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:http://www.abedia.com/wiley/index.html). 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.

Current projects

Targeted CSF drug delivery

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.

Key researcher

Dr Matt MacGregor Sharp

POSTDOCTORAL FELLOW

  • m.t.sharp@soton.ac.uk

Output

Vascular α1A Adrenergic Receptors as a Potential Therapeutic Target for IPAD in Alzheimer's Disease. Frost, M, Keable, A, Baseley, D, Sealy, A, Andreea Zbarcea, D et al.. Pharmaceuticals (Basel). 2020;13 (9):. doi: 10.3390/ph13090261. PubMed PMID:32971843 PubMed Central PMC7560129.

Demonstrating a reduced capacity for removal of fluid from cerebral white matter and hypoxia in areas of white matter hyperintensity associated with age and dementia. MacGregor Sharp, M, Saito, S, Keable, A, Gatherer, M, Aldea, R et al.. Acta Neuropathol Commun. 2020;8 (1):131. doi: 10.1186/s40478-020-01009-1. PubMed PMID:32771063 PubMed Central PMC7414710.

ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes. Keable, A, O'Neill, R, MacGregor Sharp, M, Gatherer, M, Yuen, HM et al.. Int J Mol Sci. 2020;21 (12):. doi: 10.3390/ijms21124371. PubMed PMID:32575521 PubMed Central PMC7352194.

The Pattern of AQP4 Expression in the Ageing Human Brain and in Cerebral Amyloid Angiopathy. Owasil, R, O'Neill, R, Keable, A, Nimmo, J, MacGregor Sharp, M et al.. Int J Mol Sci. 2020;21 (4):. doi: 10.3390/ijms21041225. PubMed PMID:32059400 PubMed Central PMC7072949.

Solving an Old Dogma: Is it an Arteriole or a Venule?. MacGregor Sharp, M, Criswell, TP, Dobson, H, Finucane, C, Verma, A et al.. Front Aging Neurosci. 2019;11 :289. doi: 10.3389/fnagi.2019.00289. PubMed PMID:31695607 PubMed Central PMC6817770.

Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. Albargothy, NJ, Johnston, DA, MacGregor-Sharp, M, Weller, RO, Verma, A et al.. Acta Neuropathol. 2018;136 (1):139-152. doi: 10.1007/s00401-018-1862-7. PubMed PMID:29754206 PubMed Central PMC6015107.

The fine anatomy of the perivascular compartment in the human brain: relevance to dilated perivascular spaces in cerebral amyloid angiopathy. MacGregor Sharp, M, Bulters, D, Brandner, S, Holton, J, Verma, A et al.. Neuropathol Appl Neurobiol. 2019;45 (3):305-308. doi: 10.1111/nan.12480. PubMed PMID:29486067 .

The meninges as barriers and facilitators for the movement of fluid, cells and pathogens related to the rodent and human CNS. Weller, RO, Sharp, MM, Christodoulides, M, Carare, RO, Møllgård, K et al.. Acta Neuropathol. 2018;135 (3):363-385. doi: 10.1007/s00401-018-1809-z. PubMed PMID:29368214 .

The perivascular pathways for influx of cerebrospinal fluid are most efficient in the midbrain. Dobson, H, Sharp, MM, Cumpsty, R, Criswell, TP, Wellman, T et al.. Clin Sci (Lond). 2017;131 (22):2745-2752. doi: 10.1042/CS20171265. PubMed PMID:29021222 .

The structure of the perivascular compartment in the old canine brain: a case study. Criswell, TP, Sharp, MM, Dobson, H, Finucane, C, Weller, RO et al.. Clin Sci (Lond). 2017;131 (22):2737-2744. doi: 10.1042/CS20171278. PubMed PMID:28982724 .

Arterial Pulsations cannot Drive Intramural Periarterial Drainage: Significance for Aβ Drainage. Diem, AK, MacGregor Sharp, M, Gatherer, M, Bressloff, NW, Carare, RO et al.. Front Neurosci. 2017;11 :475. doi: 10.3389/fnins.2017.00475. PubMed PMID:28883786 PubMed Central PMC5574214.

Vascular basement membrane alterations and β-amyloid accumulations in an animal model of cerebral small vessel disease. Held, F, Morris, AWJ, Pirici, D, Niklass, S, Sharp, MMG et al.. Clin Sci (Lond). 2017;131 (10):1001-1013. doi: 10.1042/CS20170004. PubMed PMID:28348005 .

Quantitative Assessment of Cerebral Basement Membranes Using Electron Microscopy. Sharp, MM, Page, A, Morris, A, Weller, RO, Carare, RO et al.. Methods Mol Biol. 2017;1559 :367-375. doi: 10.1007/978-1-4939-6786-5_25. PubMed PMID:28063057 .

Investigating the Lymphatic Drainage of the Brain: Essential Skills and Tools. Albargothy, NJ, Sharp, MM, Gatherer, M, Morris, A, Weller, RO et al.. Methods Mol Biol. 2017;1559 :343-365. doi: 10.1007/978-1-4939-6786-5_24. PubMed PMID:28063056 .

Vascular basement membranes as pathways for the passage of fluid into and out of the brain. Morris, AW, Sharp, MM, Albargothy, NJ, Fernandes, R, Hawkes, CA et al.. Acta Neuropathol. 2016;131 (5):725-36. doi: 10.1007/s00401-016-1555-z. PubMed PMID:26975356 PubMed Central PMC4835509.

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-β from the mouse brain. Hawkes, CA, Gatherer, M, Sharp, MM, Dorr, A, Yuen, HM et al.. Aging Cell. 2013;12 (2):224-36. doi: 10.1111/acel.12045. PubMed PMID:23413811 .

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Funding

Codiak funded project "Exosomes in neurological diseases" £373,727