Duchenne's muscular dystrophy (DMD) is a severe, incurable, X-linked recessive disorder resulting in chronic muscle wasting caused by any of >7,000 mutations in the dystrophin gene. Wheelchair dependency typically starts around 12 years, assisted ventilation is generally required by 20 years, and life expectancy is about 27 years. Unfortunately, dystrophin is very large, comprising 3,685 amino acids and an mRNA of 14kb, complicating delivery of complete dystrophin via adeno-associated virus (AAV), which is limited by a strict payload limit of 5kb. The ideal gene therapy for DMD would be long-term replacement of the complete dystrophin protein. One option other than AAV would be lentivirus (LV), which has been used to deliver full-length dystrophin in vitro. GigaMune has developed a novel next-generation LV platform (GigaLentiTM) for in vivo delivery of any gene to any cell in vivo. The basis of GigaLentiTM is an abrogated fusogenic pseudotype which leverages cell-surface targeting by an antibody fragment (scFv) for highly efficient, cell type-specific gene delivery. We have engineered GigaLentiTM to specifically deliver gene payloads to T and B cells in vitro, but we have not yet engineered muscle-specific LVs. The Specific Aim of this Phase I SBIR project is to use in vitro models to develop a novel lentiviral technology for efficient and specific delivery of the full-length dystrophin gene to muscle cells for modulation of DMD.
Public Health Relevance Statement: PROJECT NARRATIVE Project Title: Delivery of Full Length Dystrophin to Muscle Cells for DMD Gene Therapy Organization: GigaMune Inc. PI: David Johnson, Ph.D. Gene therapy has the promise to dramatically improve clinical outcomes for patients with Duchenne's muscular dystrophy (DMD), but current methods do not provide full-length dystrophin for patients, reducing efficacy. We are developing a new therapeutic method for DMD patients which delivers full-length dystrophin to muscle cells.
Project Terms: Acceleration; Adeno-Associated Viruses; Dependoparvovirus; adeno associated virus group; Dependovirus; aminoacid; Amino Acids; Automobile Driving; driving; B-Lymphocytes; B blood cells; B cell; B cells; B-Cells; B-cell; Biotechnology; Biotech; Cells; Cell Body; Control Groups; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Duchenne muscular dystrophy; Duchene; Duchenne; Duchenne-Griesinger syndrome; Ellis-van Creveld (EvC) syndrome; Pseudohypertrophic Muscular Dystrophy; X-linked dilated cardiomyopathy; X-linked muscular dystrophy; X-linked recessive muscular dystrophy; benign X-linked recessive muscular dystrophy; childhood pseudohypertrophic muscular dystrophy; classic X-linked recessive muscular dystrophy; mild X-linked recessive muscular dystrophy; progressive muscular dystrophy of childhood; pseudohypertrophic adult muscular dystrophy; pseudohypertrophic muscular paralysis; Economics; economic; Engineering; Exons; gene therapy; DNA Therapy; Gene Transfer Clinical; Genetic Intervention; gene repair therapy; gene-based therapy; genetic therapy; genomic therapy; Genes; Grant; Human; Modern Man; Immunoglobulin Fragments; Antibody Fragments; In Vitro; Life Expectancy; Methods; mRNA Precursor; Pre-mRNA; RNA, Messenger, Precursors; Muscle; Muscle Tissue; muscular; Muscular Atrophy; Muscle Atrophy; muscle breakdown; muscle degradation; muscle deterioration; muscle loss; muscle wasting; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Occupations; Jobs; Professional Positions; Paper; Patients; Production; Proteins; Publishing; Messenger RNA; mRNA; Specificity; T-Lymphocyte; T-Cells; thymus derived lymphocyte; Technology; Testing; Wheelchairs; Wheel Chairs; mobile assistance device; mobile assistance system; mobile assistive device; mobile assistive system; Work; Dystrophin; Antisense Oligonucleotides; Anti-Sense Oligonucleotides; Antisense Agent; anti-sense agent; anti-sense oligo; antisense oligo; gRNA; Guide RNA; promotor; promoter; improved; Chronic; Clinical; Phase; Variation; Variant; Lentivirinae; Lentivirus; Link; Training; Cardiac Muscle Cells; Cardiocyte; Heart Muscle Cells; Heart myocyte; cardiomyocyte; Cardiac Myocytes; Cell Surface Proteins; Voluntary Muscle; Skeletal Muscle; Myotubes; Rhabdomyocyte; Skeletal Fiber; Skeletal Muscle Cell; Skeletal Muscle Fiber; Skeletal Myocytes; Muscle Fibers; Tropism; Therapeutic; Nature; Dependence; cell type; American; Muscle Cells; Myocytes; muscle pharmacology; novel; Cell surface; drug development; Integrin alpha Subunits; Integrin a Subunits; alpha Integrins; a-Integrins; Integrin alpha Chains; Molecular Interaction; Binding; Address; Length; Dose; Doctor of Philosophy; Ph.D.; PhD; Mutate; in vitro Assay; in vitro Model; in vivo; Patient-Focused Outcomes; Patient outcome; Patient-Centered Outcomes; patient oriented outcomes; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Transcript; Gene Delivery; muscle engineering; immunogenicity; next generation; transduction efficiency; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; murine model; mouse model; cell transduction; transduced cells; cellular transduction; patient population; birth complications; delivery complications; CRISPR approach; CRISPR based approach; CRISPR method; CRISPR methodology; CRISPR technique; CRISPR technology; CRISPR tools; CRISPR-CAS-9; CRISPR-based method; CRISPR-based technique; CRISPR-based technology; CRISPR-based tool; CRISPR/CAS approach; CRISPR/Cas method; CRISPR/Cas9; CRISPR/Cas9 technology; Cas nuclease technology; Clustered Regularly Interspaced Short Palindromic Repeats approach; Clustered Regularly Interspaced Short Palindromic Repeats method; Clustered Regularly Interspaced Short Palindromic Repeats methodology; Clustered Regularly Interspaced Short Palindromic Repeats technique; Clustered Regularly Interspaced Short Palindromic Repeats technology; CRISPR/Cas technology; lipid based nanoparticle; lipid nanoparticle; ventilation
