In this comprehensive discussion, Dr. Susanne Back, a leading expert in Central Nervous System (CNS) pharmacology, delves into the emerging role of antisense oligonucleotides (ASOs) in neuroscience drug discovery. She explores the benefits and challenges of ASOs, their administration methods, and the importance of in vivo modeling for assessing bioavailability in diseases like ALS. This interview provides valuable insights into the future of ASO-based therapies for neurological conditions.

Understanding the Potential of Antisense Oligonucleotides

Antisense oligonucleotides represent a promising approach in the treatment of neurological disorders. These synthetic molecules can modulate RNA expression or splicing, thereby altering protein production. Dr. Back explains how ASOs are being utilized to target specific genetic mutations associated with diseases such as ALS. The precision of these molecules makes them particularly attractive for conditions with strong genetic links. Additionally, the approval of ASOs by regulatory bodies for rare diseases has bolstered confidence in their safety and efficacy.

ASOs function by interacting with RNA transcripts to either reduce, restore, or modify protein expression. Unlike viral vector-based gene therapies, ASOs share more similarities with small molecule drugs in terms of development and manufacturing processes. This characteristic, combined with their targeted nature, positions ASOs as a viable option for treating a wide range of neurological conditions. Dr. Back highlights the importance of robust preclinical models in validating the effectiveness of ASOs, ensuring that they can be safely and efficiently translated into clinical settings.

Challenges and Considerations in ASO Development and Administration

The transition of ASO programs into in vivo environments presents unique challenges. Dr. Back emphasizes the necessity of strong evidence linking a target to the disease pathology, especially for complex conditions like ALS. Preclinical models must be carefully selected based on genetic insights to guide pharmacological studies effectively. Efficient study design is crucial to avoid unnecessary delays, given the urgency of finding treatments for progressive diseases.

Administering ASOs poses significant hurdles due to their inability to cross the blood-brain barrier. Direct administration into the CNS, typically via intrathecal injection, is necessary. Alternative methods, such as conjugating ASOs to antibodies or using focused ultrasound to disrupt the blood-brain barrier, are also under investigation. Assessing the distribution and bioavailability of ASOs in vivo involves various techniques, including tissue dissection, liquid chromatography-mass spectrometry, and PET imaging. These methods provide critical data on ASO levels in different brain regions and their long-lasting therapeutic effects, which can persist for weeks after a single dose.