Screening chimeric GAA variants in preclinical study results in hematopoietic stem cell gene therapy candidate vectors for Pompe disease

Dogan, Yildirim; Barese, Cecilia; Schindler, Jeffrey W.; Yoon, John K.; Unnisa, Zeenath; Guda, Swaroopa; Jacobs, Mary E.; Oborski, Christine; Maiwald, Tim; Clarke, Diana L.; Schambach, Axel; Pfeifer, Richard W.; Harper, Claudia; Mason, Chris; Til, Niek P. van

doi:10.1016/j.omtm.2022.10.017

Cited by 8 publications

(15 citation statements)

References 101 publications

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“…The GAA protein in the GAAco group was much more pronounced, compared to the GILT-group, which may be caused by the reduced ability of GAA protein secretion and cellular retainment of the GILT-protein as proposed by Dogan et al . (14) Immunophenotyping of single cell suspensions of glial cells showed an overall decrease in the percentage of microglia and increase in the proportion of astrocytes in untreated Gaa −/− and in GAAco-treated animals (Figure 5A and S6D). In contrast, the percentage of microglial cells and astrocytes was restored to WT levels in the GILT treatment group (Figure 5A).…”

Section: Resultsmentioning

confidence: 96%

“…In a previous study, a codon-optimized GILT-R37A-tagged GAA transgene (subsequently called GILT ) was selected as a lead vector. (14) This vector contained the myeloproliferative sarcoma virus enhancer, negative control region deleted, dl587rev primer-binding site substituted (MND) promoter to drive GILT expression. In this study, to assess long-term expression and efficacy in Gaa −/− mice, we performed a lentiviral vector dose titration on Gaa −/− Lin-cells (multiplicity of infection (MOI): 0.75, 1.5 and 3), which were transplanted in both 9-12 weeks-old 7.5 Gy irradiated male and female Gaa −/− recipients.…”

Section: Resultsmentioning

confidence: 99%

“…As we and others have previously demonstrated this fusion peptide improves enzyme secretion and enhances the reduction of glycogen, myofiber, and CNS vacuolation in critical tissues. (12–14) Additionally, the GILT-tagged vector sequence included an R37A mutein, which has been proven to significantly diminish signaling mediated by the insulin receptor. (14)…”

Section: Introductionmentioning

confidence: 99%

“…(12–14) Additionally, the GILT-tagged vector sequence included an R37A mutein, which has been proven to significantly diminish signaling mediated by the insulin receptor. (14)…”

Section: Introductionmentioning

confidence: 99%

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Preclinical lentiviral vector-mediated hematopoietic stem and progenitor cell gene therapy corrects Pompe disease-related muscle and neurological manifestations

Yoon,

Schindler,

Loperfido

et al. 2023

Preprint

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Pompe disease, a rare genetic neuromuscular disorder, is caused by a deficiency of acid alpha-glucosidase (GAA), leading to the accumulation of glycogen in lysosomes and the progressive development of muscle weakness. The current standard treatment, enzyme replacement therapy (ERT), is not curative and demonstrates poor penetration into skeletal muscle and the central and peripheral nervous systems, susceptibility to immune responses against the recombinant enzyme, and the need for high doses and frequent infusions. To overcome these limitations, lentiviral vector-mediated hematopoietic stem and progenitor cell (HSPC) gene therapy has been proposed as a next-generation approach for treating Pompe disease. This study demonstrates the potential of lentiviral HSPC gene therapy to reverse the pathological effects of Pompe disease in a preclinical mouse model. It includes a comprehensive safety assessment via integration site analysis, along with single-cell RNA sequencing analysis of CNS samples to gain insights into the underlying mechanisms of phenotype correction.One Sentence Summary:Preclinical hematopoietic stem cell gene therapy for the treatment of Pompe disease.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…(12–14) Additionally, the GILT-tagged vector sequence included an R37A mutein, which has been proven to significantly diminish signaling mediated by the insulin receptor. (14)…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Preclinical lentiviral vector-mediated hematopoietic stem and progenitor cell gene therapy corrects Pompe disease-related muscle and neurological manifestations

Yoon,

Schindler,

Loperfido

et al. 2023

Preprint

Self Cite

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“…A similar approach has been used in other preclinical studies to create engineered GAA coding sequences, distinct peptide tags and codon optimizations. The use of LVGT with glycosylation-independent lysosomal targeting tags increased secretion and reduced glycogen, myofiber and CNS vacuolation in tissues, but maintained low GAA enzyme activity [81 ▪▪ ].…”

Section: Gene Therapy For Pompe Diseasementioning

confidence: 99%

Current avenues of gene therapy in Pompe disease

Leon-Astudillo,

Trivedi,

Sun

et al. 2023

Current Opinion in Neurology

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Purpose of review Pompe disease is a rare, inherited, devastating condition that causes progressive weakness, cardiomyopathy and neuromotor disease due to the accumulation of glycogen in striated and smooth muscle, as well as neurons. While enzyme replacement therapy has dramatically changed the outcome of patients with the disease, this strategy has several limitations. Gene therapy in Pompe disease constitutes an attractive approach due to the multisystem aspects of the disease and need to address the central nervous system manifestations. This review highlights the recent work in this field, including methods, progress, shortcomings, and future directions. Recent findings Recombinant adeno-associated virus (rAAV) and lentiviral vectors (LV) are well studied platforms for gene therapy in Pompe disease. These products can be further adapted for safe and efficient administration with concomitant immunosuppression, with the modification of specific receptors or codon optimization. rAAV has been studied in multiple clinical trials demonstrating safety and tolerability. Summary Gene therapy for the treatment of patients with Pompe disease is feasible and offers an opportunity to fully correct the principal pathology leading to cellular glycogen accumulation. Further work is needed to overcome the limitations related to vector production, immunologic reactions and redosing.

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Advances in Pompe Disease Treatment: From Enzyme Replacement to Gene Therapy

Colella

2024

Mol Diagn Ther

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Screening chimeric GAA variants in preclinical study results in hematopoietic stem cell gene therapy candidate vectors for Pompe disease

Cited by 8 publications

References 101 publications

Preclinical lentiviral vector-mediated hematopoietic stem and progenitor cell gene therapy corrects Pompe disease-related muscle and neurological manifestations

Preclinical lentiviral vector-mediated hematopoietic stem and progenitor cell gene therapy corrects Pompe disease-related muscle and neurological manifestations

Current avenues of gene therapy in Pompe disease

Advances in Pompe Disease Treatment: From Enzyme Replacement to Gene Therapy

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