R01AR079572

Gene Therapy for Glycogen Storage Disease Type III - Abstract

Glycogen Storage Disease Type III (GSD III) is an autosomal recessive inherited disorder caused by deficiency of glycogen debranching enzyme (GDE) that leads to excessive accumulation of abnormal glycogen (limit dextrin) in muscle and liver tissues. The majority of patients (~85%) have both muscle and liver involvement (GSD IIIA), while others have disease limited to the liver (GSD IIIB). In the absence of an effective therapy, patients with GSD III are experiencing progressive liver failure and muscle damage accompanied by increased morbidity and mortality.

Adeno-associated virus (AAV) mediated gene therapy has shown promise for treating inherited muscle and liver disorders with successful translation to clinical trials. However, this approach has not been advanced for GSD III because AAV is not capable of delivering the large (4.6 KB) human GDE cDNA, due to its small packaging capacity.

We have developed an innovative gene therapy approach with AAV9 in a mouse model of GSD IIIA with two key components incorporated: 1) a small bacterial GDE analog to overcome the limitation of small AAV carrying capacity; and 2) a novel immunotolerizing dual promoter to prevent cytotoxic T lymphocyte (CTL) response to the bacterial enzyme and enable long-term pullulanase expression in all affected tissues. The overall objective of this project is to identify a path forward for clinical translation of this promising therapy.

It is commonly known that the therapeutic outcomes of AAV vectors in mouse models do not always translate into humans. Current AAV serotypes, especially AAV9, transduce muscle and liver in mice with high efficiency; however, high doses of AAV9 required to transduce skeletal muscles in human patients can lead to adverse hepatotoxicity or even liver failure.

In this proposal, we aim to identify a lead therapeutic candidate AAV vector in GSD IIIA mice using high potency cross-species compatible AAV capsids (CCAAVs) containing a de-immunized transgene expression cassette to minimize gene therapy related immune responses and reduce the effective vector dose (Aim 1A). We will validate the lead AAV vector in GSD IIIA patient muscle cells and human liver chimeric mice to increase its clinical translatability (Aim 1B). We will then examine the long-term efficacy of the lead AAV vector in GSD IIIA mice (Aim 2), and test its safety and efficacy in GSD IIIA dogs (Aim 3).

Data generated from the proposed studies will lay the foundation for translating this innovative gene therapy to patients with GSD III. The concept of using a bacterial enzyme to treat human diseases through gene therapy may open up new alternatives for therapeutic development for metabolic disorders caused by defects in large genes. The immunotolerizing dual promoter technology can also be broadly used for treating other conditions that affect multiple tissues with gene therapy.

Duke University

THE NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES (NIAMS) MISSION IS TO SUPPORT RESEARCH INTO THE CAUSES, TREATMENT, AND PREVENTION OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES; TRAINING OF BASIC AND CLINICAL SCIENTISTS TO CARRY OUT THIS RESEARCH; AND DISSEMINATION OF INFORMATION ON RESEARCH PROGRESS IN THESE DISEASES. THE EXTRAMURAL PROGRAM PROMOTES AND SUPPORTS BASIC, TRANSLATIONAL, AND CLINICAL STUDIES OF SYSTEMIC RHEUMATIC AND AUTOIMMUNE DISEASES, SKIN BIOLOGY AND DISEASES, BONE BIOLOGY AND DISEASES, MUSCLE BIOLOGY AND DISEASES, AND JOINT BIOLOGY AND DISEASES AND ORTHOPAEDICS. NIAMS SYSTEMIC RHEUMATIC AND AUTOIMMUNE DISEASES PROGRAMS ADDRESS BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH, INCLUDING CLINICAL TRIALS AND OBSERVATIONAL AND MECHANISTIC STUDIES, FOCUSED ON IMMUNE-MEDIATED ARTHRITIS AND AUTOIMMUNE-RELATED ACUTE AND CHRONIC DISORDERS IN ADULTS AND CHILDREN. NIAMS SKIN BIOLOGY AND DISEASES PROGRAMS SUPPORT BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH IN SKIN, INCLUDING BOTH COMMON AND RARE SKIN DISEASES. THESE PROGRAMS INCLUDE INVESTIGATIONS OF THE BASIC MOLECULAR, CELLULAR, AND DEVELOPMENTAL BIOLOGY OF SKIN, AS WELL AS STUDIES OF SKIN AS AN IMMUNE, SENSORY, ENDOCRINE, AND METABOLIC ORGAN. NIAMS BONE BIOLOGY AND DISEASES PROGRAMS SUPPORT RESEARCH ON THE CONTROL OF BONE FORMATION, RESORPTION, AND MINERALIZATION AS WELL AS THE EFFECTS OF SIGNALING MOLECULES ON BONE CELLS. THEY SUPPORT CLINICAL STUDIES OF INTERVENTIONS TO PREVENT FRACTURES ASSOCIATED WITH OSTEOPOROSIS AND RESEARCH INTO LESS COMMON BONE DISEASES. NIAMS MUSCLE BIOLOGY AND DISEASES PROGRAMS ENCOURAGE RESEARCH ON MUSCLE DEVELOPMENTAL BIOLOGY, GROWTH, MAINTENANCE, AND HYPERTROPHY; PHYSIOLOGY OF CONTRACTION; STRUCTURAL BIOLOGY OF THE CONTRACTILE APPARATUS; DISEASE MECHANISMS; BIOMARKERS AND OUTCOME MEASURES; AND DEVELOPMENT AND CLINICAL TESTING OF THERAPIES FOR CONDITIONS INCLUDING THE MUSCULAR DYSTROPHIES. NIAMS JOINT BIOLOGY, DISEASES, AND ORTHOPAEDICS PROGRAMS SUPPORT A BROAD SPECTRUM OF RESEARCH CENTERED ON THE INTERPLAY AMONG THE BODYS MUSCLES, BONES, AND CONNECTIVE TISSUES. THEY ENCOURAGE TISSUE ENGINEERING AND REGENERATIVE MEDICINE RESEARCH, MOLECULAR BIOLOGY, IMAGING, AND CLINICAL RESEARCH, AND THE TREATMENT AND PREVENTION OF ORTHOPAEDIC CONDITIONS. NIAMS PARTICIPATES IN THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAMS. THE SBIR PROGRAM IS INTENDED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE STTR PROGRAM IS INTENDED TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.846 - Arthritis, Musculoskeletal and Skin Diseases Research

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [HHS - NIH]

Durham, North Carolina 27705 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 366% from $707,476 to $3,295,110.