Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome

Mucopolysaccharidosis-plus syndrome (MPS-PS) is a novel autosomal recessive disorder caused by a mutation in the VPS33A gene. This syndrome presents with typical symptoms of mucopolysaccharidosis, as well as congenital heart defects, renal, and hematopoietic system disorders. To date, twenty-four patients have been described. There is no specific therapy for MPS-PS; clinical management is therefore limited to symptoms management. The clinical course is rapidly progressive, and most patients die before 1–2 years of age. We describe a currently 6-year-old male patient with MPS-PS presenting with multiorgan involvement. Symptoms started at four months of age when he progressively suffered from numerous acute and potentially life-threatening events. When he was two years old, he developed secondary hemophagocytic lymphohistiocytosis (HLH), which was successfully treated with steroids. To date, this child represents the oldest patient affected by MPS-PS described in the literature and the first one presenting with a life-threatening secondary HLH. The prolonged steroid treatment allowed a stabilization of his general and hematological conditions and probably determined an improvement of his psychomotor milestones and new neurological acquisitions with an improvement of quality of life. HLH should be suspected and adequately treated in MPS-PS patients presenting with suggestive symptoms of the disease. The usefulness of a prolonged steroid treatment to improve the clinical course of children with MPS-PS deserves further investigation.

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“…Accordingly, more effective and feasible therapies are required. Clinical trials for the efficacy of gene therapy in MPS I are ongoing [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Mucopolysaccharidosis-Plus Syndrome, a Rapidly Progressive Disease: Favorable Impact of a Very Prolonged Steroid Treatment on the Clinical Course in a Child

Faraguna

Musto

Crescitelli

et al. 2022

Genes

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“…On the other hand, gene-corrected cystinosis progenitor cells can represent an interesting source of cells for autologous cell therapy. Recently, ex vivo hematopoietic stem cell gene therapy using autologous hematopoietic stem and progenitor cells (HSPCs) transduced with lentiviral vector technology was reported to be successful in Hurler disease, another rare lysosomal storage disorder, yielding extensive metabolic correction in peripheral tissues and the central nervous system [ 57 ]. Further studies investigating the potential of Cys-uKPCs to integrate into cystinosis structures in vitro (e.g., organoids) or in (damaged) kidneys in cystinosis animal models, are required to explore these exciting possibilities.…”

Section: Discussionmentioning

confidence: 99%

Urine-Derived Kidney Progenitor Cells in Cystinosis

Veys

Berlingerio

David

et al. 2022

Cells

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Nephropathic cystinosis is an inherited lysosomal storage disorder caused by pathogenic variants in the cystinosin (CTNS) gene and is characterized by the excessive shedding of proximal tubular epithelial cells (PTECs) and podocytes into urine, development of the renal Fanconi syndrome and end-stage kidney disease (ESKD). We hypothesized that in compensation for epithelial cell losses, cystinosis kidneys undertake a regenerative effort, and searched for the presence of kidney progenitor cells (KPCs) in the urine of cystinosis patients. Urine was cultured in a specific progenitor medium to isolate undifferentiated cells. Of these, clones were characterized by qPCR, subjected to a differentiation protocol to PTECs and podocytes and assessed by qPCR, Western blot, immunostainings and functional assays. Cystinosis patients voided high numbers of undifferentiated cells in urine, of which various clonal cell lines showed a high capacity for self-renewal and expressed kidney progenitor markers, which therefore were assigned as cystinosis urine-derived KPCs (Cys-uKPCs). Cys-uKPC clones showed the capacity to differentiate between functional PTECs and/or podocytes. Gene addition with wild-type CTNS using lentiviral vector technology resulted in significant reductions in cystine levels. We conclude that KPCs present in the urine of cystinosis patients can be isolated, differentiated and complemented with CTNS in vitro, serving as a novel tool for disease modeling.

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“…LV HSPC gene therapy has been successfully applied in clinical trials for the treatment of metabolic diseases, such as metachromatic leukodystrophy (MLD) [ 111 ], Fabry disease [ 112 ] and Hurler disease [ 113 ], as well as for peroxisomal disorder X-linked cerebral adrenoleukodystrophy (CALD), with reported follow-ups of 12 years after transplantation [ 114 , 115 , 116 ]. Overall, more than 350 patients have been treated with lentiviral hematopoietic stem cell gene therapy for monogenic disorders without any serious genotoxic-related adverse events [ 117 ].…”

Section: Gene Therapy For Pompe Diseasementioning

confidence: 99%

Gene Therapy Developments for Pompe Disease

et al. 2022

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Pompe disease is an inherited neuromuscular disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). The most severe form is infantile-onset Pompe disease, presenting shortly after birth with symptoms of cardiomyopathy, respiratory failure and skeletal muscle weakness. Late-onset Pompe disease is characterized by a slower disease progression, primarily affecting skeletal muscles. Despite recent advancements in enzyme replacement therapy management several limitations remain using this therapeutic approach, including risks of immunogenicity complications, inability to penetrate CNS tissue, and the need for life-long therapy. The next wave of promising single therapy interventions involves gene therapies, which are entering into a clinical translational stage. Both adeno-associated virus (AAV) vectors and lentiviral vector (LV)-mediated hematopoietic stem and progenitor (HSPC) gene therapy have the potential to provide effective therapy for this multisystemic disorder. Optimization of viral vector designs, providing tissue-specific expression and GAA protein modifications to enhance secretion and uptake has resulted in improved preclinical efficacy and safety data. In this review, we highlight gene therapy developments, in particular, AAV and LV HSPC-mediated gene therapy technologies, to potentially address all components of the neuromuscular associated Pompe disease pathology.

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Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome

Cited by 101 publications

References 32 publications

Mucopolysaccharidosis-Plus Syndrome, a Rapidly Progressive Disease: Favorable Impact of a Very Prolonged Steroid Treatment on the Clinical Course in a Child

Mucopolysaccharidosis-Plus Syndrome, a Rapidly Progressive Disease: Favorable Impact of a Very Prolonged Steroid Treatment on the Clinical Course in a Child

Urine-Derived Kidney Progenitor Cells in Cystinosis

Gene Therapy Developments for Pompe Disease

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