Reprogramming-based models of neurodevelopmental disorders and uses thereof
The present invention relates to iPSC produced from fibroblast obtained from a subject affected by a neurodevelopmental disorder entailing intellectual disability (ID) and/or a disorder belonging to the Autism Spectrum Disorder (ASD) and/or Schizophrenia (SZ) and uses thereof. The present invention also relates to a cortical neural progenitor cell or a terminally differentiated cortical glutamatergic or gabaergic neuronal cell or a neural crest stem cell line, a mesenchymal stem cell line produced from the iPSC or iPSC line. The invention also relates to method for identifying a compound for the treatment and/or prevention of a neurodevelopmental disorder entailing intellectual disability (ID) and/or a disorder belonging to the Autism Spectrum Disorder (ASD) and/or Schizophrenia (SZ) and to a LSD1 inhibitor or a HDAC2 inhibitor for use in the treatment of such disorders.
1. A method of preventing and/or treating an at least one behavior-cognitive defect in an individual with a copy number variation (CNV) at 7q11.23 , comprising:
administering an LSD1 inhibitor to said individual; wherein the said administration disrupts the transcriptional repressive activity of LSD1 on lysine 4 of histone H3 tails;
wherein the degree of LSD1 inhibition sufficiently reduces the function of the GTF2I transcriptional co-repressor complex;
wherein the disruption of GTF2I function increases BEND4 upregulation;
wherein genes which are imputable to GTF2I also change expression significantly upon LSD1 inhibition, such as but not limited to expression of one or more of IGF1R, SDH2, ARRB1, NRK, EPHA4, IGFBP3, SERINC5, PRICKLE1, NLGN2, PTPRD, COX7B, ADCY1, MAP2, EDHA4, and COL9A1, or any combination therein.
2. The method of claim 1 , wherein the subject has an intellectual disability and/or Autism Spectrum Disorder.
3. The method of claim 1 , wherein the copy number variations (CNV) at 7q11.23 causes 7dupASD.
4. The method of claim 1 , wherein the copy number variations (CNV) at 7q11.23 causes a 7q11.23 microduplication-dependent Schizophrenia.
5. The method of claim 1 , wherein the LSD1 inhibitor is N-[4-[trans-2-aminocyclopropyl]phenyl]-3-(2-oxooxazolidin-3-yl)benzamide hydrochloride.
6. The method of claim 1 , wherein the LSD1 inhibitor is (trans)-N1-((1R, 2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine hydrochloride.
7. The method of claim 1 , wherein treatment with the LSD1 inhibitor significantly increases expression of one or more of IGFBP3, ANXA2, MAP2, ELF3, EPHA4, ATP2A3, PRICKLE1, NRK, CDH2, IGFBP5, GLDC, DPPA2, ARRB1, SERINC5, COL9A1, or COX7B.
8. The method of claim 1 , wherein treatment with the LSD1 inhibitor significantly decreases expression of one or more of NLGN2, MYSM1, PTPRD, ATAD5, IGF1R, or RHBDF2.
9. The method of claim 1 , wherein treatment with the LSD1 inhibitor significantly alters expression of one or more of NACAD, JAZF1, ADCY1, ZNF578, NID1, ITPR2, FOXN3, or FAM189A2.
10. The method of claim 1 , wherein the at least one behavioral-cognitive defect is selected from the group consisting of autistic-like behaviors, attention deficit hyperactivity disorder (ADHD), language impairment, anxiety, intellectual disability, global developmental delay, learning difficulties, impairment in adaptive behavior, language delay, oral motor and speech sound delay, oral motor and speech sound disorder, social anxiety, separation anxiety, social phobia, autism spectrum disorder (ASD), selective mutism, oppositional defiant disorder (ODD), repetitive behaviors/movements, stereotypies, compromised visuo-motor integration, social communication impairment/deficits or any combination thereof.