Gene therapy approaches for lysosomal storage disorders, a good model for the treatment of mendelian diseases

Tomanin, Rosella; Zanetti, Alessandra; Zaccariotto, Eva; D’Avanzo, Francesca; Bellettato, Cinzia Maria; Scarpa, Maurizio

doi:10.1111/j.1651-2227.2012.02674.x

Cited by 18 publications

(14 citation statements)

References 65 publications

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“…4 Besides the combined use of HSCT and ERT, other treatments for MPSs are under evaluation: substrate degradation, 42 site specific administration of ERT, 43 chaperone administration 44 and cell and genebased therapeutic approaches. [45][46][47][48][49] What are mucopolysaccharidoses for the cardiologist?…”

Section: Specific Treatmentsmentioning

confidence: 99%

Molecular Basis, Diagnosis and Clinical Management of Mucopolysaccharidoses

2013

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Mucopolysaccharidoses (MPSs) are a group of hereditary, monogenic disorders caused by lysosomal storage of glycosaminoglycans. Their incidence as a group is between 1:25,000 and 1:45,000. At present 11 different enzyme deficiencies are know to be responsible of 7 similar but distinct diseases. The diagnosis is suspected clinically but must be confirmed through biochemical, enzymatic and molecular analysis. Prenatal diagnosis is feasible for each disease. The phenotype worsens with age, due to progressive storage, and mainly involves mucosal tissue, upper airways and lungs, bones and joints, central and peripheral nervous system, heart, liver, eye and ear. Any type of MPSs, is characterized by a wide variability of phenotype ranging from a severe fetal-neonatal disease to an attenuated form diagnosed in adult individuals. Recently new treatments, like hematopoietic stem cell transplantation and enzymatic replacement therapy, became available for many of these disorders entailing the urgency of early diagnosis to allow access to therapies. Thanks to therapies these patients have a longer life than in the past and this implies that also palliative treatments, of which the cardiological ones have a prominent part, must be undertaken diligently. The cardiologist may face, more frequently than expected, with the need to diagnose a patient with MPS who was not recognized by other specialists. The echocardiographic features of these patients are typical and may help in the clinical diagnosis. The future probably deserves to these disorders other new treatments or combination therapies, which might further improve prognosis of these diseases

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Section: Specific Treatmentsmentioning

confidence: 99%

Molecular Basis, Diagnosis and Clinical Management of Mucopolysaccharidoses

2013

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“…Results in central nervous system treatment have been obtained in MPSII and MPSVII mouse models through different strategies, 6, 7, 8, 9 but the translation to humans is hampered by risk of toxicity and immune responses. 10, 11, 12, 13 Moreover, late diagnosis, lack of specimens from early symptomatic patients and the absence of in vitro models limit the elucidation of the neuro-pathogenetic events involved in the development of Hunter disease. Self-renewing neural stem cells (NSCs), capable of differentiation into neural phenotypes, create a model for dissecting neurogenesis in vivo and for investigating the onset and progression of neurodegenerative diseases in vitro .…”

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confidence: 99%

Murine neural stem cells model Hunter disease in vitro: glial cell-mediated neurodegeneration as a possible mechanism involved

et al. 2013

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Mucopolysaccharidosis type II (MPSII or Hunter Syndrome) is a lysosomal storage disorder caused by the deficit of iduronate 2-sulfatase (IDS) activity and characterized by progressive systemic and neurological impairment. As the early mechanisms leading to neuronal degeneration remain elusive, we chose to examine the properties of neural stem cells (NSCs) isolated from an animal model of the disease in order to evaluate whether their neurogenic potential could be used to recapitulate the early phases of neurogenesis in the brain of Hunter disease patients. Experiments here reported show that NSCs derived from the subventricular zone (SVZ) of early symptomatic IDS-knockout (IDS-ko) mouse retained self-renewal capacity in vitro, but differentiated earlier than wild-type (wt) cells, displaying an evident lysosomal aggregation in oligodendroglial and astroglial cells. Consistently, the SVZ of IDS-ko mice appeared similar to the wt SVZ, whereas the cortex and striatum presented a disorganized neuronal pattern together with a significant increase of glial apoptotic cells, suggesting that glial degeneration likely precedes neuronal demise. Interestingly, a very similar pattern was observed in the brain cortex of a Hunter patient. These observations both in vitro, in our model, and in vivo suggest that IDS deficit seems to affect the late phases of neurogenesis and/or the survival of mature cells rather than NSC self-renewal. In particular, platelet-derived growth factor receptor-α-positive (PDGFR-α+) glial progenitors appeared reduced in both the IDS-ko NSCs and in the IDS-ko mouse and human Hunter brains, compared with the respective healthy controls. Treatment of mutant NSCs with IDS or PDGF throughout differentiation was able to increase the number of PDGFR-α+ cells and to reduce that of apoptotic cells to levels comparable to wt. This evidence supports IDS-ko NSCs as a reliable in vitro model of the disease, and suggests the rescue of PDGFR-α+ glial cells as a therapeutic strategy to prevent neuronal degeneration.

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“…Recombinant viral-and nonviral-based gene transfer vectors have been employed that were delivered either directly into the CNS or into the systemic circulation (43)(44)(45)(46). Transplantation of stem cells that were genetically modifi ed ex vivo has also shown promise.…”

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Gene therapy for the neurological manifestations in lysosomal storage disorders

Cheng¹

2014

Journal of Lipid Research

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precise mechanistic links between these altered biochemical and cellular states and disease pathophysiology and pathogenesis remain unclear. Typically, disease severity is correlated with the level of residual activity, with individuals harboring lower levels presenting with more aggressive and severe disease manifestations. A large percentage of individuals, particularly those with signifi cantly diminished lysosomal function, also exhibit CNS involvement, the extent of which is dependent on the nature of the specifi c storage metabolites and the differential sensitivity of the resident cell types to the accumulated substrates. Although individually each LSD may be relatively rare, as a group, these disorders have an incidence of approximately 1 per 5,000 live births ( 4, 5 ).Of the approximately 50 LSDs that have been identifi ed thus far, the majority (greater than 70%) exhibit significant CNS involvement ( 6 ). This fi nding is not surprising given that lysosomes and related organelles are ubiquitously present in most cell types and are involved not only in recycling cellular debris but also in maintaining cellular homeostasis ( 7-9 ). Irrespective of the LSD, these CNS diseases are typically characterized by generalized infl ammation and neurodegeneration in multiple brain regions. In a subset of the diseases, altered calcium homeostasis and oxidative stress may also contribute to the overall pathology ( 10 ). Moreover, each specifi c disease may initially present with a unique temporal and spatial alteration that is dictated by the nature of the storage metabolites prior to the development of a more generalized global derangement ( 11 ). In some diseases, the symptoms are evident in neonates, whereas in others, they become apparent only in early childhood. Consequently, some LSDs may require early therapeutic intervention to affect broad and potentially all regions of the CNS. The lysosomal storage disorders (LSDs) are a heterogeneous group of inherited metabolic diseases that result from a defi ciency in one or more of the 80 enzymes or transporters that normally reside within the lysosomal compartment ( 1-3 ). A reduction or loss of one or more of these activities results in the progressive and relentless accumulation of undegraded macromolecules, a consequent derangement of proper lysosomal and autophagosomal functions, and ultimately, cellular demise. However, the

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Gene therapy approaches for lysosomal storage disorders, a good model for the treatment of mendelian diseases

Abstract: Lysosomal storage disorders represent a good model of study of gene therapeutic procedures that are, or could be, relevant to the treatment of several other mendelian diseases.

Cited by 18 publications

References 65 publications

Molecular Basis, Diagnosis and Clinical Management of Mucopolysaccharidoses

Molecular Basis, Diagnosis and Clinical Management of Mucopolysaccharidoses

Murine neural stem cells model Hunter disease in vitro: glial cell-mediated neurodegeneration as a possible mechanism involved

Gene therapy for the neurological manifestations in lysosomal storage disorders

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