Extracellular Vesicles (EVs) for Nucleic Acid, Protein–and Mitochondria Delivery!
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We are interested in harnessing the unique bioactive cargo and homing abilities of EVs including microvesicles and exosomes for delivery of nucleic acids, proteins and functional organelles such as mitochondria!
Check out the first 30 minutes of this video – this is a talk that Dr. Manickam gave at the 2021 UNC Rising Stars in Drug Carriers webinar series: UNC Rising Stars Webinar talk
See recent papers:
- D S. Manickam. “Delivery of mitochondria via extracellular vesicles – A new horizon in drug delivery.” Journal of Controlled Release, 2022 Vol. 343 Pages 400-407.2022_JCR Oration
- A. D’Souza, A. Burch, K. M. Dave, A. Sreeram, M. J. Reynolds, D. X. Dobbins, Y. S. Kamte, W. Zhao, C. Sabatelle, Gina M. Joy, Vishal Soman, Uma R. Chandran, Sruti S. Shiva, N. Quillinan, P. S. Herson and D S. Manickam. Microvesicles transfer mitochondria and increase mitochondrial function in brain endothelial cells, Journal of Controlled Release, 2021. 2021_D’Souza_JCR https://www.sciencedirect.com/science/article/pii/S0168365921004442
- D’Souza, A., K.M. Dave, R.A. Stetler, and D.S. Manickam, Targeting the blood-brain barrier for the delivery of stroke therapies. Advanced Drug Delivery Reviews, 2021. 2021 ADDR review
- Dave KM, Zhao W, Hoover C, D’Souza A, and S Manickam D, Extracellular Vesicles Derived from a Human Brain Endothelial Cell Line Increase Cellular ATP Levels. AAPS PharmSciTech, 2021. 22(1): p. 18. https://rdcu.be/cc1mc
BDNF Gene Delivery to the Blood-Brain Barrier (BBB)
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Cerebral ischemia/reperfusion injury (stroke) is the 4th leading cause of death, major cause of adult disability and kills someone every 4 minutes in the U.S. Neuroplasticity refers to the capability of the brain to adapt to injury, restructure itself to compensate for lost functions and use existing functions. Neurotrophins like brain-derived neurotrophic factor (BDNF) will sustain neuronal cell survival and improve the overall neuroplasticity upon brain injury. Insufficient delivery of BDNF across the BBB is a challenge that needs to be addressed to utilize the clinical potential of BDNF. We propose to use DNA nanoparticles (DNA NPs) to deliver BDNF DNA to treat ischemic stroke. It is known that the signaling network that exists between BBB and brain cortex (composed of neuronal cells commonly affected in stroke) allows the BBB to function as a depot secreting neuroprotective agents to combat and restore normal functions upon tissue injury. Our strategy is to deliver BDNF DNA NPs to brain microvessel endothelial cells lining the BBB and allow the secreted BDNF to act on the neurons that are damaged during stroke.
Funding
Dr. Manickam’s AACP New Investigator Award
2017 Hunkele Dreaded Disease Award
Collaborations
Representative publications
- W. Zhao, L. Han, Y. Bae and D. S. Manickam. “Lucifer Yellow is a Robust Paracellular Permeability Marker in a Cell Model of the Human BBB.” Journal of Visualized Experiments. 2019. https://www.jove.com/video/58900/lucifer-yellow-robust-paracellular-permeability-marker-cell-model
siRNA Delivery for Chronic Neuropathic/Inflammatory Pain Therapy
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Effective therapies for treating chronic neuropathic pain is an unmet research need. Most current therapies are modestly effective and are palliative small-molecule drugs that are accompanied by significant side effects. This drives the need to develop curative therapies targeting the underlying pathophysiological processes that could potentially be more effective. The role BDNF as a central pain modulator has been unequivocally demonstrated by its function in the induction and maintenance of tissue and nerve injury-induced chronic pain [1]. Our goal is to deliver short interfering RNA (siRNA) against BDNF to target the pathophysiological processes that cause chronic neuropathic pain. In another project, we are looking at the possibility to target ion channel expression using siRNA to decrease heat hypersensitivity in inflammatory pain.
Collaborations
Representative publications
- K.M. Dave, L. Ali and D.S. Manickam. “Characterization of the SIM-A9 cell line as a model of activated microglia in the context of neuropathic pain” PLOS ONE. 2020. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231597
- , , , , , Development of lipidoid nanoparticles for siRNA delivery to neural cells. DOI: 10.1208/s12248-021-00653-2, AAPS Journal Rising Stars in Drug Carriers special issue. Khare_et_al-2021-The_AAPS_Journal see editorial: The AAPS Journal Theme Issue_Rising Stars in Drug Delivery and Novel Carriers
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Gene Therapy for Glioblastoma
In collaboration with Prof. Craig Duvall at Vanderbilt, we are exploring zwitterionic PMPC polymers for DNA delivery to glioma cells.
Representative publications
- K.M. Dave, L. Han, M. A. Jackson, L. Kadlecik, C. L. Duvall, D. S. Manickam. “DNA Polyplexes of a Phosphorylcholine-based Zwitterionic Polymer for Gene Delivery” Pharmaceutical Research, 2020. https://link.springer.com/article/10.1007/s11095-020-02899-5