Lentiviral gene therapy prevents anti-human acid α-glucosidase antibody formation in murine Pompe disease

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

doi:10.1016/j.omtm.2022.04.016

Cited by 16 publications

(17 citation statements)

References 99 publications

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“… 32 , 41 , 79 , 80 Immunogenicity to rhGAA has previously been investigated in Gaa −/− mice in HSPC gene therapy settings. 13 , 14 , 30 In our 16-week follow-up study with stabilized hematopoietic reconstitution of genetically modified cells in Gaa −/− mice, the GAA enzyme activity in PB leukocytes and plasma was supraphysiological and sustained without evidence of immune responses to the recombinant proteins in the treatment groups, suggesting the occurrence of advantageous immune tolerance to the transgene product.…”

Section: Discussionmentioning

confidence: 80%

“… 29 In preclinical studies using HSPC gene therapy in Gaa −/− mice, robust immune tolerance induction against rhGAA was also observed. 13 , 14 , 30 Importantly, liver-directed AAV gene therapy has been reported to promote immune tolerance induction to rhGAA in Gaa −/− mice by either restricting expression to hepatocytes, 31 low-dose AAV vector administration, 32 or a secretable GAA. 33 …”

Section: Introductionmentioning

confidence: 99%

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

Dogan

Barese

Schindler

et al. 2022

Molecular Therapy - Methods & Clinical Development

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

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

Dogan

Barese

Schindler

et al. 2022

Molecular Therapy - Methods & Clinical Development

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“…Das dadurch entstehende neue Protein wird an alle Körperzellen abgegeben und z. B. ein Enzymdefekt in den Zellen korrigiert 21 22 23 24 25 .…”

Section: Hereditäre Metabolische Myopathienunclassified

“…Das dadurch entstehende neueProtein wird an alle Körperzellen abgegeben und z. B. ein Enzymdefekt in den Zellen korrigiert[21][22][23][24][25].Ein weiterer Therapieansatz ist die sog. Substratreduktionstherapie, d. h. eine Therapie, die die primäre Produktion von Glykogen verringert.…”

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Molekulare Therapien erblicher Myopathien im Erwachsenenalter – eine kursive Rundschau

Schoser

2022

Fortschr Neurol Psychiatr

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ZusammenfassungUnterschiedliche Formen der molekularen Therapie sind zu einer neuen Möglichkeit in der Präzisionsbehandlung erblicher neuromuskulärer Erkrankungen geworden. Dieser kursive Überblick über die molekularen Therapien bei hereditären Myopathien wird sich auf ausgewählte aktuelle Phase 1 bis 3 Studien zu häufigen hereditären Myopathien im Erwachsenenalter wie die Dystrophinopathie Becker-Kiener, die Fazioskapulohumerale Muskeldystrophie, Calpainopathie, und die Dysferlinopathie fokussieren. Die Therapieoptionen zum Morbus Pompe dienen als Beispiel für die hereditären metabolischen Myopathien.

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“…These new insights show that for the treatment of patients with Pompe disease, the brain presents a new challenge. It is therefore important to better understand the extent and nature of these brain abnormalities and provide effect parameters for upcoming clinical trials with next-generation therapies, such as lentiviral gene therapy [ 15 , 16 ], which include the brain as an additional target.…”

Section: Introductionmentioning

confidence: 99%

Diffusion tensor imaging of the brain in Pompe disease

et al. 2022

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Enzyme replacement therapy has drastically changed prospects of patients with Pompe disease, a progressive metabolic myopathy. As classic infantile patients survive due to treatment, they exhibit progressive white matter abnormalities, while brain involvement in late-onset patients is not fully elucidated. To study the underlying microstructure of white matter, we acquired structural (T1, T2, FLAIR) and diffusion tensor imaging (DTI) of the brain in 12 classic infantile patients (age 5–20 years) and 18 late-onset Pompe patients (age 11–56 years). Structural images were scored according to a rating scale for classic infantile patients. Fractional anisotropy (FA) and mean diffusivity (MD) from classic infantile patients were compared to a reference population, using a Wilcoxon signed-rank, one sample test. Effect sizes (Hedges’ G) were used to compare DTI metrics across different tracts. For late-onset patients, results were compared to (reported) tractography data on normal aging. In classic infantile patients, we found a significant lower FA and higher MD (p < 0.01) compared to the reference population. Large-association fibers were most severely affected. Classic infantile patients with advanced white matter abnormalities on structural MRI showed the largest deviations from the reference population. FA and MD were similar for younger and older late-onset patients in large WM-association fibers. We conclude that, while no deviations from typical neurodevelopment were found in late-onset patients, classic infantile Pompe patients showed quantifiable, substantially altered white matter microstructure, which corresponded with disease stage on structural MRI. DTI holds promise to monitor therapy response in future therapies targeting the brain.

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Lentiviral gene therapy prevents anti-human acid α-glucosidase antibody formation in murine Pompe disease

Cited by 16 publications

References 99 publications

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

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

Molekulare Therapien erblicher Myopathien im Erwachsenenalter – eine kursive Rundschau

Diffusion tensor imaging of the brain in Pompe disease

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