Description:
Background
Intracerebral hemorrhage (ICH) is a devastating form of stroke, with the highest mortality of all stroke subtypes. Rapid accumulation of blood and immune cells result in oxidative stress, inflammation, and the accumulation of toxic hemolytic products at the site of the stroke, leading to significant injury to the brain. There are no effective treatments currently available for ICH.
Technology Description
Lactoferrin is an endogenous glycoprotein with anti-microbial and immunoregulatory functions, with the potential to curtail the inflammatory response and promote repair. However, endogenous lactoferrin has limited therapeutic potential due to its short half-life in the blood and its difficulty penetrating the blood-brain barrier. Researchers at UTHealth have optimized lactoferrin by creating a novel fusion protein that has been demonstrated to combat multiple aspects of ICH pathogenesis.
Key Preclinical Findings:
- The Half-Life and Mean Retention Time for PRC14 were significantly increased as compared to recombinant human lactoferrin (rhLTF) alone, by 5.8 fold.
- Upon IV administration, PRC14 is found in the brain, indicating its blood-brain-barrier penetration.
- PRC14 is more effective in reducing ICH-induced neurological deficit (as measured with four different behavioral tests) than rhLTF – Autologous blood injection model of ICH in mice.
- PRC14 is more effective in reducing ICH-induced neurological deficit (as measured with four different behavioral tests) than deferoxamine (agent recently tested in clinical trail) – Autologous blood injection model of ICH in mice
- Using a mouse ICH model to assess dose-response to five PRC14 treatment doses, the investigators have established the optimal therapeutic dose of PRC14, based on measuring neurological deficit and brain edema.
- Using optimal dose of PRC14 in mouse model of ICH, PRC14 was shown to have at least a 24h therapeutic window, which is much longer than most therapies tested to date for ICH.
- Using Spontaneously Hypertensive Rats (SHR), it was demonstrated that PRC14 is highly effective in reducing neurological deficit after ICH.
- Using 20-22 months old male and female mice, PRC14 was shown to be highly effective in reducing neurological deficit caused by ICH in these aged animals, independent of their sex.
- Using pig lobar ICH model (based on autologous blood injection), it was demonstrated that PRC14 could reduce brain edema, as assessed by brain edema formation and hematoma resolution, at days 7-14 after ICH
Key in vitro Findings:
- Primary rodent microglia treated with PRC14 have stronger phagocytic capacity toward RBC (in vitro model of hematoma clearance)
- Primary rodent microglia treated with PRC14 showed reparative phenotype with reduced pro-inflammatory properties
Stage of Development
- Studies of PRC14 in rodents have shown reduction in neurological deficit, reduction in edema, and faster hematoma clearance with a 24 hour window of treatment opportunity. Promising results have also been demonstrated in a pig model of ICH.
- This technology is well positioned to advance into clinical studies. Stroke care is a primary area of expertise at both UTHealth and UTHealth’s affiliated hospital, Memorial Hermann Hospital. There is a large cohort of ICH patients as well as significant clinical expertise available for future clinical studies in this area.
Intellectual Property Status
Issued U.S. Patent 10,442,852
Technology is available for licensing
Inventors: Jaroslaw Aronowski, Marian Kruzel
Jaroslaw Aronowski, Ph.D., M.D. (Professor and Vice-Chair of Neurology at UTHealth) is a distinguished researcher in intracerebral hemorrhage and ischemic stroke.
Marian Kruzel, Ph.D. (President, PharmaReview) has decades of experience in working with lactoferrin as a therapeutic agent.
Both PIs have a long track record of collaboration, including studies supported by both a phase I and phase II STTR award. They both have been involved in translational research for over two decades, including successful translation of their bench research discoveries into clinical trials.
Related publications:
Zhao X, et al. (2017). Nat Commun. 2017 Sep 19;8(1):602. doi: 10.1038/s41467-017-00770-7.
Zhao X, et al. (2020). Lactoferrin and hematoma detoxification after intracerebral hemorrhage. Biochem Cell Biol. 0(0) 1–14. PMID: 32438861
UTHealth Ref. No.: 2014-0045