effects.

What are some challenges associated with using ASOs?

One major challenge is delivering ASOs into the central nervous system (CNS), as it has a natural barrier called the blood-brain barrier that restricts entry of most molecules. Additionally, maintaining therapeutic levels and distribution within target tissues over time can be difficult. There are also potential off-target effects to consider.

What methods are being used to overcome these challenges?

Several strategies are under investigation to improve ASO delivery into the CNS, including chemical modifications for better stability and targeting capabilities, conjugation with antibodies or nanoparticles, as well as non-invasive techniques such as focused ultrasound disruption of the blood-brain barrier.

How do you assess the distribution and bioavailability of ASOs in vivo?

To measure ASO distribution in CNS tissues, we use a variety of methods including tissue dissection followed by liquid chromatography-mass spectrometry, hybridization ELISA or qPCR. Microdialysis is also used for repeated microsampling measurements of concentrations in plasma and cerebrospinal fluid (CSF). PET imaging with radio-labeled ASOs provides another approach to track distribution in living animals.

Could you comment on the half-life of ASOs in CSF and CNS tissues?

The half-life of ASOs can vary depending on their chemistry, but generally, they have much longer therapeutic effects compared to small molecules. In studies with mouse models, for example, we’ve observed knockdown effects lasting up to eight weeks after a single intrathecal injection.