WO2022058405A2 - Inhibiteurs d'histone-désacétylase et leurs utilisations - Google Patents

Inhibiteurs d'histone-désacétylase et leurs utilisations Download PDF

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WO2022058405A2
WO2022058405A2 PCT/EP2021/075426 EP2021075426W WO2022058405A2 WO 2022058405 A2 WO2022058405 A2 WO 2022058405A2 EP 2021075426 W EP2021075426 W EP 2021075426W WO 2022058405 A2 WO2022058405 A2 WO 2022058405A2
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inhibitor
gtf2i
use according
histone
histone deacetylase
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PCT/EP2021/075426
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WO2022058405A3 (fr
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Giuseppe Testa
Francesca Cavallo
Flavia TROGLIO
Giovanni FAGA
Daniele Fancelli
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Ifom - Istituto Firc Di Oncologia Molecolare
Istituto Europeo Di Oncologia S.R.L
Universita' Degli Studi Di Milano
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to histone deacetylase inhibitors and their pharmaceutical compositions for use for the prevention and/or treatment of autism spectrum disorder, in particular 7Dup and other forms of intellectual disability and autism.
  • Autism spectrum disorder comprises a highly prevalent group of neurodevelopmental disorders (NDD) affecting almost 1% of children. Children diagnosed with ASD exhibit impairments in language and social interaction coupled to stereotyped behaviors and, in many cases, the co-occurrence of varying degrees of intellectual disability [1],
  • ASD Due to its extremely high prevalence and the lack of effective therapies, ASD represents a major unmet medical need.
  • ASD phenotypically and genetically highly heterogeneous with over 400 identified causal genetic alterations reinforcing the view of ASD as a collection of rare genetic conditions [2],
  • the presence of similar core symptoms across the genetic spectrum of ASD suggests that few paradigmatic syndromes might make the understanding of ASD causes and therapeutic interventions feasible.
  • 7Dup patients show a range of ASD traits, especially in terms of varying degrees of language impairments_and social restriction. Even though 7Dup shares intellectual disability and developmental delay with the WBS, patients show the typical autistic traits, such as deficits in speech and social withdrawal (Fig. 1A).
  • the combination of symmetrically opposite CNVs resulting into symmetrically opposite behavioral phenotypes offers unique opportunities to dissect the dosage-vulnerable circuits that affect language competence and sociability. Consequently, compounds that modulate gene dosage alterations may provide therapeutic options into ASD pathophysiology that so far has been notoriously difficult.
  • iPSCs induced pluripotent stem cells
  • HTS high-throughput screening
  • HDACi histone deacetylase inhibitors
  • GTF2I recruits lysine demethylase 1 (LSD1) to repress transcription of critical neuronal genes, an effect that is rescued by inhibition of LSD1 [22], a potential target for therapeutic intervention.
  • LSD1 lysine demethylase 1
  • BAZ1B is a chromatin remodeler that is involved in maintenance and migration of neural crest cells playing an important role in the evolution of modem human faces and thus being a prime candidate to study disease-associated craniofacial alterations [24, 25]
  • CLIP2 is a microtubule-binding protein abundantly expressed in neurons whose haploinsufficiency might contribute to the cerebellar and hippocampal dysfunctions observed in the WBS [26]
  • EIF4H is a translation initiation factor mediating protein synthesis that might be involved in growth retardation in EIF4H knockout mice [27, 28],
  • HTS high-throughput screening
  • CNS central nervous system
  • iPSCs induced pluripotent stem cell lines
  • HDACi histone deacetylase inhibitors
  • the present data represent a unique opportunity for the development of a specific class of compounds for treating 7Dup and other forms of intellectual disability and autism.
  • the present invention provides a histone deacetylase inhibitor for use in the treatment of autism spectrum disorder and/or intellectual disability, especially forms of the autism spectrum disorder and/or intellectual disability featuring an increase in GTF2I levels.
  • GTF2I levels it is intended an increase with respect to the level of GTF2I in a healthy subject or in a subject not affected by an autism spectrum disorder and/or intellectual disability.
  • GTF2I has emerged as critical gene within 7ql l.23 region CNV for its role in cognitive- behavioral defects observed in mouse model and human studies (Malieri et al. 2011, Crespi et al. 2014). The levels of mRNA and protein of this transcription factor result altered compared with levels in healthy control -derived cells, mirroring the genetic dosage imbalance. GTF2I level is measured in in vitro patient-derived neuronal culture both at mRNA and at protein levels by RT-qPCR and Western Blot techniques, respectively. Then GTF2I levels may be measured at protein level and/or at mRNA level.
  • the autism spectrum disorder is 7Dup.
  • the inhibitor is a pan HD AC or HDAC1 and/or HDAC2 and/ or HDAC3 and/or HDAC6 inhibitor.
  • GTF2I levels may be measured at protein level and/or at mRNA level in any biological sample obtained from the subject.
  • said inhibitor is a hydroxamic acid, a benzamide or an aminobenzamide.
  • said inhibitor is selected from the group consisting of: Vorinostat, Romidepsin , Panobinostat, Belinostat, Entinostat, Domatinostat, Resminostat, Rocilinostat, Trichostatin A, Valproic acid, Dacinostat, Bisthianostat, Quisinostat hydrochloride, CUDC-101 , Scriptaid, Tefinostat, Givinostat, Mocetinostat, Chidamide, Abexinostat, Pracinostat, Butyric acid, Pivanex, 4-phenylbutyric acid (or sodium phenylbutyrate), Tucidinostat (or chidamide), Nanatinostat, Fimepinostat, Remetinostat, Ricolinostat, Tinostamustine, JNJ-26481585, RG2833, M344, APH-0812, CG-745, CKD-506, CKD-581, CXD-101, FX-322, YPL-001
  • said inhibitor is Vorinostat, Mocetinostat or RG2833.
  • the inhibitor is combined with a further therapeutic agent.
  • the further therapeutic agent is selected from the group consisting of: atypical antipsychotic drugs, psychostimulants, antidepressant agent, anti-epileptic agent, clonidine, rivastigmine, memantine, guanfacine, buspirone, atomoxetine, an epigenetic compound, a LSD1 inhibitor, a DNMT inhibitor, a histone methyltransferase (HMT) inhibitor, a EZH1/2 inhibitor, a PRMT inhibitor, a BET inhibitor, a DOT1L inhibitor, APTA-16, a Histone Lysine N Methyltransferase (EHMT2 or G9a) inhibitor, a dual inhibitor against G9a and DNMTs, a menin-MLLl (or KMT2A) interaction inhibitor, a SETD2 inhibitor.
  • atypical antipsychotic drugs atypical antipsychotic drugs, psychostimulants, antidepressant agent, anti
  • the further therapeutic agent may be any pharmacological intervention to treat ASD, in particular aspecific clinical issues associated with ASD (i.e. irritability, agitation, aggression, sleep disorders, seizures, hyperactivity, anxiety) and comprise different classes of drugs including: Atypical antipsychotic drugs: risperidone, aripiprazole, quetiapine, ziprasidone, olanzapine, Psychostimulants: methylphenidate, amphetamines, Adderall, dexmethylphenidate, Antidepressants: selective serotonine reputate SSRIs (Fluoxetine, sertraline, citalopram, escitalopram, and fluvoxamine, paroxetine), tryciclics (Mirtazapine), Anti-epileptic agent: lamotrigine, oxcarbazepine, diazepam, levetiracetam, divalproex Sodium, clonazepam, carbamazepine
  • the further therapeutic agent may also be an epigenetic compound: a molecule that targets an epigenetic regulator or may itself be an epigenetic regulator.
  • said epigenetic regulator is preferably defined as any protein able to directly regulate genic transcription through interaction with DNA, RNA or chromatin.
  • a molecule that targets an epigenetic regulator may be selected from the group consisting of: LSD1 inhibitors, DNMT inhibitors, histone methyltransferase (HMT) inhibitors such as EZH1/2 inhibitors or PRMT inhibitors, BET inhibitors.
  • LSD1 inhibitors LSD1 inhibitors
  • DNMT inhibitors DNMT inhibitors
  • HMT histone methyltransferase
  • EZH1/2 inhibitors EZH1/2 inhibitors or PRMT inhibitors
  • BET inhibitors BET inhibitors.
  • the LSD1 inhibitor may be selected from the group consisting of: N-[4-[(lS,2R)-2- aminocyclopropyl]phenyl]-4-(4-methylpiperazin-l-yl)benzamide (DDP38003) and stereoisomers thereof such as N-[4-[(trans)-2-aminocyclopropyl]phenyl]-4-(4 methylpiperazin- l-yl)benzamide (DDP37368), ORY-1001 (or iadademstat), CC-90011, ORY- 2001 (or vafidemstat), any one or more of the compounds disclosed in WO2011131576, W02014086790, WO2015181380, WO2016034946, WO2017198780 or WO2019034774, all of which are herein enclosed by reference, GSK-2879552, IMG-7289 (or bomedemstat), INCB059872, 4SC-202 (or domatinostat), Seclidemstat
  • the DNMT inhibitor may be selected from the group consisting of: 5-azacytidine, 5-aza-2’- eoxycytidine, CC-486, 4'-thio-2'-deoxycytidine, 5aza-4'-thio-2'-deoxycytidine, Guadecitabine sodium (SGI-110), Zebularine, CP -4200, Flucytosine, Roducitabine, NSC-764276, EF-009, KM- 101, NTX-301, Sinefungin, an antisense oligonucleotide such as MG-98 or a pharmaceutically acceptable salt, hydrate or solvate thereof and/or combinations thereof.
  • the HMT inhibitor may be: an EZH1/2 inhibitor selected from the group consisting of: Tazemetostat hydrobromide, Valemetostat, ZLD1039, GSK926, GSK126, PF-06821497, UNC1999, CPI-1205, MC-3629, CPI-0209, SHR-2554, CPI-169, EBI-2554, GSK-343, HM- 97594, IONISEZH-22.5Rx, JQEZ- 5, MS-1943, ORS-1, TBL-0404, KM-301, GSK2816126 or a pharmaceutically acceptable salt, hydrate or solvate thereof and/or combinations thereof, and/or a PRMT inhibitor, such as a PRMT5 inhibitor or a PRMT1 inhibitor, preferably said PRMT5 inhibitor is selected from the group consisting of: GSK3326595, JNJ- 64619178, PF-06939999, PRT-543, PRT-811, JBI-778, GSK-3235025 or a
  • the BET inhibitor may be selected from the group consisting of: LBET762 (or molibresib), CPI- 0610, OTX015, RVX-280 (or apabetalone), ODM-207, PLX- 2853, ZEN-3694, ABBV-744, AZD-5153, BI-894999, JQ-1 BOS-475, CC-90010, CC-95775, Mivebresib, BPL23314, SYHA- 1801, ARV-771, CK-103, dBET-1, GSK-3358699, MA-2014, MS-417, NEO-2734, NHWD- 870, NUE-7770, OHM-581, PLX-51107, QCA-570, RVX-297, SF-2523, SF-2535, SRX-3177, SRX-3262, ZBC-260, DCBD-005, KM-601, MZ-1, SBX-1301, SRX-3225, ZL-0580, N
  • the invention also provides a method to identify a subject to be treated with a histone deacetylase inhibitor for the treatment of autism spectrum disorder and/or intellectual disability comprising measuring the level of GTF2I in a biological sample of said subject and comparing said measured level to a control level.
  • Control level may be the level of GTF2I in a healthy subject or a subject not affected by autism spectrum disorder and/or intellectual disability.
  • the invention also provides a method to monitor the efficacy of a histone deacetylase inhibitor for the treatment of autism spectrum disorder and/or intellectual disability in a subject comprising measuring the level of GTF2I in a biological sample of said subject and comparing said measured level to a control level.
  • Control level may be the level of GTF2I in said subject before the start of the treatment with the inhibitor or the level of GTF2I in said subject at a different time point in respect to the measurement.
  • ASD Autism spectrum disorder
  • HDAC inhibition may be measured by any conventional methods known in the art, as well as described herein.
  • HDAC inhibitors block the action of histone deacetylases, wich remove the acetyl groups from the lysine residues in core histones leading to a condensed and transcriptionally silenced chromatin (Dokmanovic M et al. 2007).
  • the action of HDACi can result in either the up-regulation or the repression of gene expression.
  • HDACi activity is analyzed at different HDAC inhibitor concentrations by measuring HDAC substrate fluorescence in in vitro assay. Test inhibitors are diluted to different concentrations and a cell nuclear extract, with fluorescent HDAC substrate are added. The reaction is allowed to proceed for 10 min at 25°C and the mixture is assayed for HDAC activity.
  • a HDAC inhibitor is any known HDAC inhibitor, for instance as indicated in Table 1 below, or in Ho et al. J. Med. Chem, https://dx.doi.org/10.1021/acs.jmedchem.0c00830, such as Vorinostat (trade name; ZOLINZA®), Romidepsin (trade name; Istodax®), Panobinostat (trade name; FARYDAK®), Belinostat, Entinostat, Domatinostat, Resminostat, Rocilinostat, Trichostatin A, Valproic acid, Dacinostat, Bisthianostat, Quisinostat hydrochloride, CUDC-101 , Scriptaid, Tefinostat, Givinostat, Mocetinostat, Chidamide, Abexinostat, Pracinostat, Butyric acid, Pivanex, 4- phenylbutyric acid (or sodium phenylbutyrate), Tucidinostat (or chidamide, trade name
  • HD AC inhibitors in particular those listed above, and pharmaceutical compositions comprising the same can be administered for the uses of the present invention by conventional methods and formulations well known in the art.
  • the administration regime, dosage and posology will be determined by the physician according to his experience, the disease to be treated and the patient’s conditions.
  • compositions will be in solid or liquid form, suitable for oral, parenteral, intravenous, intra-arterial or other suitable routes of administration.
  • the pharmaceutical compositions according to the present invention contain, along with the active ingredient or ingredients, at least one pharmaceutically acceptable carrier and/or excipient.
  • These may be particularly useful formulation coadjuvants, e.g. solubilising agents, dispersing agents, suspension agents, and emulsifying agents.
  • the HDAC inhibitor is administered in a “pharmaceutically effective amount”.
  • the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, drug combination, the age, body weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • an effective dose will be from 0.01 mg/kg to 100 mg/kg, preferably 0.05 mg/kg to 50 mg/kg.
  • Compositions may be administered individually to a patient or may be administered in combination with other agents, drugs, hormones, irradiation or surgery.
  • the therapeutically effective dose can be estimated initially either in cell culture assays or in animal models, usually mice, rats, guinea pigs, rabbits, dogs, monkeys or pigs.
  • FIG. 1 Symmetric copy number variations at 7qll.23.
  • Ubc human Ubiquitin constitutive promoter
  • rtTA TET transactivator promoter gene
  • NGN2 Neurogenin2 gene
  • Puro ⁇ Puromicin resistance gene
  • Bsd ⁇ Blasticidin resistance gene
  • white triangles represent terminal repeats of the transposon.
  • FIG. 1 NGN2-mediated conversion of iPSCs to iNs.
  • ROCKi ROCK inhibitor
  • Doxy doxycycline
  • Puro puromycin.
  • C Day 28 WBS01CN3 neurons express mature excitatory cortical neuron markers: NeuN, TUBB3, Synapsin 1/2, MAP2, VGLUT1 and SATB2.
  • Relative expression was measured by RT-qPCR, to GAPDH and results were arbitrarily normalized to mRNA levels of CTL (asterisks indicate statistical significance according to a one way ANOVA test: *P ⁇ 0.05, **P ⁇ 0.005, ***P ⁇ 0.0005, ****P ⁇ 0.0001).
  • Figure 3. HTS workflow outline. A Compounds were tested at 10 pM for 48 h on NGN2 neurons seeded in 96-well plates. After RNA extraction and cDNA preparation, custom TaqMan Array 384-well plates were assembled through an automated TEC AN Freedom EVO workstation. RT-qPCR were performed in QuantStudioTM 7 Flex Real-Time PCR System.
  • B D API-stained (left) and GFP-positive (right) WBS01CN3 NGN2 neurons counted with Cellomics during differentiation.
  • Figure 4 Primary screening of a pharmaceutical compound library.
  • a Composition of the compound library (1478 compounds).
  • B Robustness of primary HTS setup For each batch of plates, control run statistics with average Ct values (Avg.) of GAPDH and SRSF9 housekeeping genes, their S.D. and CV are summarized.
  • C Exclusion and inclusion criteria of the primary screening D Scatter plot of the primary screening. Fold changes compared with DMSO control were plotted for each gene (BAZ1B, CLIP2, EIF4H, GTF2I) in WBS01CN3 NGN2 neurons. Selected hits are shown for GTF2I.
  • HDAC inhibitors lower the mRNA and the protein levels of GTF2I in 7Dup iNs.
  • a Relative expression of BAZ1B, CLIP2, EIF4H and GTF2I mRNA (mean ⁇ S.D.) in WBS01CN3 and DupO2K iNs (n 2) treated with Domatinostat compared to control (DMSO). Error bars represent variation between lines of the two genotypes (Holm-Sidak-corrected t test ***p ⁇ 0.001).
  • CTL CtlOlC, Ctl08A;
  • WBS WBS01CN3, WBS02C;
  • 7Dup DUP01GN4, DupO2K.
  • B Representative images of tracings from 7Dup, healthy CTL and WBS iPSC-derived neurons.
  • FIG. 7 Effect of HD AC inhibitors on the expression levels of WBSCR genes.
  • HDAC inhibitors slightly impact on cell viability and lower GTF2I protein levels.
  • Cell viability, Histone H3 acetylation and GTF2I protein levels were measured in NGN2-induced neurons DIV28 exposed to the indicated doses of the selected HDAC inhibitors.
  • A. Cell viability of four iN DUP lines after being treated with Vorinostat, Mocetinostat, or RG2833 for 48 h.
  • HDAC inhibitors lower GTF2I protein levels in 7Dup cortical organoids. GTF2I protein levels were measured in cortical organoids DIV100 exposed to the indicated doses of the selected HDAC inhibitors for 15 days.
  • A Representative immunoblot showing levels of GTF2I, and ac-H3 in DUP04A cortical organoids; GAPDH, loading control.
  • B Quantification from two 7Dup lines in two different rounds of differentiation treated with HDACi for 15 days relative to mock control (mean ⁇ SE).
  • iPSC lines were infected with an activator lentivirus, containing the reverse tetracycline transactivator (rtTA) constitutively expressed under the control of the UbC promoter, and an effector lentivirus, containing an NGN2-P2A-EGFP-T2A-Puro cDNA under the control of the tetracycline responsive element [29] (Fig. IB, top).
  • Infected iPSCs were sorted as single cells in 96-well plates, selected based on the round morphology of colonies and gradually expanded. Selected lines were then induced for one day adding doxycycline to the medium. GFP- positive lines were then selected and expanded, further being stabilized and characterized. Through this system the inventors generated the iPSC monoclonal line WBS01CN3 (WBS) and DUP01GN4 (7Dup).
  • Mouse Ngn2 cDNA under tetracycline-inducible promoter (tetO), was transfected into iPSCs by a newly developed enhanced PiggyBac (ePB) transposon system [9, 30, 31] (Fig. IB, bottom).
  • ePB enhanced PiggyBac
  • NNN2 inducible Neurogenin-2
  • Electroporations were performed using the Neon Transfection System (MPK 10096, Thermo Fisher Scientific). iPSCs were selected using blasticidin 5 pg/ml (R21001, Gibco) for five days and stable iPSC lines were stocked. Through the ePB system the inventors generated the following polyclonal lines: CtlOlC, Ctl08A (CTL): WBS01C , WBS02C (WBS); Dup03B, DupO4A, DupOlG, DupO2K (7Dup).
  • iPSCs cortical glutamatergic neurons
  • GIBCO Accutase
  • mTeSRTM mTeSRTM supplemented with ROCK inhibitor
  • iPSCs were then cultured in MEM1, composed by DMEM/F12 1 :1 (Euroclone/Gibco) supplemented with NEAA 1%, N2 1%, BDNF 10 ng/ml, NT-3 10 ng/ml, Laminin 0,2 pg/ml and 2 pg/ml doxycycline hydrochloride, from day 0 to day 1.
  • MEM1 composed by DMEM/F12 1 :1 (Euroclone/Gibco) supplemented with NEAA 1%, N2 1%, BDNF 10 ng/ml, NT-3 10 ng/ml, Laminin 0,2 pg/ml and 2 pg/ml doxycycline hydrochloride, from day 0 to day 1.
  • NBM Plus composed by Neurobasal Plus (Thermo Fisher Scientific) supplemented with 50x B27 Plus supplement (GIBCO, Thermo Fisher Scientific), Glutamax 0.25% (Thermo Fisher Scientific) and 2 pg/ml doxycycline hydrochloride.
  • NBM Plus composed by Neurobasal Plus (Thermo Fisher Scientific) supplemented with 50x B27 Plus supplement (GIBCO, Thermo Fisher Scientific), Glutamax 0.25% (Thermo Fisher Scientific) and 2 pg/ml doxycycline hydrochloride.
  • differentiated neuronal cells were dissociated with Accutase and seeded into poly-D-lysine coated 96-well plates (3842, Corning) at a density of 20.000 cells/well in NBM Plus; culture medium was then changed 50% once a week until day
  • Neurons were fixed in 4% paraformaldehyde in PBS for 15 min. at room temperature immediately after removal of culture medium, and pipetting was done slowly to prevent dislodging cells from coverslips. The cells were then washed 3 times for 5 min. with PBS, permeabilized with 0.1% Triton X-100 in PBS for 15 min., and blocked in 5 % donkey serum in PBS for 30 min. After blocking, the cells were incubated with primary antibodies diluted in blocking solution overnight at +4°C. The cells were washed 3 times with PBS for 5 min. and incubated with secondary antibodies at room temperature for 1 h. Nuclei were then stained with DAPI solution 1 :5000 at room temperature for 10 min. Coverslips were rinsed in sterile water and mounted on a glass slide with 7-8 pl of Mowiol mounting medium.
  • Neurons in 96-well plates were fixed in 4% paraformaldehyde in PBS, permeabilized with 0.1 % Triton X-100 and then counterstained with DAPI (1 :5000) to enable autofocusing of the automated Thermo Scientific ArrayScan VTI High-content screening microscope (Cellomics). Cell counting of validated objects was done in the DAPI channel and in the GFP channel.
  • the TECAN has been programmed to prepare up to 20 96-well plates in a single run, which would produce 1080 individual datapoints.
  • the modular robotic scripts were designed as building blocks for users with minimal automation programming experience to assemble an automated process from cells preparation to sample analysis.
  • the inventors prepared scripts for compound treatment, RNA and cDNA dilution (and predilution if necessary), reagent addition (Cells-to-CT, RT), and sample re-positioning in prespotted 384-well plates.
  • Each module contained user-friendly interfaces for inputs of assay variables, such as volumes, dilution factors and plate maps.
  • the liquid-handling robot used in this work is a Tecan Freedom EVO-2 150 liquid handling unit equipped with a 96-well headadapter with filter tips; the pipetting volume range was from 10 to 1000 pl.
  • the Freedom EVO worktable was loaded with three solution reservoir carriers (1 x Trough 100 ml, 3 Pos. and 2 x Trough 25 ml, 3 Pos.), two 96-well plate carriers (96-well, 6 Pos.), and one 384-well plate carrier (96-well, 3 Pos.).
  • Quantitative RT-PCR A custom TaqMan Cells-to-CTTM kit (Invitrogen AMI 729) was used to extract the RNA and perform reverse transcription to obtain cDNA, according to the manufacturer’s instructions. After media aspiration, 30 pl of 2x lysis solution, with diluted DNasel, were added to 30 pl of the remaining buffer in each well; then the plate was incubated for 5 min. at room temperature. Subsequently Stop solution (3 pl) was added and the solution was incubated at room temperature for 2 min. Then, 30 pl of lysates were transferred to a new PCR plate with 40 pL of reverse transcription enzyme mix previously added to each well. The thermal cycling conditions were: 60 min. at 42°C, and 5 min. at 85 °C.
  • cDNA was diluted with 50 pl of water and then a 5 -pl aliquot of each cDNA reaction was added to 5 pl of each TaqMan master mix reaction into pre-spotted custom 384-well plates.
  • a QuantStudio 6 Flex Real-Time PCR system (Applied Biosystems) was utilized to determine the Ct values. Relative mRNA expression levels were normalized and analyzed through the comparative delta-delta Ct method using the QBase Biogazelle software.
  • the inventors used a strategy based on fold-difference analysis of target genes to housekeeping genes, comparing compound- to DMSO control-treated wells. Hits were defined as more than 2- fold increase or less than 0,5-fold decrease in at least three out of four genes, or in at least GTF2I. Thirty -five compounds fulfilled the first criteria and 36 compounds the second one in the primary screening.
  • pAb anti-GTF2I 1 1000 (A301- 330A, Bethyl Laboratories), pAb anti-GAPDH 1 :5000 (ABS16, Merck Millipore), Histone H3K9ac 1 : 1000 (Abeam ab4441), Cleaved PARP (Asp214) 1 : 1000 (CellSignal. 5625). and secondary antibody horseradish peroxidase-conjugated donkey anti-rabbit (Pierce).
  • Epigenetic compound library Selleckchem Cat. N° LI 900; Bioactive compound library: Food and Drug Administration (FDA) approved and clinical compounds selected from the Library of Pharmacologically Active Compounds (LOPAC, Sigma) and the Spectrum Collection (MicroSource Inc).
  • FDA Food and Drug Administration
  • Protein extraction and immunoblotting Proteins were extracted from iNs grown in 10 cm or 6-well plates by washing the cells with ice- cold PBS, followed by immersion in lysis buffer (25 mM Hepes pH 7.5, 300 mM NaCl, 10% glycerol, 1% NP-40) supplemented with cOmpleteTM protease inhibitor cocktail (Sigma). Lysates were sonicated using the Bioruptor Sonication System (UCD200) for three cycles of 30 s with 60-s breaks at high power and then centrifuged at 13.000g for 15 min. Protein quantification was performed using the Bradford protein assay (Bio-Rad) following the manufacturer's instructions.
  • Protein extracts (10-20 pg per sample) were run on a precast NuPAGE 4-12% Bis-Tris Gel (NP0335BOX, Life Technologies), transferred to a nitrocellulose membrane and blocked in TBST (50 mM Tris, pH 7.5, 150 mM NaCl and 0,1% Tween-20) and 5% milk at room temperature for 1 h.
  • Primary and secondary antibodies were diluted in TBST and 5% milk.
  • the immunoreactive bands were detected by ECL (GE Healthcare) and imaged with a ChemiDoc XRS system (Bio-Rad Laboratories). Densitometric analysis was performed using the ImageLab 4.1 Software (Bio-Rad Laboratories).
  • Number of viable cells was estimated by automatic counting with Fiji.
  • 3xl0 5 cells/well were plated in poly-D-lysine coated 6-well flat bottom plates (Coming) with 4 replicates per condition and induced to differentiate into neurons for 28 days.
  • Cells were treated with HDACi for 48h and neurons images were acquired at 20x magnification using the ScanR Microscope. Image acquisition was done in automated manner, recording 9 field each well; two channels were acquired per batch for GFP and visible light. Measurements were performed every 24 h. Each data point was normalized to a DMSO treated well.
  • Cortical organoids were differentiated as previously described (Lopez-Tobon 2019). Briefly 2x10 A5 iPSCs cells per well were plated into ultra-low-attachment 96well plastic plates (Corning) in FGF2-free knockout serum medium. For the first 24 h (day 0), the medium was supplemented with the ROCK inhibitor Y-27632 (EMD Chemicals). For neural induction, dorsomorphin (Merck, 5 pM) and SB-431542 (Tocris, 10 pM) were added to the medium until day 5.
  • ROCK inhibitor Y-27632 EMD Chemicals
  • dorsomorphin Merck, 5 pM
  • SB-431542 Tocris, 10 pM
  • NM neural medium
  • Neurobasal Invitrogen 10888
  • B-27 serum substitute without vitamin A Invitrogen 12587
  • GlutaMax 1 100 (Fisher 35050071), 100 U/ml penicillin and streptomycin (Invitrogen) and 50 mM b -Mercaptoethanol (Gibco 31350010).
  • the NM was supplemented with 20 ng/ml FGF2 (Thermo) and 20 ng/ml EGF (Tocris) for 19 days with daily medium change in the first 10 days, and every other day for the subsequent 9 days.
  • HEK 293T cells Five million HEK 293T cells were plated in 10 cm plates and grown in 10% fetal bovine serum in DMEM. On the next day, cells were transfected with plasmids for gag-pol (10 pg), rev (10 pg), VSV-G (5 pg) and the target construct (15 pg) CaMKIIa-mK02, using the calcium phosphate method [79], On the next day, the medium was changed. On the day after, the medium was spun down in a high-speed centrifuge at 30,000g, at 4 °C for 2 h. The supernatant was discarded and 100 pl of PBS were added to the pellet and left overnight at 4 °C. On the next day, the solution was triturated, distributed into 10-pl aliquots and frozen at -80 °C.
  • neurons were infected with virus bearing CaMKIIa- mK02; specifically, 10 pl virus per 6cm plate from a standard preparation (see Virus preparation).
  • virus bearing CaMKIIa- mK02 specifically, 10 pl virus per 6cm plate from a standard preparation (see Virus preparation).
  • an appropriate number of vials of mouse astrocytes were thawed into a 10 cm plate, in order to obtain at least 1.25 million of astrocytes at day 8.
  • infected neurons were digested with accutase for 5 min., washed with PBS, counted, and seeded at a total density of at least 30.000 cells/cm 2 (300.000 cells/well in a 6-well plate) in a 1 :50 ratio with not infected neurons and in a 1 :1 ratio with mouse astrocytes, in poly-D-lysine-coated coverslips. Over the following weeks, the coverslips were monitored and those with at least 10 visible individual neurons were kept for image acquisition.
  • images of neurons were acquired at lOx magnification using the Leica DM6 Multifluo Fluorescence Microscope. Image acquisition was done in a semi-automated manner, with manual picking of individual neurons and batch acquisition. Two channels were acquired per batch for GFP and mK02.
  • NGN2-driven neurogenesis retains the defining transcriptional imbalances of 7qll.23 CNV
  • the inventors set out to establish HTS-proof conditions for the differentiation and maintenance of patient-derived cortical neurons, starting off with the NGN2-driven system of iPSC differentiation [29] and adapting it to HTS as follows.
  • the inventors reasoned that, in a HTS setting inherently prone to fluctuations in numerous technical variables, the use of lines with a fixed number of integrations would help reduce the confounding variables inherent to the differentiation of polyclonal batches with an unchecked diversity of copy number integrations of the NGN2 transgene.
  • the inventors used an NGN2 expressing lentivirus to generate a stable monoclonal iPSC line originally reprogrammed from a patient harboring the WBS deletion (hereafter WBS01CN3 line).
  • WBS01CN3 line a stable monoclonal iPSC line originally reprogrammed from a patient harboring the WBS deletion.
  • the inventors used a new formulation medium (NBM Plus) that allowed to replace astrocytes and minimize media changes, thus also reducing the automation complexity of the HTS.
  • NBM Plus new formulation medium
  • the inventors adapted the differentiation protocol to a HTS platform by first seeding the iPSCs and culturing them in large batches on Matrigel-coated 15 cm dishes and then detaching them for seeding on poly-D-lysine coated 96-well plates (Figure 2A).
  • the inventors validated the robustness of this protocol by both immunocytochemistry and qRT-PCR. Forced NGN2 expression converted iPSCs into mature neuronal morphology in 28 days with a rapid decline of the neural progenitor marker Nestin and an increase in the expression of the synaptic marker Synaptophysin (Figure 2B).
  • iPSC-derived NGN2-induced neurons expressed glutamatergic markers like vGLUTl, cortical markers such as SATB2 and the expected combination of both early neuron markers like TUBB3 and mature neuron markers as MAP2, NeuN and the synaptic marker Synapsin 1/2 (Figure 2C).
  • the inventors also analyzed the expression levels of SATB2,MAP2 and SYN1 in both WBS and 7Dup iNs compared to healthy control (CTL) iNs, using SyntaxinlA (STX1A), a WBSCR gene, as internal control of symmetrical dosage imbalance.
  • the inventors confirmed that the transcriptional levels of BAZ1B, CLIP2, EIF4H and GTF2I mirrored the symmetrical gene dosage in both WBS and 7Dup iNs compared to healthy control (CTL) iNs, confirming that the gene dosage imbalance is maintained upon cortical neuronal differentiation (Figure 2D) and hence that it represents a rational target for a mechanistically-based therapeutic intervention.
  • the inventors defined disease-relevant models for WBS and 7Dup suitable for HTS.
  • the inventors tested the differentiation protocol with a WBS line (WBS01CN3) to establish the proper conditions for adaptation to a miniaturized HTS format (Figure 3A).
  • the inventors obtained optimal cell-plating settings for 96-well plates using poly- D-lysine coated plates by seeding 20.000 cells/well.
  • Cellular growth and percentage of GFP positive cells were monitored by automated cell counting after Dapi-nuclear staining through five weeks of differentiation. An expected slight decrease of total cell number was observed over the course of differentiation, while GFP positive cells percentage remained stable around a 70%.
  • the inventors envisaged that promising compounds could restore mRNA levels of four genes in the WBS region, namely GTF2I, BAZ1B, CLIP 2 and EIF4H. Therefore, the inventors selected TaqMan qRT-PCR assays for measuring the expression levels of these genes against their internal controls GAPDH, SRSF9 and RPS18. Transcript levels were measured after cell lysis, RNA extraction, qRT-PCR and data quantification. DMSO had no major impact on growth of iNs and on mRNA levels up to 0,5 % DMSO (v/v) ( Figure 3D).
  • the inventors proceeded with a moderate-sized screening of around 100 96-well plates of iNs.
  • the inventors screened a library of 1478 small molecules in biological triplicate (4434 treatment conditions in total).
  • the present screening library comprises an extensive variety of compounds, including e.g. central nervous system (CNS) agents, natural compounds, hormonal agents, epigenetic and immune system modulators, antioxidants (Figure 4A).
  • CNS central nervous system
  • the compounds were selected analysing an internally available Chemical Collection of more than 200.000 compounds composed by FDA approved drugs, bioactive compounds (including preclinical and clinical compounds), a kinase target library, a fragment library and a commercially available screening library.
  • the inventors used the WBS patient-derived monoclonal line WBS01CN3 for the first HTS, looking for molecules that restore the gene dosage of BAZ1B, CLIP2, EIF4H and GTF2I n patient-specific iNs.
  • the inventors measured parameters of the screening workflow, as coefficient of variation (CV), to demonstrate consistency in Ct values in the four batches of cell plates. Differences in Ct values were minimal among replicate wells of the same batch giving a CV ⁇ 20% ( Figure 4B).
  • the strategy the inventors used to nominate candidate hits out of the 1478 compounds tested in triplicate was based on fold-difference analysis of WBS genes to housekeeping genes, comparing compound wells to DMSO control -treated wells.
  • HDAC inhibitors specifically lower the mRNA and the protein levels of GTF2I in 7Dup induced neurons.
  • the inventors generated several polyclonal lines, i.e. Dup03B, DupO4A, DupOlG, DupO2K, using the ePB based system containing the same NGN2 cassette that the inventors used for the monoclonal lines.
  • the inventors thus tested domatinostat at the same concentration (10 pM for 48 h) in 28 day-old 7Dup iNs (i.e. harboring the symmetrically opposite genetic lesion) and confirmed the specific effect of lowering GTF2I levels (Figure 5A).
  • the inventors thus set out to expand this observation to other compounds within the epigenetic subset of the present HTS library.
  • the inventors thus went on to validate the G7F2/-lowering effect of the three selected compounds on multiple 7Dup patient-derived lines, so as to secure the generalizability of their findings across a heterogeneity of human backgrounds harboring the 7ql l.23 duplication.
  • the inventors confirmed that the three selected HDACi lower the expression levels of GTF2I in 7Dup 28 day- old neurons derived from four genetically different iPSC lines, i.e. Dup03B (Figure 5C), DupO4A (Figure 5E), DupOlG (Figure 5G) and DupO2K (Figure 51).
  • HDAC inhibitors have minor effect on cell viability and lower protein levels of GTF2I in 7Dup cortical organoids.
  • the inventors relied on the effect obtained at the protein level and on cell viability, to evaluate the compounds capable of fine-tuning the level of GTF2I, avoiding excessive decreases that might spill into the WBS dosage range.
  • the inventors examined the effects of HDAC inhibitors on cell viability in iPSC-derived NGN2-induced neurons. To do this, iN at day 28 were treated once with increasing concentrations (0.1-10 pM) of Vorinostat, Mocetinostat and RG2388 for 48 h ( Figure 8 A) and living cells were counted 48 hours post-treatment in four different lines. Treatment with Vorinostat, Mocetinostat and RG2388 at 0.1 and 1 pM had no significant effect on cell viability (Figure 8 A).
  • Vorinostat and Mocetinostat at highest concentration induced a 20- 30% reduction of cell viability (Figure 8 A) and have raised apoptosis as confirmed by Cleaved- PARP accumulation (Figure 8 B).
  • the effect on GTF2I level was confirmed as dose dependent in four different patient-derived iN lines ( Figure 8 B, D).
  • WBS and 7Dup are two paradigmatic neurodevelopmental disorders whose unique alignment of symmetrically opposite CNV and symmetrically opposite phenotypes in sociality and language provides unique glimpses into the molecular architecture of ASD.
  • This first exploration, viaHTS, of a large chemical space in search of clinically relevant compounds to restore the transcriptional dosage of key WBSCR genes led us to the following results.
  • the inventors introduced an adaptation of the NGN2-driven conversion of iPSCs into functional iNs [29, 36] to an automation-intensive HTS format, which can serve as template to streamline further drug screening and/or repurposing campaigns targeting cortical glutamatergic neurons.
  • HDACi prevent the deacetylation of histones thereby facilitating gene expression.
  • HDACi vorinostat, mocetinostat and RG2833
  • vorinostat is an FDA-approved Pan HDAC -inhibitor that crosses the BBB [48]; mocetinostat is a class I selective HDACi that passes the BBB in mice [48], and RG2833 is a brain-penetrant HDACi with a specificity for HDACI and HDAC3 [49] (Table 1).
  • vorinostat is among four HDACi, along with panobinostat, belinostat and depsipeptide (romidepsin), that have already received FDA approval for the treatment of a number of conditions, including refractory cutaneous T-cell lymphoma, refractory multiple myeloma and peripheral T-cell lymphoma, respectively [50, 51, 52, 53], Besides existing approval, the present results provide additional support for vorinostat as the most promising HDACi amongst the ones the inventors identified. Specifically, the inventors probed the effect of the three compounds also at the protein level, aiming at scoring the best performance on two criteria: i) the narrow range of the effect, i.e.
  • HDAC 1 and 3 are included in class I HDAC, while HDAC 6 belongs to another class (lib).
  • HDAC 1 is expressed primarily in neurons and it mainly functions in combination with HDAC2 in several repressor complexes; HDAC3 is the most highly expressed class I HDAC in the brain and it is also predominantly expressed in neurons, playing an essential role in brain development [55]; lastly, HDAC6 is involved in processes related to neurodegeneration, binding to ubiquitinated protein aggregates [56],
  • Drug repositioning has the potential to provide new therapeutic alternatives for patients as well as “new” innovative use for “old” drugs thus delivering relevant clinical improvement while reducing their clinical development time compared to de novo development of new chemical entities.
  • HDACIs Histone deacetylase inhibitors
  • Lane AA Chabner BA. Histone deacetylase inhibitors in cancer therapy. J Clin Oncol. 2009 Nov 10;27(32):5459-68.
  • Panobinostat A histone deacetylase inhibitor for the treatment of relapsed or refractory multiple myeloma. Am J Health Syst Pharm. 2016 Apr l;73(7):441-50.
  • HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington’s disease transgenic mice. Proc Natl Acad Sci USA. 2008 Oct 7;105(40): 15564-9.

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Abstract

La présente invention concerne des inhibiteurs d'histone-désacétylase et des compositions pharmaceutiques les comprenant, destinés à être utilisés pour la prévention et/ou le traitement d'un trouble du spectre de l'autisme, en particulier 7Dup, et d'autres formes de déficience intellectuelle et d'autisme.
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