This is a fast-track SBIR grant proposal. As effective gene therapy (GT) products using adeno-associated viral (AAV) vectors advance to clinical applications, the translation faces critical challenge of high prevalence of aAA) antibodies (Abs) in humans. Currently, only individuals negative of aAAV-Abs are eligible for AAV GT treatment. The goal of this SBIR project is to develop a therapeutic product capable of effectively depleting Abs towards clinical application and commercialization, in order to make potentially life-saving AAV GT products available to all patients in need of administration and re-administration. To address the challenge of pre-existing aAAV-Abs, we have developed a new effective Ab-depleting protein product, antibody cleaver (AbC), based on the demonstrated IgG degrading enzymes of Streptococci (IdeS). IdeS specifically cleaves IgG of humans, primate, sheep and rabbit (but not mouse) origin. Numerous studies demonstrate effective transient IgG degradation by IdeS in animals and humans, with no detectable dose limiting toxicity. Our preliminary studies showed effective Ab depletion by an IV AbC infusion, leading to the transient clearance of pre-existing aAAV9-Abs and allowing effective transduction in rabbitized aAAV9-Abs- positive MPS IIIA mice after an IV scAAV9-hSGSH delivery. We believe that IV AbC administration offers a great tool to overcome the pre-existing aAAV-Abs for the translation of rAAV GT to treat diseases in humans. This proposal is to further develop and establish an optimal AbC Ab-depletion regimen for systemic rAAV9 gene delivery. In Phase I studies, we will identify optimal AbC product. Once validated, in Phase II, the optimal Ab-C product will be evaluated in pre-clinical studies in animal models (Aim #2, 3), to assess the efficacy and therapeutic potential of transient Ab-depletion by AbC. In Phase II, we will also optimize the AbC production procedures for scale-up manufacture towards clinical application and commercialization (Aim #4). Notably, The Phase II studies will lead to an IND and subsequent clinical trials to bridge the AbC administration with systemic scAAV9-hSGSH gene replacement therapy clinical trials in patients with MPS IIIA, for which an IND were recently submitted. More importantly, the AbC Ab depletion may offer the answer to the challenge posed by pre-existing Abs to gene therapy products using AAV and other viral vectors in general.
Public Health Relevance Statement: Project narrative: Gene therapy products using adeno-associated-virus (AAV) vector have shown to be promising for treating diseases in humans. However, AAV is widespread in humans with high prevalence of anti-AAV antibodies in human population, and currently, only individuals who do not have anti-AAV antibodies are eligible for AAV gene therapy treatment. This proposal is to develop an effective antibody-degrading protein product to transiently remove the pre-existing anti-AAV antibodies for AAV gene therapy, towards clinical application and commercialization.
Project Terms: Mice Mammals; Murine; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Patients; Primates; Primates Mammals; Production; Proteins; Oryctolagus cuniculus; Domestic Rabbit; Rabbits; Rabbits Mammals; Safety; Sheep; Ovine; Ovis; Streptococcus; Temperature; Testing; Time; Toxicology; Translations; translation; Blood Sample; Blood specimen; Procedures; Phase; Individual; Blocking Antibodies; Immunological response; host response; immune system response; immunoresponse; Immune response; Therapeutic; tool; Life; Viral; Infusion procedures; Infusion; infusions; protein purification; Animal Model; Animal Models and Related Studies; model of animal; Toxic effect; Toxicities; Histopathology; Modeling; Adverse event; Adverse Experience; Bedstraw; Cleavers; Galium; protein expression; Tissue Sample; gene replacement therapy; Address; Dose; Dose Limiting; Applications Grants; Grant Proposals; High Prevalence; Therapy Clinical Trials; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Viral Vector; Gene Delivery; Development; developmental; preclinical study; pre-clinical study; vector; determine efficacy; efficacy analysis; efficacy assessment; efficacy determination; efficacy examination; evaluate efficacy; examine efficacy; efficacy evaluation; Biodistribution; Population; Recombinant adeno-associated virus; rAAV; recombinant AAV; Recombinant adeno-associated virus (rAAV); transduction efficiency; AAV vector; adeno-associated virus vector; adeno-associated viral vector; clinical relevance; clinically relevant; clinical applicability; clinical application; murine model; mouse model; commercialization; safety testing; commercial scale manufacturing; manufacturing ramp-up; scale up batch; scale up production; upscale manufacturing; manufacturing scale-up; Phase I Study; phase 1 study; phase II study; phase 2 study; Regimen; Injections; genetic condition; genetic disorder; Genetic Diseases; Animals; Antibodies; anti-viral antibody; antiviral antibody; Viral Antibodies; cell growth; Cellular Expansion; Cellular Growth; Cells; Cell Body; Clinical Chemistry; Clinical Trials; Codon Nucleotides; Codon; Disease; Disorder; Eligibility Determination; Eligibility; Protocol Screening; Enzymes; Enzyme Gene; Face; faces; facial; gene therapy; DNA Therapy; Gene Transfer Clinical; Genetic Intervention; gene repair therapy; gene-based therapy; genetic therapy; genomic therapy; Viral Genes; Goals; Growth; Generalized Growth; Tissue Growth; ontogeny; Hematology; Human; Modern Man; Immunoglobulin G; 7S Gamma Globulin; IgG; Mus; Mice
