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Principal Investigator: Forrest M Kievit
Organization: PROTRANSIT NANOTHERAPY, LLC
Fiscal Year: 2020
Award: $259,938
Funding agency: National Institute of Neurological Disorders and Stroke
ABSTRACT
Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide and comes with a
significant economic burden associated with emergency room visits and hospitalizations. Oxidative stress-
mediated secondary injury post-TBI is a considerable risk factor for mortality and long-term impairment.
Immediately following TBI, a cascade of biological responses leads to increased production of reactive oxygen
species (ROS), a critical mediator of the subsequent pathophysiological events that manifest through lipid
peroxidation (LPO), oxidation of proteins and DNA, neuroinflammation, and neurodegeneration. While
technological and clinical advancements have improved the outcome for individuals suffering from TBI, there is
currently no effective neuroprotective therapy specific for the prevention and treatment of TBI-related secondary
injury associated with oxidative stress. Super antioxidants, superoxide dismutase (SOD), and catalase (Cat)
have the potential to attenuate the spread of inflammation and brain tissue damage if administered shortly after
a TBI. However, the activity of antioxidants is short-lived and rapidly cleared, limiting therapeutic strategies based
on exogenous delivery. ProTransit is developing an antioxidant-loaded nanoparticles (NP) delivery system, Pro-
NP™, for the treatment of TBI-related secondary injury, as (1) there is currently no effective neuroprotective
therapy specific for TBI-related secondary damage; (2) prior attempts have failed clinical translation due to
ineffectual drug delivery and retention, and unintended toxicity; and (3) super antioxidants like SOD and Cat are
effective but short-lived and rapidly cleared without a robust drug delivery system. The proposed research will
address and improve upon current approaches by providing a delivery system, Pro-NP™ that can (1) deliver
super antioxidants in a sustained manner, (2) rapidly accumulate and be retained in the damaged brain, and (3)
improve TBI recovery. Thus, this proposal will provide a therapeutic strategy for TBI-related secondary brain
damage, which is not available through current TBI treatment plans.
In contrast with current secondary TBI therapeutic strategies, Protransit’s core patented nanotechnology,
Pro-NP™, can deliver biologically active antioxidant enzymes, like SOD and Cat, with sustained release and
increased target engagement with the site of injury. With increased accumulation and retention in a damaged
brain, antioxidant-loaded Pro-NP™, can exert a protective effect and prevent the spread of biochemical
derangements to surrounding healthy brain, potentially providing a significant advantage over other tested
therapies. Overall, this Phase I STTR project will determine the feasibility of SOD/Cat-loaded Pro-NP™ to inhibit
the development of secondary injury related to TBI. Further, this project will lay the foundation for a Phase II
STTR in which we will investigate the pharmacokinetics, biodistribution, and safety profile of Pro-NP™ for the
treatment of TBI.
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