Similar Therapeutic Efficacy Between a Single Administration of Gene Therapy and Multiple Administrations of Recombinant Enzyme in a Mouse Model of Lysosomal Storage Disease

Ferla, Rita; Claudiani, Pamela; Cotugno, Gabriella; Saccone, Paola; Leonibus, Elvira De; Auricchio, Alberto

doi:10.1089/hum.2013.213

Cited by 31 publications

(48 citation statements)

References 46 publications

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“…The fact that GDE is a large cytosolic protein of 175 kDa with two different enzymatic domains 32 complicates the design of AAV vectors expressing the enzyme, and it does not allow for the development of gene therapy strategies based on cross-correction. 19,33,34 To overcome this limitation, we developed a dual AAV vector strategy 13,14,20,35 to express GDE transgene in liver and muscle.…”

Section: Discussionmentioning

confidence: 99%

Rescue of GSDIII Phenotype with Gene Transfer Requires Liver- and Muscle-Targeted GDE Expression

et al. 2018

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Glycogen storage disease type III (GSDIII) is an autosomal recessive disorder caused by a deficiency of glycogen-debranching enzyme (GDE), which results in profound liver metabolism impairment and muscle weakness. To date, no cure is available for GSDIII and current treatments are mostly based on diet. Here we describe the development of a mouse model of GSDIII, which faithfully recapitulates the main features of the human condition. We used this model to develop and test novel therapies based on adeno-associated virus (AAV) vector-mediated gene transfer. First, we showed that overexpression of the lysosomal enzyme alpha-acid glucosidase (GAA) with an AAV vector led to a decrease in liver glycogen content but failed to reverse the disease phenotype. Using dual overlapping AAV vectors expressing the GDE transgene in muscle, we showed functional rescue with no impact on glucose metabolism. Liver expression of GDE, conversely, had a direct impact on blood glucose levels. These results provide proof of concept of correction of GSDIII with AAV vectors, and they indicate that restoration of the enzyme deficiency in muscle and liver is necessary to address both the metabolic and neuromuscular manifestations of the disease.

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Section: Discussionmentioning

confidence: 99%

Rescue of GSDIII Phenotype with Gene Transfer Requires Liver- and Muscle-Targeted GDE Expression

et al. 2018

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“…This results in long-term therapeutic efficacy in rodent and feline models of MPS VI. 9–13 Gene therapy was at least as effective as weekly infusions of recombinant human ARSB (rhARSB) in a mouse model of MPS VI, 12 suggesting that it may be preferable to ERT, especially because it potentially requires a single intravenous administration. This bodes well for further investigating the safety and efficacy of intravenous administrations of AAV2/8 in patients with MPS VI.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of Anti–Adeno-Associated Virus Serotype 8 Neutralizing Antibodies and Arylsulfatase B Cross-Reactive Immunologic Material in Mucopolysaccharidosis VI Patient Candidates for a Gene Therapy Trial

et al. 2015

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Recombinant vectors based on adeno-associated virus serotype 8 (AAV8) have been successfully used in the clinic and hold great promise for liver-directed gene therapy. Preexisting immunity against AAV8 or the development of antibodies against the therapeutic transgene product might negatively affect the outcomes of gene therapy. In the prospect of an AAV8-mediated, liver-directed gene therapy clinical trial for mucopolysaccharidosis VI (MPS VI), a lysosomal storage disorder caused by arylsulfatase B (ARSB) deficiency, we investigated in a multiethnic cohort of MPS VI patients the prevalence of neutralizing antibodies (Nab) to AAV8 and the presence of ARSB cross-reactive immunologic material (CRIM), which will either affect the efficacy of gene transfer or the duration of phenotypic correction. Thirty-six MPS VI subjects included in the study harbored 45 (62.5%) missense, 13 (18%) nonsense, 9 (12.5%) frameshift (2 insertions and 7 deletions), and 5 (7%) splicing ARSB mutations. The detection of ARSB protein in 24 patients out of 34 (71%) was predicted by the type of mutations. Preexisting Nab to AAV8 were undetectable in 19/33 (58%) analyzed patients. Twelve out of 31 patients (39%) tested were both negative for Nab to AAV8 and CRIM-positive. In conclusion, this study allows estimating the number of MPS VI patients eligible for a gene therapy trial by intravenous injections of AAV8.

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“…However, pre-existing neutralizing antibodies for AVV8 negatively affected the outcomes of this therapy (103). In a study in MPS VI mice, the efficacy of a single administration of AVV-mediated gene therapy targeting the liver was compared to weekly ERT (104). Both therapies had a similar impact on GAG levels in urine and tissues and animal motor performance, while improvements in skeletal skull abnormalities were slightly better with gene therapy.…”

Section: Future Directionsmentioning

confidence: 99%

Mucopolysaccharidosis VI pathophysiology diagnosis and treatment

Harmatz¹

2017

Front Biosci

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Mucopolysaccharidosis VI (MPS VI), or Maroteaux-Lamy syndrome, is an autosomal recessive lysosomal storage disorder caused by deficient activity of the enzyme arylsulfatase B (ASB). Progressive accumulation of glycosaminoglycans (GAGs) in organs and tissues leads to the development of multisystem clinical manifestations. The presentation of MPS VI is genotypically and phenotypically diverse, with a large number of potential disease-causing mutations and a phenotypic spectrum ranging from very slowly to very rapidly progressing disease. Diagnosis of MPS VI relies on presence of clinical features, increased GAG levels in urine or low ASB activity in dried blood spots, and measurement of enzyme activity levels in leukocytes or fibroblasts. The management of MPS VI involves enzyme replacement therapy and medical and surgical treatment of disease manifestations. Liquid chromatography/tandem mass spectrometry of GAG-derived disaccharides in blood or urine is emerging as a valuable method in the diagnosis, prognosis and assessment of therapeutic efficacy in MPS VI.

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Similar Therapeutic Efficacy Between a Single Administration of Gene Therapy and Multiple Administrations of Recombinant Enzyme in a Mouse Model of Lysosomal Storage Disease

Cited by 31 publications

References 46 publications

Rescue of GSDIII Phenotype with Gene Transfer Requires Liver- and Muscle-Targeted GDE Expression

Rescue of GSDIII Phenotype with Gene Transfer Requires Liver- and Muscle-Targeted GDE Expression

Prevalence of Anti–Adeno-Associated Virus Serotype 8 Neutralizing Antibodies and Arylsulfatase B Cross-Reactive Immunologic Material in Mucopolysaccharidosis VI Patient Candidates for a Gene Therapy Trial

Mucopolysaccharidosis VI pathophysiology diagnosis and treatment

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