targeted CSF drug delivery

The recent major success in the treatment of neurodegenerative diseases has been provided by intrathecal administration of anti-sense oligonucleotides (ASOs) in the form of Nusirensen, invented by Biogen and IONIS (31). Our group has demonstrated the exact pathways that small molecules take from the cerebrospinal compartment into the brain parenchyma and this pathway is now of major interest for the delivery of novel therapeutics into the brain (32)(33). Adeno associated viral therapies and siRNA are already in use as efficient therapies in other conditions, for example with great success even by our haematologists in Southampton. Since adeno associated viruses (AAV) infect both dividing and non-dividing cells and have a long-lasting expression from a single delivery with no pathogenicity, they have been employed in several clinical trials for central nervous system diseases (trials database: AAVs can be tagged with a non-harmful green fluorescent protein (GFP) enabling visualisation of their movement after delivery. The route of delivery of AAVs via the cerebrospinal fluid is under consideration by several groups internationally.

Exosomes are naturally occurring, extracellular vesicles that have evolved as an intercellular messenger system. Therapeutics using exosomes are currently being developed through systemic or regional dosing to ensure enough drug gets to the desired target while limiting potential off-target side effects.

As our prior work has defined that pathways for distribution of nanoparticles and solutes differ between intracerebral administration and administration via the CSF (34), we possess the knowledge and skills to define the pattern of distribution of AAVs, exosomes and siRNA after both types of administration (intracerebral and CSF delivery). This is an urgent and necessary step in order to target neurodegenerative conditions.

We are currently exploring collaborative projects with Alcyone, Alnylam and Codiak. Contact if you would like to discuss the distribution of your agents into the brain.

related projects

Exosomes in neurological diseases

This project will utilize the unique expertise in CNS molecular movement biology and neuropathology developed at University of Southampton to explore the CNS biodistribution and potential CNS clinical applications of engineered exosomes developed by Codiak Biosciences. The project will clarify subcellular exosome molecular interactions in brain tissue and also study human neuropathology specimens for specific targets and biological pathways of interest to Codiak.

Biodistribution of Alnylam pharmaceutical RNAi Agents in Mouse brain

Alnylam pharmaceuticals has led the translation of RNAi (RNA interference) from Nobel Prize-winning discovery into an innovative, entirely new class of medicines. Founded in 2002 by a team of distinguished life sciences leaders, Alnylam’s vision is to harness the potential of RNAi therapeutics to transform the lives of people living with diseases for which there are limited or inadequate treatment options.

In collaboration with Alnylam we are working to assess the potential of custom designed siRNA’s as therapeutic agents for neurological diseases. We are administering siRNA’s intrathecally and characterising there biodistribution in different brain regions, cell types and subcellular compartments by assessing siRNA accumulation in neuron, microglia, astrocytes and oligodendrocytes, endothelial and vascular smooth muscle cells.

Targeted AAV therapy of CNS disorders

Alcyone therapeutics are mission-driven to overcome the challenges in CNS therapy development through applying precision CNS delivery & dosing technologies to novel gene therapy technologies. Alcyone’s pipeline currently includes 12 AAV (adeno-associated virus) gene therapy programs and four gene therapy platform technologies targeting severe CNS disorders

In collaboration with Alcyone we are working to assess the biodistribution of intrathecally administered adeno associated viruses within the central nervous system.