PLP1-Targeting Antisense Oligonucleotides Improve FOXG1 Syndrome Mice
, Seonghee Jung 1, Yuanyuan Deng 1, Nicolle Morey 1, Gabriella Chan 1, Andre Bongers 2, Yazi D. Ke 1, Lars M. Ittner 1,†and Fabien Delerue 1,*,†Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsFOXG1 is a rare neurodevelopmental disorder of the telencephalon for which there is neither cure nor clinically translatable experimental models. In this experimental research the Authors describe a clinical case of FOXG1 syndrome (10-yr-old male diagnosed at age 2 years after a screening for common neurodevelopmental disorder gene variants). The clinical phenotype was consistent with the features reported in the FOXG1 syndrome pts (i.e., infantile spasms, severe drug-resistent epilepsy, chorea and cortical visual impairment). Delayed myelination of the anterior portion of the corpus callosum, severe cerebral atrophy and pachygyria were found at the MRI imaging. Starting from the clinical case, the AAs were able to recapitulate the SNV deletion in a mice model of the disease (Foxg1 c946del). In doing so they generated the apparently first clinically-relevant mouse model of FOXG1 syndrome and provide a comprehensive analysis of this mouse line, thus revealing new mechanistic insights into the FOXG1 syndrome. Further, the AAs demonstrate that postnatal administration of Plp1-targeting antisense oligonucleotides in the Foxg1 c946del mice improves neurological deficits, thus suggesting a new target for therapeutic strategies mitigating disease phenotypes in FOXG1 syndrome patients. In my own opinion, the current study opens new horizons on the FOXG1 syndrome, and the corresponding Ms. is nicely written.
Author Response
FOXG1 is a rare neurodevelopmental disorder of the telencephalon for which there is neither cure nor clinically translatable experimental models. In this experimental research the Authors describe a clinical case of FOXG1 syndrome (10-yr-old male diagnosed at age 2 years after a screening for common neurodevelopmental disorder gene variants). The clinical phenotype was consistent with the features reported in the FOXG1 syndrome pts (i.e., infantile spasms, severe drug-resistent epilepsy, chorea and cortical visual impairment). Delayed myelination of the anterior portion of the corpus callosum, severe cerebral atrophy and pachygyria were found at the MRI imaging. Starting from the clinical case, the AAs were able to recapitulate the SNV deletion in a mice model of the disease (Foxg1 c946del). In doing so they generated the apparently first clinically-relevant mouse model of FOXG1 syndrome and provide a comprehensive analysis of this mouse line, thus revealing new mechanistic insights into the FOXG1 syndrome. Further, the AAs demonstrate that postnatal administration of Plp1-targeting antisense oligonucleotides in the Foxg1 c946del mice improves neurological deficits, thus suggesting a new target for therapeutic strategies mitigating disease phenotypes in FOXG1 syndrome patients. In my own opinion, the current study opens new horizons on the FOXG1 syndrome, and the corresponding Ms. is nicely written.
We thank the reviewer for their comments and agree that the present study opens new horizons with at least one interesting therapeutic target. To the best of our knowledge, the c946del mice are indeed the first clinically-relevant mouse model ever generated.
Reviewer 2 Report
Comments and Suggestions for AuthorsThis manuscript has the following shortcomings:
1 Sections 4.10-13 related to animal behavior experiments should be supplemented with references to relevant methods. Meanwhile, these experiments did not set a positive control group, especially those related to epilepsy, which poses difficulties for readers to understand.
2 There is no annotation of 'a' in Fig4a.
Comments on the Quality of English LanguageMinor editing of English language required.
Author Response
This manuscript has the following shortcomings:
1) Sections 4.10-13 related to animal behavior experiments should be supplemented with references to relevant methods. Meanwhile, these experiments did not set a positive control group, especially those related to epilepsy, which poses difficulties for readers to understand.
We thank the reviewer for their comments and have now added the following note and reference related to the behavioural tests: All behavioral tests have been carried out as per Ke et al. [61].
We are a bit confused with the comment related to the “positive control group”. Indeed, sections 4.10-13 include the following behavioural tests: Rotarod, Grip strength, Elevated-plus-maze and Open field. These tests do not relate to epilepsy. Furthermore, in each of these tests, two groups are compared: the heterozygous c946del+/Δ, and their wildtype littermates (WT) as Controls. Note that, as mentioned in the manuscript, homozygous c946del Δ /Δ are not viable and cannot therefore be tested.
2) There is no annotation of 'a' in Fig4a.
We apologise for this editing oversight and have now added the Fig.4a numbering on the revised manuscript.
3) Minor editing of English language required.
We have thoroughly reviewed the manuscript for typos and grammatical errors but have not been able to identify obvious mistakes. We believe this should not prevent the readers from fully understand and/or validate our study. Note that reviewer 1 found the manuscript well written, and we previously submitted it to two native English speakers for proof-reading.
