IGF2-tagging of GAA promotes full correction of murine Pompe disease at a clinically relevant dosage of lentiviral gene therapy

Liang, Qiushi; Catalano, Fabio; Vlaar, Eva C.; Pijnenburg, Joon M.; Stok, Merel; Helsdingen, Yvette van; Vulto, Arnold G.; Ploeg, Ans T. van der; Til, Niek P. van; Pijnappel, W.W.M. Pim

doi:10.1016/j.omtm.2022.09.010

Cited by 18 publications

(25 citation statements)

References 114 publications

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“…shRNAs were obtained as bacterial stocks from the MISSION shRNA library. Viral concentrates were generated as described in [ 18 , 19 ]. Lentiviral titers were determined by transducing the lentiviral particles onto 240,000 MPCs in a dilution curve.…”

Section: Methodsmentioning

confidence: 99%

A knock down strategy for rapid, generic, and versatile modelling of muscular dystrophies in 3D-tissue-engineered-skeletal muscle

in ‘t Groen,

Franken,

Bock

et al. 2024

Skeletal Muscle

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Background Human iPSC-derived 3D-tissue-engineered-skeletal muscles (3D-TESMs) offer advanced technology for disease modelling. However, due to the inherent genetic heterogeneity among human individuals, it is often difficult to distinguish disease-related readouts from random variability. The generation of genetically matched isogenic controls using gene editing can reduce variability, but the generation of isogenic hiPSC-derived 3D-TESMs can take up to 6 months, thereby reducing throughput. Methods Here, by combining 3D-TESM and shRNA technologies, we developed a disease modelling strategy to induce distinct genetic deficiencies in a single hiPSC-derived myogenic progenitor cell line within 1 week. Results As proof of principle, we recapitulated disease-associated pathology of Duchenne muscular dystrophy and limb-girdle muscular dystrophy type 2A caused by loss of function of DMD and CAPN3, respectively. shRNA-mediated knock down of DMD or CAPN3 induced a loss of contractile function, disruption of tissue architecture, and disease-specific proteomes. Pathology in DMD-deficient 3D-TESMs was partially rescued by a candidate gene therapy treatment using micro-dystrophin, with similar efficacy compared to animal models. Conclusions These results show that isogenic shRNA-based humanized 3D-TESM models provide a fast, cheap, and efficient tool to model muscular dystrophies and are useful for the preclinical evaluation of novel therapies.

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Section: Methodsmentioning

confidence: 99%

A knock down strategy for rapid, generic, and versatile modelling of muscular dystrophies in 3D-tissue-engineered-skeletal muscle

in ‘t Groen,

Franken,

Bock

et al. 2024

Skeletal Muscle

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“…Currently, third generation self-inactivating LV vectors are used to decrease these risks [79]. Attention has been drawn to the modification of the LV vector to improve receptor affinity, like in the case of IGF2 [80 ▪ ]. Liang et al [80 ▪ ] created a vector that contains a codon-optimized GAA sequence fused to codon-optimized human IGF2 (LV-IGF2.GAAco) leading to correction of glycogen accumulation, autophagy, motor function and brain glycogen content at a much lower VCN.…”

Section: Gene Therapy For Pompe Diseasementioning

confidence: 99%

“…Attention has been drawn to the modification of the LV vector to improve receptor affinity, like in the case of IGF2 [80 ▪ ]. Liang et al [80 ▪ ] created a vector that contains a codon-optimized GAA sequence fused to codon-optimized human IGF2 (LV-IGF2.GAAco) leading to correction of glycogen accumulation, autophagy, motor function and brain glycogen content at a much lower VCN. A similar approach has been used in other preclinical studies to create engineered GAA coding sequences, distinct peptide tags and codon optimizations.…”

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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“…We previously found 15 correction of brain pathology of Ids y/− mice after hematopoietic stem and progenitor cell-mediated lentiviral gene therapy (HSPC-LVGT) with vectors encoding iduronate 2-sulfatase (IDS) tagged with either insulin-like growth factor 2 (IGF2) 16 , 17 or receptor-associated protein minimal peptide (RAP12x2), 18 as well as with the previously published fusion protein IDS.ApoE2, 19 , 20 driven by the ubiquitous MND promoter. We showed that tagging of IDS with IGF2 and ApoE2, but not RAP12x2, improves prevention of brain pathology of Ids y/− mice.…”

Section: Introductionmentioning

confidence: 99%

Lentiviral Gene Therapy for Mucopolysaccharidosis II with Tagged Iduronate 2-Sulfatase Prevents Life-Threatening Pathology in Peripheral Tissues But Fails to Correct Cartilage

Catalano,

Vlaar,

Dammou

et al. 2024

Human Gene Therapy

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Deficiency of iduronate 2-sulfatase (IDS) causes Mucopolysaccharidosis type II (MPS II), a lysosomal storage disorder characterized by systemic accumulation of glycosaminoglycans (GAGs), leading to a devastating cognitive decline and life-threatening respiratory and cardiac complications. We previously found that hematopoietic stem and progenitor cell-mediated lentiviral gene therapy (HSPC-LVGT) employing tagged IDS with insulin-like growth factor 2 (IGF2) or ApoE2, but not receptor-associated protein minimal peptide (RAP12x2), efficiently prevented brain pathology in a murine model of MPS II. In this study, we report on the effects of HSPC-LVGT on peripheral pathology and we analyzed IDS biodistribution. We found that HSPC-LVGT with all vectors completely corrected GAG accumulation and lysosomal pathology in liver, spleen, kidney, tracheal mucosa, and heart valves. Full correction of tunica media of the great heart vessels was achieved only with IDS.IGF2co gene therapy, while the other vectors provided near complete ( IDS.ApoE2co ) or no ( IDSco and IDS.RAP12x2co ) correction. In contrast, tracheal, epiphyseal, and articular cartilage remained largely uncorrected by all vectors tested. These efficacies were closely matched by IDS protein levels following HSPC-LVGT. Our results demonstrate the capability of HSPC-LVGT to correct pathology in tissues of high clinical relevance, including those of the heart and respiratory system, while challenges remain for the correction of cartilage pathology.

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IGF2-tagging of GAA promotes full correction of murine Pompe disease at a clinically relevant dosage of lentiviral gene therapy

Cited by 18 publications

References 114 publications

A knock down strategy for rapid, generic, and versatile modelling of muscular dystrophies in 3D-tissue-engineered-skeletal muscle

A knock down strategy for rapid, generic, and versatile modelling of muscular dystrophies in 3D-tissue-engineered-skeletal muscle

Current avenues of gene therapy in Pompe disease

Lentiviral Gene Therapy for Mucopolysaccharidosis II with Tagged Iduronate 2-Sulfatase Prevents Life-Threatening Pathology in Peripheral Tissues But Fails to Correct Cartilage

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