Gene Therapy for Lysosomal Storage Disorders: Ongoing Studies and Clinical Development

Massaro, Giulia; Geard, Amy; Liu, Wenfei; Coombe-Tennant, Oliver; Waddington, Simon N.; Baruteau, Julien; Gissen, Paul; Rahim, Ahad A.

doi:10.3390/biom11040611

Cited by 35 publications

(27 citation statements)

References 315 publications

(164 reference statements)

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“…A cross-correction of cells defective for lysosomal enzymes has been successfully achieved in some lysosomal diseases through either an in vivo or ex vivo gene therapy strategy 51 . Recently, a clinical trial on ex vivo gene therapy using autologous hematopoietic stem cells transduced with recombinant lentivirus carrying aGLA was conducted and published with promising results 19 .…”

Section: Discussionmentioning

confidence: 99%

Genetically Modified Cell Transplantation Through Macroencapsulated Spheroids with Scaffolds to Treat Fabry Disease

et al. 2021

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Cell transplantation is expected to be another strategy to treat lysosomal diseases, having several advantages compared to enzyme replacement therapy, such as continuous enzyme secretion and one-time treatment to cure diseases. However, cell transplantation for lysosomal diseases holds issues to be resolved for the clinical field. In this study, we developed a new ex vivo gene therapy platform using a transplant pack, which consists of a porous membrane made of ethylene-vinyl alcohol in the pack-type and spheroids with scaffolds. These membranes have countless pores of less than 0.1 µm2 capable of secreting proteins, including alpha-galactosidase enzyme, and segregating the contents from the host immune system. When the packs were subcutaneously transplanted into the backs of green fluorescent protein (GFP) mice, no GFP-positive cells migrated to the transplanted pack in either autogenic or allogenic mice. The transplanted cells in the pack survived for 28 days after transplantation. When cells overexpressing alpha-galactosidase were used as donor cells for the packs and implanted into Fabry disease model mice, the accumulation of the alpha-galactosidase enzyme was also observed in the livers. In this study, we reported a new ex vivo therapeutic strategy combining macroencapsulation and cellular spheroids with scaffolds. This pack, macroencapsulated spheroids with scaffolds, can also be applied to other types of lysosomal diseases by modifying genes of interest.

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Section: Discussionmentioning

confidence: 99%

Genetically Modified Cell Transplantation Through Macroencapsulated Spheroids with Scaffolds to Treat Fabry Disease

et al. 2021

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“…The extent of transplanted HSPC efficacy in cystinosis was surprising, especially considering that cystinosin is a transmembrane lysosomal protein as opposed to a secreted enzyme that can be recaptured by adjacent diseased cells [ 54 , 55 , 56 ]. In order to identify the cellular mechanism of action of this approach, we demonstrated for the first time that transplanted HSPCs, after differentiating into macrophages, transferred cystinosin-bearing lysosomes to the adjacent endogenous host cells via tunneling nanotubes (TNTs) [ 57 ].…”

Section: Preclinical Proof Of Concept and Mechanism Of Action For Using Hspc For Cystinosismentioning

confidence: 99%

“…Moreover, in contrast to the MLV, lentiviral vectors are not associated with oncogenesis and therefore may represent a safety advantage over oncoretroviral gene therapy vectors. In the last 12 years, 400–500 patients have been treated with lentiviral ex vivo gene therapy, including three regulatory approved products in Europe for thalassemia, metachromatic leukodystrophy, and cerebral-adrenoleukodystrophy (C-ALD) [ 56 , 69 , 70 , 71 , 72 , 73 , 74 ]. Thousands more oncology patients have been treated with lentiviral-transduced T cells, known as CARTs.…”

Section: Ex Vivo Gene Modified Cell Therapy: a Safer Approach Than Allogeneic Transplantationmentioning

confidence: 99%

Hematopoietic Stem Cell Gene Therapy for Cystinosis: From Bench-to-Bedside

Cherqui

2021

Cells

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Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. The gene involved is the CTNS gene that encodes cystinosin, a seven-transmembrane domain lysosomal protein, which is a proton-driven cystine transporter. Cystinosis is characterized by the lysosomal accumulation of cystine, a dimer of cysteine, in all the cells of the body leading to multi-organ failure, including the failure of the kidney, eye, thyroid, muscle, and pancreas, and eventually causing premature death in early adulthood. The current treatment is the drug cysteamine, which is onerous and expensive, and only delays the progression of the disease. Employing the mouse model of cystinosis, using Ctns−/− mice, we first showed that the transplantation of syngeneic wild-type murine hematopoietic stem and progenitor cells (HSPCs) led to abundant tissue integration of bone marrow-derived cells, a significant decrease in tissue cystine accumulation, and long-term kidney, eye and thyroid preservation. To translate this result to a potential human therapeutic treatment, given the risks of mortality and morbidity associated with allogeneic HSPC transplantation, we developed an autologous transplantation approach of HSPCs modified ex vivo using a self-inactivated lentiviral vector to introduce a functional version of the CTNS cDNA, pCCL-CTNS, and showed its efficacy in Ctns−/− mice. Based on these promising results, we held a pre-IND meeting with the Food and Drug Administration (FDA) to carry out the FDA agreed-upon pharmacological and toxicological studies for our therapeutic candidate, manufacturing development, production of the GMP lentiviral vector, design Phase 1/2 of the clinical trial, and filing of an IND application. Our IND was cleared by the FDA on 19 December 2018, to proceed to the clinical trial using CD34+ HSPCs from the G-CSF/plerixafor-mobilized peripheral blood stem cells of patients with cystinosis, modified by ex vivo transduction using the pCCL-CTNS vector (investigational product name: CTNS-RD-04). The clinical trial evaluated the safety and efficacy of CTNS-RD-04 and takes place at the University of California, San Diego (UCSD) and will include up to six patients affected with cystinosis. Following leukapheresis and cell manufacturing, the subjects undergo myeloablation before HSPC infusion. Patients also undergo comprehensive assessments before and after treatment to evaluate the impact of CTNS-RD-04 on the clinical outcomes and cystine and cystine crystal levels in the blood and tissues for 2 years. If successful, this treatment could be a one-time therapy that may eliminate or reduce renal deterioration as well as the long-term complications associated with cystinosis. In this review, we will describe the long path from bench-to-bedside for autologous HSPC gene therapy used to treat cystinosis.

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“…Indeed, Srikanth and Feldman reported a very interesting study on the extracellular Dickkopf-1 (Dkk1)-mediated downregulation of the canonical Wnt pathway in an induced-pluripotent stem cell model of neuronopathic Gaucher disease [13]. Three other elegant reviews also contributed to this Special Issue: the work of Pinto e Vairo and colleagues reported a summarizing overview on the relevance of precision medicine in the field of lysosomal storage disorders [14], while Massaro and colleagues included their comprehensive summary of the currently available and developing gene therapy approaches and clinical trials in the management of lysosomal diseases [15]. Gleason and colleagues reported an excellent collection of data related to the significance of exosomes in the context of lysosomal disorders pathogenesis, but the authors also emphasized the clinical application of exosomes as therapeutic delivery vehicles [16].…”

mentioning

confidence: 99%