Gene therapy for glycogen storage disease type III

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Baodong  Sun
Organization: DUKE UNIVERSITY
Fiscal Year: 2024
Award: $646,060
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases

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 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 does not always
translate into human. 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 led 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.

Terms: <21+ years old><AAV vector><AAV-based vector><Adeno-Associated Viruses><Adult><Adult Human><Affect><Age><Age Months><B subtilis><B. subtilis><Bacillus subtilis><Biochemical><Biological Markers><Blood><Blood Reticuloendothelial System><Blood Serum><Body Tissues><CMV><Canine Species><Canis familiaris><Capsid><Cardiac><Carrying Capacities><Cell Body><Cell-Mediated Lympholytic Cells><Cells><Chickens><Clinical Trials><Complementary DNA><Cori's Disease><Cytolytic T-Cell><Cytomegalovirus><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><DNA Therapy><DNA cassette><Data><Debrancher Deficiency><Defect><Dependoparvovirus><Dependovirus><Development><Dextrins><Disease><Disorder><Dogs><Dogs Mammals><Dose><Enhancers><Enzyme Gene><Enzymes><Female><Forbes Disease><Foundations><Gallus domesticus><Gallus gallus><Gallus gallus domesticus><Gender><Gene Transfer Clinical><Genes><Genetic Alteration><Genetic Change><Genetic Intervention><Genetic defect><Glycogen><Glycogen Debranching Enzyme><Glycogen Debranching Enzyme Deficiency><Glycogen Storage Disease Type III><Glycogenosis 3><Goals><HCMV><Hepatic Cells><Hepatic Cirrhosis><Hepatic Disorder><Hepatic Failure><Hepatic Parenchymal Cell><Hepatocyte><Hepatotoxic effect><Hepatotoxicity><Hereditary><Hereditary Disease><Histologic><Histologically><History><Human><Immune response><Immunological response><Inborn Genetic Diseases><Infant><Inherited><Inherited disorder><Innate Immune Response><Knock-out><Knockout><Laboratories><Lead><Limit Dextrinosis><Liver><Liver Cells><Liver Cirrhosis><Liver Failure><Liver Toxicity><Liver diseases><Measurement><Mediating><Metabolic Diseases><Metabolic Disorder><Mice><Mice Mammals><Modern Man><Morbidity><Morbidity - disease rate><Murine><Mus><Muscle><Muscle Cells><Muscle Disease><Muscle Disorders><Muscle Fibers><Muscle Tissue><Muscle function><Muscular Diseases><Mutation><Myocardium><Myocytes><Myopathic Conditions><Myopathic Diseases and Syndromes><Myopathic disease or syndrome><Myopathy><Myotubes><ORFs><Open Reading Frames><Organ><Outcome><Patients><Pb element><Protein Coding Region><Recording of previous events><Research><Rhabdomyocyte><Safety><Salivary Gland Viruses><Serotyping><Serum><Skeletal Fiber><Skeletal Muscle><Skeletal Muscle Cell><Skeletal Muscle Fiber><Skeletal Myocytes><Technology><Testing><Thesaurismosis><Tissues><Toxic effect><Toxic effect on liver cells><Toxicities><Translating><Translations><Urine><Voluntary Muscle><adaptive immune response><adeno associated virus group><adeno-associated viral vector><adeno-associated virus vector><adulthood><aged mice><aged mouse><ages><amylo 1,6 glucosidase deficiency><analog><autosome><beta Actin><bio-markers><biologic marker><biomarker><cDNA><canine><canine animal model><canine model><cardiac muscle><cell type><clinical candidate><clinical translation><clinically translatable><curative intervention><curative therapeutic><curative therapy><curative treatments><cytomegalovirus group><de-immunization><de-immunize><debrancher glycogen storage disease><deimmunization><deimmunize><determine efficacy><develop therapy><developmental><dietary><dog model><domestic dog><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><elderly mice><enhancer cassette><evaluate efficacy><examine efficacy><experience><expression cassette><gene cassette><gene repair therapy><gene therapy><gene-based therapy><genetic cassette><genetic therapy><genome editing><genome mutation><genomic editing><genomic therapy><glycogenosis type III><heart muscle><heavy metal Pb><heavy metal lead><hepatic body system><hepatic disease><hepatic organ system><hepatic toxicity><hepatopathy><hepatoxicity><hereditary disorder><heritable disorder><histories><host response><human disease><humanized mice><humanized mouse><immune system response><immunoresponse><improved><inborn error><inherited diseases><inherited genetic disease><inherited genetic disorder><innovate><innovation><innovative><integration cassette><intervention development><killer T cell><liver disorder><liver function><metabolism disorder><mortality><mouse model><murine model><muscular><muscular disorder><novel><old mice><prevent><preventing><promoter><promoter cassette><promotor><reporter cassette><resistance cassette><response><selectable cassette><selection cassette><sex><skeletal><stop cassette><therapeutic agent development><therapeutic candidate><therapeutic development><therapeutic outcome><therapy development><therapy outcome><transcription cassette><transcriptional cassette><transduction efficiency><transgene cassette><transgene expression><translation><treatment development><urinary><vector><β-Actin>