SBIR-STTR Award

?The goal of this proposal is to develop an enzyme replacement therapy (ERT) approach for rare genetic diseases that is effective in mitigating the problem of immune sensitization that has hindered previous ERT technologies. Enzyme replacement therapies remain the most effective treatment for those rare genetic diseases for which approved recombinant enzyme products are available. ERTs have been crucial in treating several lysosomal diseases (LDs), which in their severe forms present with devastating multi-organ pathologies in affected children. However, the induction of patient anti-ERT antibodies (immune sensitization) has emerged as a significant limitation in the effectiveness of ERTs, altering enzyme distribution and activity. Because early/infantile-onset forms comprise the most severe mutations, the development of immune sensitization is much more prevalent in younger patients. These children often show dramatic life-saving improvements upon treatment onset. However, progress stops or quickly declines as these patients develop neutralizing antibodies to the ERT drug. Most currently approved ERTs for LDs exploit the same Mannose-6-Phospate (M6P) receptor for uptake into disease cells and the predominant class of anti-ERT antibodies interfere with this uptake process. However, the ERT technology developed by BioStrategies LC uses an alternative ERT-RTB fusion mechanism for cell uptake and we have found in preliminary experiments using Hurler MPS I lysosomal disease cell cultures that active ERT-RTB was successfully delivered in the presence of neutralizing antibody containing serum from immune-sensitized animals. Based on these promising in vitro results, our goal in this SBIR Phase 1 is to demonstrate in vivo efficacy, including enzyme delivery and glucosaminoglycan (GAG) substrate reduction, in ERT-sensitized Hurler mice. We previously demonstrated that IDUA: RTB shows broad bio-distribution and corrects GAG substrate levels in the MPS I mouse model. Specific aims for Phase I include to: 1) Develop MPS I mice that are immune sensitized to the rhIDU ERT product and 2) Compare IDUA activity and GAG levels in selected tissues in rhIDU-sensitized mice following treatments with either rhIDU or IDUA:RTB. Success of these experiments will demonstrate that a significant increase of ERT enzyme activity is delivered to organs of IDUA sensitized Hurler mice after treatment with IDUA-RTB verses rhIDU. Based on a successful Phase I feasibility study, Phase II research will target statistically significant assessments in the MSP I animal model and application of the RTB lectin platform to other diseases such as Pompe and other diseses where immune sensitization problems have most significantly impacted successful ERT treatments. The long-term goal is to develop new immune mitigating ERTs for patients that will provide sustainable efficacy of these therapies for lysosomal and other protein deficiency diseases.

Public Health Relevance Statement:


Public Health Relevance:
The childhood human genetic diseases belonging to the group of lysosomal disorders and bone developmental diseases currently under development at BioStrategies represent some of the most devastating disease afflictions known and the most costly to patients, their families, and the public health care system. Currently available enzyme replacement therapeutics (ERTs) for several of these diseases, although effective for many patients, suffer from problems of safety, high cost, product effectiveness including immune sensitivity problem studied in this project. The new therapeutics innovations developed in this SBIR Phase I feasibility project would address many of these issues by developing ERTs that are more effectively targeted to diseased cell types and tissues and that are safer and cheaper to supply to patient populations by virtue of employing newer plant-based production technologies. The innovative drug delivery technology developed in this project would further the goal of reducing the cost and suffering of patients with these devastating genetic diseases.

Project Terms:
Address; Affect; Aftercare; Animal Model; Animals; Antibodies; base; Biodistribution; Biological Assay; Brain; Canis familiaris; Cell Culture Techniques; cell type; Cells; Child; Childhood; Collaborations; cost; Deficiency Diseases; Development; Developmental Bone Diseases; Disease; Disease model; Dog Diseases; Drug Delivery Systems; effective therapy; Effectiveness; enzyme activity; enzyme replacement therapy; Enzymes; Family; Feasibility Studies; Fibroblasts; Gaucher Disease; Gifts; glucosaminoglycans; Glycogen storage disease type II; Goals; Healthcare Systems; Heart; Hereditary Disease; Human; Human Genetics; IGF Type 2 Receptor; Immune; Immune Sera; Immunization; immunogenicity; Immunoglobulin G; In Vitro; in vivo; infancy; innovation; Kidney; L-Iduronidase; Lectin; Life; Lysosomal Storage Diseases; Mammalian Cell; Mannose; Measures; Mediating; Modeling; mouse model; Mucopolysaccharidosis I; Mucopolysaccharidosis VI; Mus; Mutation; neutralizing antibody; novel therapeutics; Organ; Pathology; patient population; Patients; Pharmaceutical Preparations; Phase; Plants; Polysaccharides; pre-clinical; Process; Production; Protein Deficiency; Public Health; public health relevance; Rattus; receptor; Recombinant Proteins; Recombinants; Reporting; Research; research study; response; Route; Safety; Serum; Small Business Innovation Research Grant; success; System; Technology; Testing; Therapeutic; therapeutic enzyme; Tissues; trafficking; Treatment Efficacy; United States National Institutes of Health; uptake; Urine

The long-range goal of this research is to develop an enzyme replacement therapy (ERT) technology for genetic metabolic diseases that is effective in mitigating the problem of immune sensitization that has hindered previous ERT technologies. ERT drugs have been approved for treating almost a dozen lysosomal diseases (LDs), however, the induction of patient anti-ERT antibodies has emerged as a significant limitation for some of these drugs reducing their effectiveness. Because early/infantile-onset forms of LDs comprise the most severe mutations, the development of immune sensitization is more prevalent in younger patients. These children often show dramatic life-saving improvements upon treatment onset, however, progress may stop and quickly decline if these patients develop neutralizing antibodies to the ERT drug. Most current ERTs for LDs exploit the Mannose-6-Phospate (M6P) receptor for uptake into disease cells and the predominant class of anti-ERT antibodies interfere with this uptake process. However, the technology developed by BioStrategies LC uses an alternative plant RTB lectin-based mechanism for ERT cell uptake. Using the Hurler MPS I model we have shown in both MPS I lysosomal disease cell cultures and subsequent short-term in vivo mouse Phase I SBIR studies of IDUA:RTB that active enzyme is successfully delivered by RTB in the presence of neutralizing antibodies against mammalian cell derived IDUA (mcd-IDUA). Based on these promising preliminary results, our goal in this SBIR Phase II follow-on project is to demonstrate bio-distribution and long-term therapeutic effectiveness of RTB delivered ERT in Hurler mice at the high level of rigor that would support FDA approval to begin IND clinical trials. Specific aims of this Phase II project are to: 1) Assess short-term biodistribution and pharmacodynamics comparing our IDUA:RTB drug to the mcd-IDUA drug in immune-sensitized Hurler mice, and 2) Evaluate effects of anti-drug antibodies following long-term administration of the IDUA-RTB verses mcd-IDUA drugs. Success in these experiments would lay the foundation for further preclinical research leading to a successful IND application to FDA to initiate clinical trials in immune compromised Hurler patients. Our broader long-term goal is to develop this new ERT delivery system for treating immune-sensitized patients for other lysosomal and metabolic diseases.

Public Health Relevance Statement:
NARRATIVE –

Public Health Relevance:
The family of human genetic diseases represented by Hurlers Syndrome and other rare lysosomal disorders include some of the most devastating human afflictions known and the most costly to patients, their families, and the public health system. Although ERT drugs have been revolutionary in delivery treatments for these diseases, they have been prone to significant drawbacks including the development of immune sensitivity in patients after periods of treatments. This project addresses the need for delivering enzyme replacement therapeutics (ERT) drugs to patients by a new mechanism that significantly reduces or bypasses the immune sensitivity roadblock seen in current ERT drugs. The innovative RTB-ERT drug delivery technology developed in this project would further the US national goal of reducing genetic metabolic diseases and the suffering and costs associated with these diseases.

Project Terms:
Address; Affect; Animals; Antibodies; Antibody Therapy; Area; base; Benchmarking; Binding; Biodistribution; Brain; Bypass; Cell Culture Techniques; Cell Therapy; Cells; cellular pathology; Child; Childhood; Clinical Trials; cost; Data; Development; Disease; Drug Delivery Systems; effective therapy; Effectiveness; enzyme mechanism; enzyme replacement therapy; Enzymes; experimental study; Family; Foundations; Funding; Genetic; Genetic Diseases; genetic technology; Glycogen storage disease type II; Goals; Health system; Heart; Human; Human Genetics; Image; Immune; Immune System Diseases; Immunization; immunogenicity; Immunoglobulin G; Impairment; in vivo; Individual; infancy; Injections; innovation; Kidney; L-Iduronidase; Lectin; Life; Ligands; Longevity; Mammalian Cell; Mannose; Mediating; meetings; Metabolic Diseases; Modeling; mouse model; Mucopolysaccharidosis I; Mucopolysaccharidosis I H; Mucopolysaccharidosis VI; Mus; Mutation; neutralizing antibody; novel; Organ; Pathology; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; phase 1 study; Phenotype; Plants; Polysaccharides; pre-clinical; pre-clinical research; Process; Protocols documentation; Public Health; public health relevance; rare genetic disorder; receptor; Regimen; Reporting; Research; response; Route; Savings; Serum; skeletal; Small Business Innovation Research Grant; specific biomarkers; success; Surface; System; Technology; Testing; Therapeutic; therapeutic effectiveness; therapeutic enzyme; therapeutic genome editing; Tissues; treatment duration; treatment strategy; United States National Institutes of Health; uptake