Hematopoietic Stem Cell Gene Therapy for Storage Disease: Current and New Indications

Biffi, Alessandra

doi:10.1016/j.ymthe.2017.03.025

Cited by 76 publications

(99 citation statements)

References 64 publications

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“…Bone marrow transplantation (BMT) was the most used approach before alternative treatment options were available. The rationale is that transplanted healthy donor cells will contribute to the tissue macrophage populations and become permanent sources of enzyme (Biffi, 2017). This approach was particularly aimed at treating patients with severe CNS effects (Biffi, 2017).…”

Section: Currently Explored Therapeutic Avenuesmentioning

confidence: 99%

Lysosomal storage disorders – challenges, concepts and avenues for therapy: beyond rare diseases

2019

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The pivotal role of lysosomes in cellular processes is increasingly appreciated. An understanding of the balanced interplay between the activity of acidic hydrolases, lysosomal membrane proteins and cytosolic proteins is required. Lysosomal storage diseases (LSDs) are characterized by disturbances in this network and by intralysosomal accumulation of substrates, often only in certain cell types. Even though our knowledge of these diseases has increased and therapies have been established, many aspects of the molecular pathology of LSDs remain obscure. This Review aims to discuss how lysosomal storage affects functions linked to lysosomes, such as membrane repair, autophagy, exocytosis, lipid homeostasis, signalling cascades and cell viability. Therapies must aim to correct lysosomal storage not only morphologically, but reverse its (patho)biochemical consequences. As different LSDs have different molecular causes, this requires custom tailoring of therapies. We will discuss the major advantages and drawbacks of current and possible future therapies for LSDs. Study of the pathological molecular mechanisms underlying these 'experiments of nature' often yields information that is relevant for other conditions found in the general population. Therefore, more common diseases may profit from a correction of impaired lysosomal function.

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Section: Currently Explored Therapeutic Avenuesmentioning

confidence: 99%

Lysosomal storage disorders – challenges, concepts and avenues for therapy: beyond rare diseases

2019

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“…To establish autologous HSCT in MPS, genetic modification of the patient's cells is needed to correct the biochemical defect and restore enzyme activity. One way to accomplish this is to use integrating viruses [72]. Proof of the therapeutic potential of this strategy for MPS has been accomplished with lentiviral vectors.…”

Section: Ex Vivo Lentiviral Modification Of Hematopoietic Stem and Prmentioning

confidence: 99%

Genome Editing for Mucopolysaccharidoses

Poletto

Baldo

Gomez‐Ospina

2020

IJMS

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Genome editing holds the promise of one-off and potentially curative therapies for many patients with genetic diseases. This is especially true for patients affected by mucopolysaccharidoses as the disease pathophysiology is amenable to correction using multiple approaches. Ex vivo and in vivo genome editing platforms have been tested primarily on MSPI and MPSII, with in vivo approaches having reached clinical testing in both diseases. Though we still await proof of efficacy in humans, the therapeutic tools established for these two diseases should pave the way for other mucopolysaccharidoses. Herein, we review the current preclinical and clinical development studies, using genome editing as a therapeutic approach for these diseases. The development of new genome editing platforms and the variety of genetic modifications possible with each tool provide potential applications of genome editing for mucopolysaccharidoses, which vastly exceed the potential of current approaches. We expect that in a not-so-distant future, more genome editing-based strategies will be established, and individual diseases will be treated through multiple approaches.

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“…While treatment options for certain LSDs are still limited, therapeutic options for MPS have advanced significantly over the past decade. Enzyme replacement therapy (ERT) is now available for four MPS disorders (MPS I, MPS II, MPS IVA, and MPS VI), and hematopoietic stem cell transplantation has demonstrated effectiveness in some patients (Biffi, ; Vairo et al., ; Valayannopoulos, ). In addition, novel therapeutic approaches are currently being studied for LSDs including gene therapy, substrate reduction therapy, and chemical chaperone therapy (Macauley, ; Rastall & Amalfitano, ; Valayannopoulos, ).…”

Section: Clinical Relevancementioning

confidence: 99%

“…The primary goal of therapy in individuals with LSDs is to preserve or restore function by removing excess material accumulated in the lyso- (Biffi, 2017;Vairo et al, 2015;Valayannopoulos, 2013). In addition, novel therapeutic approaches are currently being studied for LSDs including gene therapy, substrate reduction therapy, and chemical chaperone therapy (Macauley, 2016;Rastall & Amalfitano, 2015;Valayannopoulos, 2013).…”

Section: Treatment Optionsmentioning

confidence: 99%

Mucopolysaccharidosis type VI (MPS VI) and molecular analysis: Review and classification of published variants in theARSBgene

et al. 2018

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Maroteaux–Lamy syndrome (MPS VI) is an autosomal recessive lysosomal storage disorder caused by pathogenic ARSB gene variants, commonly diagnosed through clinical findings and deficiency of the arylsulfatase B (ASB) enzyme. Detection of ARSB pathogenic variants can independently confirm diagnosis and render genetic counseling possible. In this review, we collect and summarize 908 alleles (201 distinct variants, including 3 polymorphisms previously considered as disease‐causing variants) from 478 individuals diagnosed with MPS VI, identified from literature and public databases. Each variant is further analyzed for clinical classification according to American College of Medical Genetics and Genomics (ACMG) guidelines. Results highlight the heterogeneity of ARSB alleles, with most unique variants (59.5%) identified as missense and 31.7% of unique alleles appearing once. Only 18% of distinct variants were previously recorded in public databases with supporting evidence and clinical significance. ACMG recommends publishing clinical and biochemical data that accurately characterize pathogenicity of new variants in association with reporting specific alleles. Variants analyzed were sent to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), and MPS VI locus‐specific database (http://mps6-database.org) where they will be available. High clinical suspicion coupled with diagnostic testing for deficient ASB activity and timely submission and classification of ARSB variants with biochemical and clinical data in public databases is essential for timely diagnosis of MPS VI.

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Hematopoietic Stem Cell Gene Therapy for Storage Disease: Current and New Indications

Cited by 76 publications

References 64 publications

Lysosomal storage disorders – challenges, concepts and avenues for therapy: beyond rare diseases

Lysosomal storage disorders – challenges, concepts and avenues for therapy: beyond rare diseases

Genome Editing for Mucopolysaccharidoses

Mucopolysaccharidosis type VI (MPS VI) and molecular analysis: Review and classification of published variants in theARSBgene

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