Preclinical Dose-Finding Study With a Liver-Tropic, Recombinant AAV-2/8 Vector in the Mouse Model of Galactosialidosis

Hu, Huimin; Gomero, Elida; Bonten, Erik; Gray, John T.; Allay, James A.; Wu, Yanan; Wu, Jianrong; Calabrese, Christopher; Nienhuis, Arthur W.; d’Azzo, Alessandra

doi:10.1038/mt.2011.227

Cited by 33 publications

(40 citation statements)

References 33 publications

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“…They were also capable in carrying out their everyday activities such as mating, litter delivery, nest making, taking care of newborn pups and other behavioral acts. While such improvement has not been reported in twi mice, reversal of infertility has been demonstrated in another mouse model of a lysosomal storage disease 39 . Activity patterns and exploratory behavior of our treated mice were comparable to age-matched wild-type mice (Figure 4a-d).…”

Section: Discussionmentioning

confidence: 96%

Extended Normal Life After AAVrh10-mediated Gene Therapy in the Mouse Model of Krabbe Disease

et al. 2012

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Globoid cell leukodystrophy (GLD) or Krabbe disease is a neurodegenerative disorder caused by the deficiency of the lysosomal enzyme galactocerebrosidase (GALC). This deficiency results in accumulation of certain galactolipids including psychosine which is cytotoxic for myelin-producing cells. Treatment of human patients at this time is limited to hematopoietic stem cell transplantation (HSCT) that appears to slow the progression of the disease when performed in presymptomatic patients. In this study, adeno-associated virus (AAV) serotype rh10-(AAVrh10) expressing mouse GALC was used in treating twitcher (twi) mice, the mouse model of GLD. The combination of intracerebroventricular, intracerebellar, and intravenous (iv) injection of viral particles in neonate twi mice resulted in high GALC activity in brain and cerebellum and moderate to high GALC activity in spinal cord, sciatic nerve, and some peripheral organs. Successfully treated mice maintained their weight with no or very little twitching, living up to 8 months. The physical activities of the long-lived treated mice were comparable to wild type for most of their lives. Treated mice showed normal abilities to mate, to deliver pups, to nurse and to care for the newborns. This strategy alone or in combination with other therapeutic options may be applicable to treatment of human patients.

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Section: Discussionmentioning

confidence: 96%

Extended Normal Life After AAVrh10-mediated Gene Therapy in the Mouse Model of Krabbe Disease

et al. 2012

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“…Genomic sequencing approaches, such as whole-genome and whole-exome sequencing, have demonstrated their potential to improve outcomes through identifying more effective treatments or inform better patient management [Bainbridge et al 2011; Worthey et al 2011]. Currently, there are preclinical trials for galactosialidosis and since WES has identified her diagnosis, she may benefit from a specific therapy in the near future [Hu et al 2012]. …”

Section: Discussionmentioning

confidence: 99%

Clinical utility of whole-exome sequencing in rare diseases: Galactosialidosis

Prada

Gonzaga‐Jauregui

Tannenbaum

et al. 2014

European Journal of Medical Genetics

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Rare genetic disorders can go undiagnosed for years as the entire spectrum of phenotypic variation is not well characterized given the reduced number of patients reported in the literature and the low frequency at which these occur. Moreover, the current paradigm for clinical diagnostics defines disease diagnosis by a specified spectrum of phenotypic findings; when such parameters are either missing, or other findings not usually observed are seen, the phenotype driven approach to diagnosis may result in a specific etiological diagnosis not even being considered within the differential diagnosis. The novel implementation of genomic sequencing approaches to investigate rare genetic disorders is allowing not only the discovery of new genes, but also the phenotypic expansion of known Mendelian genetic disorders. Here we report the detailed clinical assessment of a patient with a rare genetic disorder with undefined molecular diagnosis. We applied whole-exome sequencing to this patient and unaffected parents in order to identify the molecular cause of her disorder. We identified compound heterozygous mutations in the CTSA gene, responsible for causing galactosialidosis; the molecular diagnosis was further confirmed by biochemical studies. This report expands on the clinical spectrum of this rare lysosomal disorder and exemplifies how genomic approaches are further elucidating the characterization and understanding of genetic diseases.

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“…The rescue of PPCA and Neu1 activities resulted in a dramatic improvement of tissue architecture in all visceral organs tested. Remarkably, mice injected with intermediate or high dose of rAAV showed normal PPCA expression in the choroid plexus, accompanied by clearance of lysosomal storage 60 . No adverse side effects have been identified and no difference in heart and lung morphology has been observed.…”

Section: Investigated and Emerging Therapies For Gsmentioning

confidence: 97%

“…The strategy was based on the use of a recombinant adeno associated viral (rAAV) vector expressing human PPCA under the control of a liver-specific promoter (scAAV2/8LP1PPCA) 60 . The assumption was that overexpression of the enzyme restricted to the liver would minimize potential toxicity and still afford correction of systemic disease via sustained secretion of the precursor protein into the circulation followed by its uptake by cells of neighboring or distant organs.…”

Section: Investigated and Emerging Therapies For Gsmentioning

confidence: 99%

Galactosialidosis: historic aspects and overview of investigated and emerging treatment options

Annunziata

d’Azzo

2016

Expert Opinion on Orphan Drugs

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Introduction Galactosialidosis is a glycoprotein storage disease caused by mutations in the CTSA gene, encoding lysosomal protective protein/cathepsin A (PPCA). The enzyme’s catalytic activity is distinct from its protective function towards β-galactosidase (β-GAL) and neuraminidase 1 (NEU1), with which PPCA forms a complex. In this configuration the two glycosidases acquire their full activity and stability in lysosomes. Deficiency of PPCA results in combined NEU1/β-GAL deficiency. Because of its low incidence, galactosialidosis is considered an orphan disorder with no therapy yet available. Areas covered This review gives a historic overview on the discovery of PPCA, which defined galactosialidosis as a new clinical entity; the evidence for the existence of the PPCA/NEU1/β-GAL complex; the clinical forms of galactosialidosis and disease-causing CTSA mutations. Ppca−/− mice have proven to be a suitable model to test different therapeutic approaches, paving the way for the development of clinical trials for patients with galactosialidosis. Expert opinion Improved understanding of the molecular bases of disease has sparked renewed incentive from clinicians and scientists alike to develop therapies for rare conditions, like GS, and has increased the willingness of biotech companies to invest in the manufacturing of new therapeutics. Both ERT and gene therapy may become available to patients in the near future.

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Preclinical Dose-Finding Study With a Liver-Tropic, Recombinant AAV-2/8 Vector in the Mouse Model of Galactosialidosis

Cited by 33 publications

References 33 publications

Extended Normal Life After AAVrh10-mediated Gene Therapy in the Mouse Model of Krabbe Disease

Extended Normal Life After AAVrh10-mediated Gene Therapy in the Mouse Model of Krabbe Disease

Clinical utility of whole-exome sequencing in rare diseases: Galactosialidosis

Galactosialidosis: historic aspects and overview of investigated and emerging treatment options

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