Targeted exon skipping of NF1 exon 17 as a Therapeutic for Neurofibromatosis Type I. / Leier, Andre; Moore, Marc; Liu, Hui; Daniel, Michael; Hyde, Alexis M.; Messiaen, Ludwine; Korf, Bruce R.; Selvakumaran, Jamunanithy; Ciszewski, Lukasz; Lambert, Laura; Foote, Jeremy ; Wallace, Margaret R.; Kesterson, Robert A.; Dickson, George; Popplewell, Linda; Wallis, Deeann.

In: Molecular therapy. Nucleic acids, 15.03.2022.

Research output: Contribution to journalArticlepeer-review

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Targeted exon skipping of NF1 exon 17 as a Therapeutic for Neurofibromatosis Type I. / Leier, Andre; Moore, Marc; Liu, Hui; Daniel, Michael; Hyde, Alexis M.; Messiaen, Ludwine; Korf, Bruce R.; Selvakumaran, Jamunanithy; Ciszewski, Lukasz; Lambert, Laura; Foote, Jeremy ; Wallace, Margaret R.; Kesterson, Robert A.; Dickson, George; Popplewell, Linda; Wallis, Deeann.

In: Molecular therapy. Nucleic acids, 15.03.2022.

Research output: Contribution to journalArticlepeer-review

Harvard

Leier, A, Moore, M, Liu, H, Daniel, M, Hyde, AM, Messiaen, L, Korf, BR, Selvakumaran, J, Ciszewski, L, Lambert, L, Foote, J, Wallace, MR, Kesterson, RA, Dickson, G, Popplewell, L & Wallis, D 2022, 'Targeted exon skipping of NF1 exon 17 as a Therapeutic for Neurofibromatosis Type I', Molecular therapy. Nucleic acids. https://doi.org/10.1016/j.omtn.2022.03.011

APA

Leier, A., Moore, M., Liu, H., Daniel, M., Hyde, A. M., Messiaen, L., Korf, B. R., Selvakumaran, J., Ciszewski, L., Lambert, L., Foote, J., Wallace, M. R., Kesterson, R. A., Dickson, G., Popplewell, L., & Wallis, D. (2022). Targeted exon skipping of NF1 exon 17 as a Therapeutic for Neurofibromatosis Type I. Molecular therapy. Nucleic acids. https://doi.org/10.1016/j.omtn.2022.03.011

Vancouver

Leier A, Moore M, Liu H, Daniel M, Hyde AM, Messiaen L et al. Targeted exon skipping of NF1 exon 17 as a Therapeutic for Neurofibromatosis Type I. Molecular therapy. Nucleic acids. 2022 Mar 15. https://doi.org/10.1016/j.omtn.2022.03.011

Author

Leier, Andre ; Moore, Marc ; Liu, Hui ; Daniel, Michael ; Hyde, Alexis M. ; Messiaen, Ludwine ; Korf, Bruce R. ; Selvakumaran, Jamunanithy ; Ciszewski, Lukasz ; Lambert, Laura ; Foote, Jeremy ; Wallace, Margaret R. ; Kesterson, Robert A. ; Dickson, George ; Popplewell, Linda ; Wallis, Deeann. / Targeted exon skipping of NF1 exon 17 as a Therapeutic for Neurofibromatosis Type I. In: Molecular therapy. Nucleic acids. 2022.

BibTeX

@article{d118ad0ec8c44854b2bc284df1e3d07b,
title = "Targeted exon skipping of NF1 exon 17 as a Therapeutic for Neurofibromatosis Type I",
abstract = "We investigated the feasibility of utilizing an exon skipping approach as a genotype-dependent therapeutic for neurofibromatosis type 1 (NF1) by determining which NF1 exons might be skipped while maintaining neurofibromin protein expression and GTP-ase Activating Protein (GAP)-related domain (GRD) function. Initial in silico analysis predicted exons that can be skipped with minimal loss of neurofibromin function, which was confirmed with in vitro assessments utilizing an Nf1 cDNA-based functional screening system. Skipping of exons 17 or 52 fit our criteria, as minimal effects on protein expression and GRD activity were noted. Antisense phosphorodiamidate morpholino oligos (PMOs) were utilized to skip exon 17 in human cell lines with patient-specific pathogenic variants in exon 17, c.1885G>A and c.1929delG. PMOs restored functional neurofibromin expression. To determine the in vivo significance of exon 17 skipping, a homozygous deletion of exon 17 in a novel mouse model was generated. Mice were viable and exhibited a normal life-span. Initial studies did not reveal the presence of tumor development; however, altered nesting behavior and systemic lymphoid hyperplasia was noted in peripheral lymphoid organs. Alterations in T and B cell frequencies in the thymus and spleen were identified. Hence, exon skipping should be further investigated as a therapeutic approach for NF1 patients with pathogenic variants in exon 17 as homozygous deletion of exon 17 is consistent with at least partial function of neurofibromin.",
author = "Andre Leier and Marc Moore and Hui Liu and Michael Daniel and Hyde, {Alexis M.} and Ludwine Messiaen and Korf, {Bruce R.} and Jamunanithy Selvakumaran and Lukasz Ciszewski and Laura Lambert and Jeremy Foote and Wallace, {Margaret R.} and Kesterson, {Robert A.} and George Dickson and Linda Popplewell and Deeann Wallis",
year = "2022",
month = mar,
day = "15",
doi = "10.1016/j.omtn.2022.03.011",
language = "English",
journal = "Molecular therapy. Nucleic acids",
issn = "2162-2531",
publisher = "Nature Publishing Group",

}

RIS

TY - JOUR

T1 - Targeted exon skipping of NF1 exon 17 as a Therapeutic for Neurofibromatosis Type I

AU - Leier, Andre

AU - Moore, Marc

AU - Liu, Hui

AU - Daniel, Michael

AU - Hyde, Alexis M.

AU - Messiaen, Ludwine

AU - Korf, Bruce R.

AU - Selvakumaran, Jamunanithy

AU - Ciszewski, Lukasz

AU - Lambert, Laura

AU - Foote, Jeremy

AU - Wallace, Margaret R.

AU - Kesterson, Robert A.

AU - Dickson, George

AU - Popplewell, Linda

AU - Wallis, Deeann

PY - 2022/3/15

Y1 - 2022/3/15

N2 - We investigated the feasibility of utilizing an exon skipping approach as a genotype-dependent therapeutic for neurofibromatosis type 1 (NF1) by determining which NF1 exons might be skipped while maintaining neurofibromin protein expression and GTP-ase Activating Protein (GAP)-related domain (GRD) function. Initial in silico analysis predicted exons that can be skipped with minimal loss of neurofibromin function, which was confirmed with in vitro assessments utilizing an Nf1 cDNA-based functional screening system. Skipping of exons 17 or 52 fit our criteria, as minimal effects on protein expression and GRD activity were noted. Antisense phosphorodiamidate morpholino oligos (PMOs) were utilized to skip exon 17 in human cell lines with patient-specific pathogenic variants in exon 17, c.1885G>A and c.1929delG. PMOs restored functional neurofibromin expression. To determine the in vivo significance of exon 17 skipping, a homozygous deletion of exon 17 in a novel mouse model was generated. Mice were viable and exhibited a normal life-span. Initial studies did not reveal the presence of tumor development; however, altered nesting behavior and systemic lymphoid hyperplasia was noted in peripheral lymphoid organs. Alterations in T and B cell frequencies in the thymus and spleen were identified. Hence, exon skipping should be further investigated as a therapeutic approach for NF1 patients with pathogenic variants in exon 17 as homozygous deletion of exon 17 is consistent with at least partial function of neurofibromin.

AB - We investigated the feasibility of utilizing an exon skipping approach as a genotype-dependent therapeutic for neurofibromatosis type 1 (NF1) by determining which NF1 exons might be skipped while maintaining neurofibromin protein expression and GTP-ase Activating Protein (GAP)-related domain (GRD) function. Initial in silico analysis predicted exons that can be skipped with minimal loss of neurofibromin function, which was confirmed with in vitro assessments utilizing an Nf1 cDNA-based functional screening system. Skipping of exons 17 or 52 fit our criteria, as minimal effects on protein expression and GRD activity were noted. Antisense phosphorodiamidate morpholino oligos (PMOs) were utilized to skip exon 17 in human cell lines with patient-specific pathogenic variants in exon 17, c.1885G>A and c.1929delG. PMOs restored functional neurofibromin expression. To determine the in vivo significance of exon 17 skipping, a homozygous deletion of exon 17 in a novel mouse model was generated. Mice were viable and exhibited a normal life-span. Initial studies did not reveal the presence of tumor development; however, altered nesting behavior and systemic lymphoid hyperplasia was noted in peripheral lymphoid organs. Alterations in T and B cell frequencies in the thymus and spleen were identified. Hence, exon skipping should be further investigated as a therapeutic approach for NF1 patients with pathogenic variants in exon 17 as homozygous deletion of exon 17 is consistent with at least partial function of neurofibromin.

U2 - 10.1016/j.omtn.2022.03.011

DO - 10.1016/j.omtn.2022.03.011

M3 - Article

JO - Molecular therapy. Nucleic acids

JF - Molecular therapy. Nucleic acids

SN - 2162-2531

ER -