It is generally accepted that the current risk of transfusion-transmitted infections is lower than ever. In order to maintain the high level safety o the blood supply, besides donor deferral system, up to a dozen blood pathogen tests are conducted with each donated blood unit. However, despite using all those sophisticated tests, the risk of transfusion- transmitted infections still persists because: 1) the concentration of the pathogen at "window period" can be below the limit of detection, 2) known but currently not tested pathogens can be present, and 3) due to emerging and yet to be identified infectious agents. Therefore, the high efficacy anti-pathogen compound (APC) that enables the inactivation of all blood-borne pathogens (BBP) represents an unmet medical need. Depending on medical conditions, a leukodepleted blood, plasma, platelets, or red blood cell concentrates (RBCC) are transfused. Due to the absence of nuclei in platelets and RBC, targeting and inactivating BBP genomes remains one of the most advantageous approaches examined up-to-date. Large varieties of compounds have been tested but none of them was fully materialized into an effective anti-pathogen device (APD) for blood sterilization. We at ZATA consider the development of novel APCs that selectively aggregate with and damage nucleic acid (NA) molecules. On the molecular level, the structures of ZATA's APCs will consist of linear and branched polyamines (PA) with covalently attached one to three aziridinyl groups (AzG) at the termini. Distances between positive charges in the backbones of these PA coincide with the distances between negative charges in the backbones of NA. Such spacing will enable the simultaneous ion-paring (SIP) of each positive charge of APC with the corresponding negative charge of DNA/RNA resulting in the formation of strong aggregates. The aggregation, in turn, will selectively bring AzG of APC in close proximity to the nucleophilic centers of NA and fully inactivate them via alkylation of those centers. These unique properties of our APC will enable high efficacy of inactivation at low (µM) concentration of the compound. Removal of residual APC and product of its degradation from the post-treatment blood product by using of disposable cartridge integrated in a closed APC delivery system is a part of the treatment procedure that qualifies our APC as devices (i.e. not therapeutic compounds). There are three main milestones we anticipate to achieve during Phase I of the project: I - Development of the methodology that will enable the synthesis of a panel of APC (based on preliminary data) and their controls by adopting well established chemistry as described in research plan; II - Testing these compounds against representative pathogens to select optimal APD; III - Development of a simple SINGLE-step treatment procedure and biochemical evaluation of the quality of treated blood products. Feasibility of the proposed technology is supported by preliminary data. At the end of Phase I, the best APC candidate will be selected for the Phase II study and validated against major types of pathogens that can be present in blood. 510K clearance filing for optimal ZAPC is considered. Broad provisional patent application describing ZATA's APC related IP has been filed.
Thesaurus Terms: Absorption; Adopted; Aftercare; Alkylation; Amines; Analog; Analytical Method; Anthracenes; Bacteria; Base; Biochemical; Biochemistry; Biological Assay; Blood; Blood Component Transfusion; Blood Platelets; Blood Product; Blood Tests; Blood-Borne Pathogens; Capsid; Cell Membrane; Cell Nucleus; Cells; Charge; Chemicals; Chemistry; Chromophore; Complex; Data; Degradation Pathway; Dependency (Psychology); Design; Detection; Development; Devices; Dialysis Procedure; Disease Transmission; Dna; Erythrocytes; Evaluation; Excision; Genome; Genomics; Goals; Housing; In Vitro; Infection; Infectious Agent; Ions; Knock-Down; Legal Patent; Light; Literature; Maps; Medical; Methodology; Methylene Blue; Molecular; Molecular Structure; Novel; Nucleic Acids; Oligonucleotides; Parasites; Pathogen; Penetration; Phase; Phase 2 Study; Plasma; Polyamines; Procedures; Product Development; Property; Public Health Relevance; Qualifying; Research; Research And Development; Research Study; Residual State; Riboflavin; Risk; Rna; Safety; Scale Up; Scheme; Scientist; Screening Procedure; Small Molecule; Solid; Sterilization; Structure; Success; System; Technology; Testing; Theories; Therapeutic; Time; Toxic Effect; Transfusion; Treatment Step; Ursidae Family; Vascular Blood Supply; Vertebral Column; Virus; Water;
