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Optimized lactoferrin for treatment of intracerebral hemorrhage
Phone: (713) 797-0146
Email: mlkruzel@sbcglobal.net
Phone: (713) 797-0146
Email: mlkruzel@sbcglobal.net
Address:
Type: Nonprofit College or University
DESCRIPTION provided by applicant Intracerebral hemorrhage ICH is a major public health problem with highest mortality rate of all stroke subtypes and long term disability Since there are no available FDA approved therapies for ICH it is of enormous importance to establish effective treatment for this medical condition Following ICH the deposited blood is damaging initially via compression of the brain tissue mass effect and then via noxious chemical effect of
hematoma components on brain tissue The latter process involves toxicity of hemolytic products e g iron oxidative stress pro inflammatory responses proteolytic enzymes mediated extracellular matrix modification blood brain barrier disruption and deadly cerebral edema Lactoferrin LTF is a well known endogenous glycoprotein with anti microbial and immunoregulatory functions in part through its effective sequestration of free iron Using in vitr and in vivo models of ICH our novel findings demonstrate that LTF possess pleotropic mechanism of action that could effectively combat multifactorial aspects of ICH pathogenesis that it provides robust protective effect in experimental models of ICH and that a novel optimized LTF fusion of human LTF hLTF with neonatal Fc receptor for IgG PRC is more effective than hLTF alone The overall goal of this project is to begin the optimization process for using PRC as treatment for ICH Our hypothesis is that the studies proposed here will initiate the preclinical development of PRC by starting the dose optimization process and the analysis of PRC t Aim To produce PRC and to determine the optimal dosing and therapeutic time window in ICH using adult male mice Aim a To optimize and produce PRC in Chinese Hamster Ovary cells CHO Focus will be to scale up production of PRC Criteria for acceptance We will produce and purify purity sufficient quantity of PRC for this Phase I study mg Aim b Assess the efficacy of PRC in mice We will test a dose range of PRC between mg mg kg with therapeutic window of h h h and h Criteria for acceptance Improvement of neurological function by with the therapeutic time window of h compared to the vehicle pandlt All studies will follow NIH guidelines RIGOR randomization approach and all analyses will be performed by the investigators blinded regarding the treatment assignments Aim To assess t and bioavailability of PRC in mice The goal of this aim is to establish levels bioavailable pool of PRC in circulation an brain over hours range which is an equivalent of x half life time of natural LTF We will measure PRC levels in serum and in the brain parenchyma by ELISA using goat anti human LF antibodies Criteria for acceptance PRC will have at least times extended half life over the native LF and will reach brain tissue at least as efficiently as natural LTF
PUBLIC HEALTH RELEVANCE Intracerebral hemorrhage ICH is the second most common and deadliest form of stroke Currently no pharmacologic treatment strategies exist for this devastating disease The overall goal of this project is to develop a clinical prototype for early intervention in post ICH complications using fusion of human lactoferrin LF with neonatal Fc receptor for IgG PRC Studies proposed will initiate the preclinical development of this novel molecule and will involve developing optimal procedure for its production determination of optimal dosing in animal model of ICH and initial pharmacokinetic studies This will provide the foundation for future safety and efficacy studies in Phase II
* Information listed above is at the time of submission. *