Abstract
Enzyme replacement therapy (ERT) is the current standard treatment for Pompe disease, a lysosomal storage disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). ERT has shown to be lifesaving in patients with classic infantile Pompe disease. However, a major drawback is the development of neutralizing antibodies against ERT. Hematopoietic stem and progenitor cell-mediated lentiviral gene therapy (HSPC-LVGT) provides a novel, potential lifelong therapy with a single intervention and may induce immune tolerance. Here, we investigated whether ERT can be safely applied as additional or alternative therapy following HSPC-LVGT in a murine model of Pompe disease. We found that lentiviral expression at subtherapeutic dose was sufficient to induce tolerance to the transgene product, as well as to subsequently administered ERT. Immune tolerance was established within 4–6 weeks after gene therapy. The mice tolerated ERT doses up to 100 mg/kg, allowing ERT to eliminate glycogen accumulation in cardiac and skeletal muscle and normalizing locomotor function. The presence of HSPC-derived cells expressing GAA in the thymus suggested the establishment of central immune tolerance. These findings demonstrate that lentiviral gene therapy in murine Pompe disease induced robust and long-term immune tolerance to GAA either expressed by a transgene or supplied as ERT.
| Original language | English |
|---|---|
| Pages (from-to) | 520-532 |
| Number of pages | 13 |
| Journal | Molecular Therapy - Methods and Clinical Development |
| Volume | 25 |
| DOIs | |
| Publication status | Published - 9 Jun 2022 |
Bibliographical note
Funding Information:G. Wagemaker was involved in the concept of the study. This work was supported by the China Scholarship Council (Q.L.; File No. 201206240040), the Netherlands Organization for Health Research ZonMw (project number 40-40300-98-07010), the Sophia Foundation (grant S18-59), Metakids (grant 2018-083), the Prinses Beatrix Spierfonds (grant W.OP20-04), and the “Finding a Cure for Hunter Syndrome” Foundation. N.P.v.T. and W.W.M.P.P. conceived the project. Q.L. E.C.V. F.C. N.P.v.T. and W.W.M.P.P. designed the experiments. Q.L. E.C.V. F.C. and J.M.P. performed experiments. All authors analyzed and interpreted the data. Q.L.G. Wagemaker, N.P.v.T. A.T.v.d.P. and W.W.M.P.P. obtained funding. Q.L. E.C.V. F.C. N.P.v.T. and W.W.M.P.P. wrote the manuscript. All authors read and approved the final manuscript. A.T.v.d.P. has received consulting fees from Sanofi Genzyme and has provided consulting services, participated in advisory board meetings, and received grants for premarketing studies and research from industries via agreements between Erasmus MC and the industry. N.P.v.T. is an employee of AVROBIO (Cambridge, MA).
Funding Information:
G. Wagemaker was involved in the concept of the study. This work was supported by the China Scholarship Council (Q.L.; File No. 201206240040 ), the Netherlands Organization for Health Research ZonMw (project number 40-40300-98-07010 ), the Sophia Foundation (grant S18-59 ), Metakids (grant 2018-083 ), the Prinses Beatrix Spierfonds (grant W.OP20-04 ), and the “Finding a Cure for Hunter Syndrome” Foundation.
Publisher Copyright:
© 2022 The Author(s)
