Our research is currently focused on two primary goals: (i) To identify the factors affecting the diffusion of proteins, genes, viral vectors and nanoparticles inside the developing, adult and pathologic central nervous system (CNS) and (ii) To identify the pathways and mechanisms allowing substances to enter the CNS following intranasal administation, a promising alternative route for CNS drug delivery.
Protein and gene therapies for CNS disorders like Alzheimer’s disease, Parkinson’s disease and stroke have been limited by two related yet distinct problems. The first concerns the difficulty associated with delivering a protein, gene or drug delivery vector into the CNS across the barriers that separate the blood from brain interstitial and cerebrospinal fluids. The second concerns the uncertainty surrounding what happens on the brain side of these barriers once a substance is able to pass them. Surprisingly, little information exists to predict the distribution of substances following their entry into the CNS. Our research focuses on the study of diffusive and convective transport within the extracellular and perivascular spaces of the central nervous system and the development, refinement, and optimization of strategies for delivering proteins, genes, viral vectors and nanoparticles into the brain. We aim to leverage knowledge of physiology and central nervous system structure with state-of-the-art in vivo imaging methods in order to identify new ways to effectively deliver drugs to the brain and to better understand how endogenous proteins such as antibodies distribute within the central compartment.
In addition to his research program, Dr. Thorne serves on the editorial board of Fluids and Barriers of the CNS and is a founder and Council/Steering Committee member of the International Brain Barriers Society (http://www.ibbsoc.org/) as well as the elected 2016 Chair and organizer for the “Barriers of the CNS” Gordon Research Conference (http://www.grc.org/programs.aspx?id=12833).
Our diffusion work has focused on characterizing the diffusion properties of a variety of different substances in gels, brain slices and in vivo using optical imaging; this information is used to gain insights into what factors are important for drug distribution once inside the brain. Characterizing the diffusion properties of biopharmaceuticals is especially relevant for the design and enhancement of transvascular strategies for CNS drug delivery, particularly those involving nanoparticles, as well as convection enhanced drug delivery within the brain, a method of surgical infusion currently under test in clinical trials. Our research on the intranasal route of administration has helped to elucidate how and why certain proteins, viruses, nanoparticles and even cells may reach the brain from the nasal passages in sufficient quantity to produce effects. A better understanding of the mechanisms, pathways and limitations for drugs capable of transport from the nasal passages to the brain will greatly aid in the successful application of this method; indeed, clinical trials to treat developmental disorders, neurodegenerative diseases and stroke are just beginning.