Chemical Diversity

Expanding chemical diversity of therapeutic oligonucleotides for treatment of neurodegenerative disorders

Therapeutic oligonucleotide compounds (eg, siRNA, antisense) hold promise as transformative drugs for the treatment of many genetically defined neurodegenerative disorders, including Huntington’s disease and Amyotrophic Lateral Sclerosis (ALS). Therapeutic oligonucleotides silence disease genes by targeting and degrading mRNA, thus preventing the expression of toxic gene products. The inherent sequence specificity and duration of effect of therapeutic oligonucleotides provides a powerful therapeutic paradigm, as long as the disease is genetically defined and delivery to the relevant target tissue is achievable. Therapeutic oligonucleotides do not, however, cross the blood–brain barrier when delivered systemically, and local delivery by injection results in poor distribution or clinically challenging levels of toxicity. Thus, efficient and non-toxic delivery represents a major hurdle in the development of oligonucleotide drugs to treat neurodegenerative disorders.

We have demonstrated that direct administration of cholesterol-modified asymmetric siRNAs into mouse brain results in robust and long-lasting target gene silencing (Alterman et al, 2015, Molecular Therapy Nucleic Acids). Although potentially useful as a tool for modulation and study gene expression in vivo, the clinical utility of cholesterol conjugates is low due to limited distribution and narrow therapeutic index. Thus, the discovery of new chemistries that support robust retention, distribution, and efficacy in central nervous system tissues are required.

Our project focus is to identify, characterize, and develop novel chemistries that promote simple, efficient, and non-toxic delivery of oligonucleotides and potent silencing of therapeutic targets in the central nervous system in vivo. A preliminary screen of naturally occurring neuro-active steroids, endocannabinoid-like lipids, and gangliosides has identified several novel conjugates that improve neuronal uptake, efficacy, distribution, and safety of metabolically stable siRNAs throughout the central nervous system. Remarkably, different conjugates display preferential distribution to unique brain substructures or cell types. Thus, conjugate selection allows siRNA delivery via spinal fluid to be tuned to specific disease needs. This project is one of the major efforts in the lab, and successful completion of it will enable studies of gene function in the central nervous system and the development of novel oligonucleotide-based therapies for genetically defined neurodegenerative diseases.