SBIR-STTR Award

Crystalline Endolysin Treatment For Tuberculosis In Tb/Hiv Co-Infected Patients
Award last edited on: 10/10/12

Sponsored Program
SBIR
Awarding Agency
NIH : NIAID
Total Award Amount
$535,150
Award Phase
2
Solicitation Topic Code
-----

Principal Investigator
Bhami C Shenoy

Company Information

ProCrysta Biologix Inc

12 Michigan Drive
Natick, MA 01760
   (508) 318-6515
   information@procrysta.com
   www.procrysta.com
Location: Single
Congr. District: 05
County: Middlesex

Phase I

Contract Number: 1R43AI095120-01
Start Date: 4/1/11    Completed: 3/31/13
Phase I year
2011
Phase I Amount
$241,150
Though often considered to be a disease of the past, tuberculosis (TB) is still a leading killer of people worldwide. At the end of 2008, approximately 2 billion people one-third of the world's population is infected with Mycobacterium tuberculosis (MTb), the etiologic agent of TB. The World Health Organization estimates that 2 million people worldwide die of TB each year. TB is now the second most common cause of death from infectious disease in the world after human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). In the mid-1980s, a resurgence of outbreaks in the United States brought renewed attention to TB. Main reasons for increase in TB cases are due to higher vulnerability of people infected with HIV/AIDS and development of drug-resistant strains of MTb, which causes TB in human. In the latest 2010 April WHO report results show that one in every 4 TB patients diagnosed with MDR-TB in Russia and about 50% of MDR-TB burden is in China and India. Worldwide there are 440,000 MDR-TB cases and 150,000 deaths occurred in 2008. About 5.4% of MDR-TB cases have XDR-TB according to the report in March 2010.It is impractical to eliminate TB without novel, and more effective drugs, diagnostics and vaccines. The world immediately needs simpler and faster curative drugs;safer and effective drugs that can treat all forms of TB especially in immuno- compromised people with HIV/TB co-infections. As an alternative to antibiotic therapy, especially for systemic lung infections by M. tuberculosis, we are proposing to develop an enzyme therapy that can be used with various formulation conditions and delivery routes. The enzyme therapy may be as effective as antibiotic therapy because the enzyme is highly specific, and potent against the targeted bacteria. However, delivering these enzymes to the site of the infection remains a challenge. Most pharmaceutical proteins are susceptible to degradation at the site of administration, whether administered intravenously, subcutaneously, orally, topically or by any other route. We believe that a safe and effective delivery system for this application may be through the use of protein crystals, which provides highly concentrated, stable, and pure products. In addition, technologies are also needed to deliver endolysin to intracellular compartment since M. tuberculosis resides in macrophages. Cell penetrating peptides (CPP), either engineered in-frame or adsorbed/bound non-covalently to protein substrates, have been used to deliver a wide variety of molecules into a number of cell types. In this proposal we are proposing to develop a crystalline formulated recombinant endolysin therapy with cell-penetrating peptides (CPP) that can be used with various formulation conditions and delivery routes. The opportunities for CPP conjugated to endolysin are multiple since it may be able to penetrate the macrophages thereby able to kill M. tuberculosis in HIV/TB co-infected patients and may extend their life span with minimal discomfort. In Phase I, we intend to study the feasibility of using endolysins, both soluble and crystalline formulations with or without cell penetrating peptides, as a systemic delivery system in an in vivo animal model for M. tuberculosis infection. If successful, this approach will lead to the introduction of novel, efficient enzyme therapy for the treatment of M. tuberculosis infections.

Public Health Relevance:
Tuberculosis (TB) is one of the most devastating global health problems of our time, causing approximately 2 million deaths a year. As a preventive measure, currently BCG vaccine is used to avoid serious complications of TB and to reduce the rate of pediatric TB but It has little or no effectiveness for pulmonary TB in adults. We are proposing a novel crystalline endolysin that is pure, safe, effective even in immunocompromised patients, and unlike vaccines which needs immune system to generate the antibodies the endolysin can act directly on the Mycobacterium tuberculosis organism and thus prevent and treat tuberculosis in HIV/TB co-infected patients.

Thesaurus Terms:
21+ Years Old;Aids;Aids Virus;Acquired Immune Deficiency;Acquired Immune Deficiency Syndrome;Acquired Immune Deficiency Syndrome Virus;Acquired Immuno-Deficiency Syndrome;Acquired Immunodeficiency Syndrome;Acquired Immunodeficiency Syndrome Virus;Active Transcription Factor Creb;Adult;Animal Model;Animal Models And Related Studies;Antibiotic Therapy;Antibiotic Treatment;Antibodies;Antimicrobial Resistance;Antimicrobial Resistant;Area;Arginine;Arginine, L-Isomer;Assay;Attention;Bcg Tice;Bcg Vaccine;Bcg Vaccine - Connaught;Bacille Calmette-Guerin Live;Bacillius Calmette Guerin Vaccine;Bacillus Calmette Guerin Vaccine;Bacteria;Bacteriophages;Binding;Binding (Molecular Function);Bioassay;Biologic Assays;Biological Assay;Creb Protein, Human;Creb-1 Protein, Human;Creb1;Creb1 Protein, Human;Calmette Guerin Bacillus Vaccine;Calmette's Vaccine;Canine Species;Canis Familiaris;Cause Of Death;Cell Line;Cell Lines, Strains;Cellline;Cells;Cessation Of Life;Characteristics;Chemicals;Childhood;China;Clinical Trials;Clinical Trials, Unspecified;Communicable Diseases;Complex;Crystal Deposition;Crystal Formation;Crystallization;Cytolysis;Death;Development;Diagnosis;Diagnostic;Disease;Disease Outbreaks;Disorder;Dogs;Drug Formulations;Drug Resistant Tuberculosis;Drug Resistance;Drugs;E Coli;Effectiveness;Engineering;Engineerings;Enzymes;Escherichia Coli;Esterase Gene;Esteroproteases;Exhibits;Extreme Drug Resistant Tuberculosis;Extremely Drug Resistant Tuberculosis;Feasibility Studies;Fibroblasts;Formulation;Formulations, Drug;Goals;Grant;Hiv;Htlv-Iii;Human;Human Immunodeficiency Viruses;Human T-Cell Leukemia Virus Type Iii;Human T-Cell Lymphotropic Virus Type Iii;Human T-Lymphotropic Virus Type Iii;Human, Adult;Human, General;Immigrant;Immune System;Immunity;Immunocompromised;Immunocompromised Host;Immunocompromised Patient;Immunologic Deficiency Syndrome, Acquired;Immunosuppressed Host;In Vitro;India;Infection;Infectious Disease Pathway;Infectious Diseases;Infectious Diseases And Manifestations;Infectious Disorder;Killings;L-Arginine;Lav-Htlv-Iii;Lead;Length Of Life;Lipase;Longevity;Lung;Lung Tb;Lung Tuberculosis;Lymphadenopathy-Associated Virus;Lysis;M. Tb;M. Tuberculosis;M.Tb;M.Tuberculosis;Mainland China;Mammals, Dogs;Man (Taxonomy);Man, Modern;Measures;Medication;Modeling;Modification;Molecular Interaction;Mortality;Mortality Vital Statistics;Mothers;Multidrug-Resistant Tuberculosis;Mycobacteriophages;Mycobacterium Tuberculosis;Niddk;Nih;National Institute Of Diabetes And Digestive And Kidney Diseases;National Institute Of Digestive Diseases And Kidney Disorders;National Institutes Of Health;National Institutes Of Health (U.S.);Nature;Organism;Outbreaks;Particulate;Patients;Pb Element;Peptidases;Peptide Hydrolases;Peptides;Phages;Pharmaceutic Preparations;Pharmaceutical Agent;Pharmaceutical Preparations;Pharmaceuticals;Pharmacologic Substance;Pharmacological Substance;Phase;Population;Preventive;Property;Property, Loinc Axis 2;Proteases;Proteinases;Proteins;Proteolytic Enzymes;Pulmonary Tb;Pulmonary Tuberculosis;Recombinants;Reporting;Research;Resistance To Antimicrobial;Respiratory System, Lung;Route;Russia;Russian Federation (Europe);Russian S.F.S.R.;Russian Sfsr;Salts;Site;Solubility;Structure;System;System, Loinc Axis 4;Technology;Temperature;Testing;Thioglycosides;Time;Transactivator Protein;Treatment Efficacy;Triacylglycerol Hydrolase;Triacylglycerol Lipase;Triacylglycerol Acylhydrolase;Tributyrinase;Triglyceridase;Triglyceride Lipase;Triolean Hydrolase;Tuberculosis;Tuberculosis, Drug Resistance;Tuberculosis, Drug Resistant;Tuberculosis, Mdr;Tuberculosis, Multi-Drug Resistant;Tuberculosis, Multidrug Resistance;Tuberculosis, Multidrug-Resistant;Tuberculosis, Pulmonary;United States;United States National Institutes Of Health;Vaccines;Virus-Hiv;Who;World Health Organization;Xdr-Tuberculosis;Adult Human (21+);Anti-Microbial Resistance;Anti-Microbial Resistant;Antibody;Bacterial Virus;Base;Body System, Allergic/Immunologic;Camp Responsive Element Binding Protein 1;Camp Responsive Element Binding Protein 1, Human;Canine;Cell Type;Chronic Pancreatitis;Clinical Investigation;Cultured Cell Line;Disease /Disorder;Disease/Disorder;Disseminated Tb;Disseminated Tuberculosis;Distilled Alcoholic Beverage;Domestic Dog;Drug /Agent;Drug Resistant;Drug/Agent;Efficacy Testing;Endolysin;Enzyme Therapy;Ethnic Minority;Ethnic Minority Population;Expression Cloning;Gene Product;Global Health;Heavy Metal Pb;Heavy Metal Lead;Human Creb1 Protein;Human Immunodeficiency Virus;Immunosuppressed Patient;In Vivo;Inner City;Lambda-Endolysin;Life Span;Lifespan;Liquor;Living System;Macrophage;Model;Model Organism;Novel;Organ System, Allergic/Immunologic;Pediatric;Phase 1 Study;Polyanion;Polycation;Prevent;Preventing;Protein B;Prototype;Pulmonary;Recurrent Pancreatitis;Resistance To Drug;Resistance To Anti-Microbial;Resistant Strain;Resistant To Drug;Resistant To Anti-Microbial;Resistant To Antimicrobial;Therapeutic Efficacy;Therapeutically Effective;Treatment Of Bacterial Diseases;Treatment Of Bacterial Infectious Disease;Tributyrase;Tuberculosis Treatment;Tuberculous Spondyloarthropathy

Phase II

Contract Number: 5R43AI095120-02
Start Date: 00/00/00    Completed: 00/00/00
Phase II year
2012
Phase II Amount
$294,000
Though often considered to be a disease of the past, tuberculosis (TB) is still a leading killer of people worldwide. At the end of 2008, approximately 2 billion people one-third of the world's population is infected with Mycobacterium tuberculosis (MTb), the etiologic agent of TB. The World Health Organization estimates that 2 million people worldwide die of TB each year. TB is now the second most common cause of death from infectious disease in the world after human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). In the mid-1980s, a resurgence of outbreaks in the United States brought renewed attention to TB. Main reasons for increase in TB cases are due to higher vulnerability of people infected with HIV/AIDS and development of drug-resistant strains of MTb, which causes TB in human. In the latest 2010 April WHO report results show that one in every 4 TB patients diagnosed with MDR-TB in Russia and about 50% of MDR-TB burden is in China and India. Worldwide there are 440,000 MDR-TB cases and 150,000 deaths occurred in 2008. About 5.4% of MDR-TB cases have XDR-TB according to the report in March 2010.It is impractical to eliminate TB without novel, and more effective drugs, diagnostics and vaccines. The world immediately needs simpler and faster curative drugs;safer and effective drugs that can treat all forms of TB especially in immuno- compromised people with HIV/TB co-infections. As an alternative to antibiotic therapy, especially for systemic lung infections by M. tuberculosis, we are proposing to develop an enzyme therapy that can be used with various formulation conditions and delivery routes. The enzyme therapy may be as effective as antibiotic therapy because the enzyme is highly specific, and potent against the targeted bacteria. However, delivering these enzymes to the site of the infection remains a challenge. Most pharmaceutical proteins are susceptible to degradation at the site of administration, whether administered intravenously, subcutaneously, orally, topically or by any other route. We believe that a safe and effective delivery system for this application may be through the use of protein crystals, which provides highly concentrated, stable, and pure products. In addition, technologies are also needed to deliver endolysin to intracellular compartment since M. tuberculosis resides in macrophages. Cell penetrating peptides (CPP), either engineered in-frame or adsorbed/bound non-covalently to protein substrates, have been used to deliver a wide variety of molecules into a number of cell types. In this proposal we are proposing to develop a crystalline formulated recombinant endolysin therapy with cell-penetrating peptides (CPP) that can be used with various formulation conditions and delivery routes. The opportunities for CPP conjugated to endolysin are multiple since it may be able to penetrate the macrophages thereby able to kill M. tuberculosis in HIV/TB co-infected patients and may extend their life span with minimal discomfort. In Phase I, we intend to study the feasibility of using endolysins, both soluble and crystalline formulations with or without cell penetrating peptides, as a systemic delivery system in an in vivo animal model for M. tuberculosis infection. If successful, this approach will lead to the introduction of novel, efficient enzyme therapy for the treatment of M. tuberculosis infections.

Public Health Relevance:
Tuberculosis (TB) is one of the most devastating global health problems of our time, causing approximately 2 million deaths a year. As a preventive measure, currently BCG vaccine is used to avoid serious complications of TB and to reduce the rate of pediatric TB but It has little or no effectiveness for pulmonary TB in adults. We are proposing a novel crystalline endolysin that is pure, safe, effective even in immunocompromised patients, and unlike vaccines which needs immune system to generate the antibodies the endolysin can act directly on the Mycobacterium tuberculosis organism and thus prevent and treat tuberculosis in HIV/TB co-infected patients.