This is a proposal to test the feasibility of using triplex molecules for possible use as a therapeutic to correct two common gene mutations that result in Hurler Syndrome (HS). Lysosomal storage diseases (LSDs), such as HS, represent a diverse collection of monogenic disorders that have devastating clinical features. LSDs are caused by mutations in genes that encode lysosomal enzymes and other proteins that are critical for lysosomal function. HS is caused by mutations in the 1-L-iduronidase gene (IDUA). For many LSDs, treatment consists of enzyme replacement therapy and supportive care. However, enzyme replacement therapy costs from $90,000 to $565,000 per patient. Alternatively, allogeneic hematopoietic stem cell transplantation (HSCT) represents a highly effective treatment. However, allogeneic HSCT requires an HLA-matched donor, is associated with significant morbidity and mortality and is expensive, about $200,000 per patient. Genetic modification of autologous HSCT, using CD34+ cells, is emerging as a viable therapeutic alternative to allogeneic HSCT. Autologous HSCT is preferred because it is far less expensive and safer than allogeneic HSCT. One emerging approach to targeted genome modification in CD34+ cells is the use of triplex-forming oligonucleotides and peptide nucleic acids. These molecules bind to duplex DNA in a sequence-specific manner and stimulate recombination when combined with donor DNA molecules. Gene modification occurs via recruitment of the cell's own DNA repair machinery, without the need for viral vectors. Viral vectors have proven problematic in such therapies. Our Specific Aim is to test the feasibility of using triplex molecules to correct two common gene mutations in the IDUA gene that are found in up to 70% of affected Caucasians. For this technology to be viable as a commercial therapy, we must demonstrate that we can achieve a success rate of at least 10% for correction of our gene target in CD34+ cells. Next, we must demonstrate that at least 25% of these modified, human CD34+ cells engraft and properly differentiate in a mouse model of stem cell transplantation. In Phase II, we will carry out developmental and IND enabling studies to move this technology toward clinical studies.
Public Health Relevance: Hurler Syndrome (HS), a devastating genetic disease that results in multiple organ failure with progressive deterioration in the central nervous system, is caused by mutations in a single gene that is involved in the processing of large sugar molecules within compartments in our cells. Helix Therapeutics is proposing to develop a therapeutic gene targeting protocol to correct the two gene mutations that are responsible for causing 70% of the cases of HS. Our protocol would repair these mutations in isolated blood stem cells from HS patients and then reintroduce the corrected cells back into the patient with the potential of having a significant impact on the symptoms of the disease.
Thesaurus Terms: Address;Affect;Allogenic;Anderson-Fabry Disease;Angiokeratoma Corporis Diffusum;Autologous;Back;Binding;Binding (Molecular Function);Biosynthetic Proteins;Blood;Blood - Brain Barrier Anatomy;Blood-Brain Barrier;Cd34;Cd34 Gene;Caucasian;Caucasian Race;Caucasians;Caucasoid;Caucasoid Race;Cells;Central Nervous System;Cerebroside Lipidosis Syndrome;Clinical;Clinical Research;Clinical Study;Collection;Dna;Dna Alteration;Dna Damage Repair;Dna Recombination;Dna Repair;Dna Mutation;Dna Recombination (Naturally Occurring);Deoxyribonucleic Acid;Deterioration;Development;Disease;Disorder;Dorsum;Ellis-Sheldon Syndrome;Engraftment;Enzymes;Fabry Disease;Fabry's Disease;Frequencies (Time Pattern);Frequency;Gaucher Disease;Gaucher's Disease;Gauchers Disease;Gene Alteration;Gene Mutation;Gene Targeting;Genes;Genetic;Genetic Alteration;Genetic Change;Genetic Condition;Genetic Diseases;Genetic Recombination;Genetic Defect;Genetic Mutation;Genome;Glucocerebrosidase Deficiency Disease;Glucosylceramide Beta-Glucosidase Deficiency Disease;Glycosaminoglycan Alpha-L-Iduronohydrolase;Hosp;Hpca1;Hsc Transplantation;Harvest;Hb Ss Disease;Hbss Disease;Health Care Providers;Health Personnel;Healthcare Providers;Healthcare Worker;Hemato-Encephalic Barrier;Hematologist;Hematopoietic Stem Cell Transplantation;Hemoglobin S Disease;Hemoglobin Sickle Cell Disease;Hemoglobin Sickle Cell Disorder;Hereditary Disease;Hereditary Metabolic Disorder;Hospital Formularies;Hospitals;Human;Human, General;Hurler Syndrome Gargoylism;Hurler Syndrome;Hurler's Disease;Hurler's Syndrome;Iduronidase;Inborn Errors Of Metabolism;Incidence;Johnie Mcl Syndrome;L-Iduronidase;Laboratories;Legal Patent;Licensing;Lipochondrodystrophy;Live Birth;Lysosomal Enzyme Disorders;Lysosomal Storage Diseases;Mof Syndrome;Mps I H;Mammals, Mice;Man (Taxonomy);Man, Modern;Marketing;Metabolism, Inborn Errors;Mice;Modification;Molecular Disease;Molecular Interaction;Morbidity;Morbidity - Disease Rate;Mortality;Mortality Vital Statistics;Mother Cells;Mucopolysaccharidosis I H;Multiple Organ Failure;Murine;Mus;Mutation;Nervous System, Cns;Neuraxis;Neurologic;Neurological;Nonsense Mutation;Occidental;Oligo;Oligonucleotides;Organ Dysfunction Syndrome, Multiple;Pna;Patents;Patients;Peptide Nucleic Acids;Pfaundler-Hurler Syndrome;Pharmaceutical Agent;Pharmaceuticals;Pharmacologic Substance;Pharmacological Substance;Phase;Process;Progenitor Cell Transplantation;Progenitor Cells;Protein Replacement Therapy;Proteins;Protocol;Protocols Documentation;Qualifying;Recombinant Proteins;Recombination;Recombination, Genetic;Reticuloendothelial System, Blood;Sequence Alteration;Sickle Cell Anemia;Site;Stem Cell Transplantation;Stem Cell Transplant;Stem Cells;Supportive Therapy;Supportive Care;Symptoms;Targetings, Gene;Technology;Testing;Thalassemia;Therapeutic;Transplantation;United States;Universities;Unscheduled Dna Synthesis;Vial;Vial Device;Viral Vector;Work;Alpha Galactosidase Deficiency;Alpha-L-Idosiduronase;Alpha-L-Iduronidase;Base;Blood Brain Barrier;Ceramide Trihexosidosis;Chondro-Osteodystrophy-Corneal;Common Treatment;Cost;Design;Designing;Disease /Disorder;Disease-Causing Mutation;Disease/Disorder;Dysostotic Idiocy-Gargoylism-Lipochondrodystrophy Syndrome;Effective Therapy;Enzyme Replacement Therapy;Familial Splenic Anemia;Gargoylism;Gene Product;Genetic Disorder;Genetic Element;Genetic Recombination;Genetics;Genome Mutation;Glucocerebrosidosis;Glucosylceramidase Deficiency;Glucosylceramide Lipidosis;Health Care Personnel;Health Care Worker;Health Provider;Healthcare Personnel;Hereditary Disorder;Inborn Lysosomal Enzyme Disorder;Inborn Metabolism Disorder;Lipoid Histiocytosis (Kerasin Type);Medical Personnel;Medical Specialist;Member;Mouse Model;Multiple Organ System Failure;Novel;Opacities-Hepatosplenomegaly Mental Deficiency Syndrome;Repair;Repaired;Sickle Cell Disease;Sickle Disease;Sicklemia;Success;Sugar;Therapeutic Gene;Transplant;Treatment Provider;Triple Helix;University;White Race
