Gene replacement therapy in a schwannoma mouse model of neurofibromatosis type 2
Loss of function of the neurofibromatosis type 2 (NF2) tumor suppressor gene leads to the formation of schwannomas, meningiomas, and ependymomas, comprising ∼50% of all sporadic cases of primary nervous system tumors. NF2 syndrome is an autosomal dominant condition, with bi-allelic inactivation of g...
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Cell Press
2022
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my.upm.eprints.1016082023-06-15T21:34:54Z http://psasir.upm.edu.my/id/eprint/101608/ Gene replacement therapy in a schwannoma mouse model of neurofibromatosis type 2 Prabhakar, Shilpa Beauchamp, Roberta L. Cheah, Pike See Yoshinaga, Akiko Haidar, Edwina Abou Lule, Sevda Mani, Gayathri Maalouf, Katia Stemmer-Rachamimov, Anat Jung, David H. Welling, D. Bradley Giovannini, Marco Plotkin, Scott R. Maguire, Casey A. Ramesh, Vijaya Breakefield, Xandra O. Loss of function of the neurofibromatosis type 2 (NF2) tumor suppressor gene leads to the formation of schwannomas, meningiomas, and ependymomas, comprising ∼50% of all sporadic cases of primary nervous system tumors. NF2 syndrome is an autosomal dominant condition, with bi-allelic inactivation of germline and somatic alleles resulting in loss of function of the encoded protein merlin and activation of mammalian target of rapamycin (mTOR) pathway signaling in NF2-deficient cells. Here we describe a gene replacement approach through direct intratumoral injection of an adeno-associated virus vector expressing merlin in a novel human schwannoma model in nude mice. In culture, the introduction of an AAV1 vector encoding merlin into CRISPR-modified human NF2-null arachnoidal cells (ACs) or Schwann cells (SCs) was associated with decreased size and mTORC1 pathway activation consistent with restored merlin activity. In vivo, a single injection of AAV1-merlin directly into human NF2-null SC-derived tumors growing in the sciatic nerve of nude mice led to regression of tumors over a 10-week period, associated with a decrease in dividing cells and an increase in apoptosis, in comparison with vehicle. These studies establish that merlin re-expression via gene replacement in NF2-null schwannomas is sufficient to cause tumor regression, thereby potentially providing an effective treatment for NF2. Cell Press 2022 Article PeerReviewed Prabhakar, Shilpa and Beauchamp, Roberta L. and Cheah, Pike See and Yoshinaga, Akiko and Haidar, Edwina Abou and Lule, Sevda and Mani, Gayathri and Maalouf, Katia and Stemmer-Rachamimov, Anat and Jung, David H. and Welling, D. Bradley and Giovannini, Marco and Plotkin, Scott R. and Maguire, Casey A. and Ramesh, Vijaya and Breakefield, Xandra O. (2022) Gene replacement therapy in a schwannoma mouse model of neurofibromatosis type 2. Molecular Therapy - Methods & Clinical Development, 26. pp. 169-180. ISSN 2329-0501 https://www.sciencedirect.com/science/article/pii/S2329050122000912?via%3Dihub 10.1016/j.omtm.2022.06.012 |
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Loss of function of the neurofibromatosis type 2 (NF2) tumor suppressor gene leads to the formation of schwannomas, meningiomas, and ependymomas, comprising ∼50% of all sporadic cases of primary nervous system tumors. NF2 syndrome is an autosomal dominant condition, with bi-allelic inactivation of germline and somatic alleles resulting in loss of function of the encoded protein merlin and activation of mammalian target of rapamycin (mTOR) pathway signaling in NF2-deficient cells. Here we describe a gene replacement approach through direct intratumoral injection of an adeno-associated virus vector expressing merlin in a novel human schwannoma model in nude mice. In culture, the introduction of an AAV1 vector encoding merlin into CRISPR-modified human NF2-null arachnoidal cells (ACs) or Schwann cells (SCs) was associated with decreased size and mTORC1 pathway activation consistent with restored merlin activity. In vivo, a single injection of AAV1-merlin directly into human NF2-null SC-derived tumors growing in the sciatic nerve of nude mice led to regression of tumors over a 10-week period, associated with a decrease in dividing cells and an increase in apoptosis, in comparison with vehicle. These studies establish that merlin re-expression via gene replacement in NF2-null schwannomas is sufficient to cause tumor regression, thereby potentially providing an effective treatment for NF2. |
| format |
Article |
| author |
Prabhakar, Shilpa Beauchamp, Roberta L. Cheah, Pike See Yoshinaga, Akiko Haidar, Edwina Abou Lule, Sevda Mani, Gayathri Maalouf, Katia Stemmer-Rachamimov, Anat Jung, David H. Welling, D. Bradley Giovannini, Marco Plotkin, Scott R. Maguire, Casey A. Ramesh, Vijaya Breakefield, Xandra O. |
| spellingShingle |
Prabhakar, Shilpa Beauchamp, Roberta L. Cheah, Pike See Yoshinaga, Akiko Haidar, Edwina Abou Lule, Sevda Mani, Gayathri Maalouf, Katia Stemmer-Rachamimov, Anat Jung, David H. Welling, D. Bradley Giovannini, Marco Plotkin, Scott R. Maguire, Casey A. Ramesh, Vijaya Breakefield, Xandra O. Gene replacement therapy in a schwannoma mouse model of neurofibromatosis type 2 |
| author_facet |
Prabhakar, Shilpa Beauchamp, Roberta L. Cheah, Pike See Yoshinaga, Akiko Haidar, Edwina Abou Lule, Sevda Mani, Gayathri Maalouf, Katia Stemmer-Rachamimov, Anat Jung, David H. Welling, D. Bradley Giovannini, Marco Plotkin, Scott R. Maguire, Casey A. Ramesh, Vijaya Breakefield, Xandra O. |
| author_sort |
Prabhakar, Shilpa |
| title |
Gene replacement therapy in a schwannoma mouse model of neurofibromatosis type 2 |
| title_short |
Gene replacement therapy in a schwannoma mouse model of neurofibromatosis type 2 |
| title_full |
Gene replacement therapy in a schwannoma mouse model of neurofibromatosis type 2 |
| title_fullStr |
Gene replacement therapy in a schwannoma mouse model of neurofibromatosis type 2 |
| title_full_unstemmed |
Gene replacement therapy in a schwannoma mouse model of neurofibromatosis type 2 |
| title_sort |
gene replacement therapy in a schwannoma mouse model of neurofibromatosis type 2 |
| publisher |
Cell Press |
| publishDate |
2022 |
| url |
http://psasir.upm.edu.my/id/eprint/101608/ https://www.sciencedirect.com/science/article/pii/S2329050122000912?via%3Dihub |
| _version_ |
1769844419704389632 |
| score |
13.211869 |