Granted Patent
B2
US 12,201,631 · App. 17/845,961 · Granted Jan 21, 2025
Methods and compositions for reducing tactile dysfunction and anxiety associated with autism spectrum disorder, Rett syndrome, and fragile X syndrome
Assignee:
President and Fellows of Harvard College
A61K31/495A61K31/196A61K31/36A61K31/4196A61K31/437A61K31/4465A61K31/4535A61P25/00C12N15/86A61K9/0019A61K45/06
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Abstract
The present invention features a method of reducing tactile dysfunction or anxiety in a subject diagnosed with Autism Spectrum Disorder, Rett Syndrome, or Fragile X syndrome by administering a GABA A agent having reduced blood brain barrier or by expressing a nucleic acid encoding an exogenous alpha or beta subunit of a GABA A receptor in dorsal root ganglion neurons in the subject using a vector.
Claims (16)
1. A method of reducing anxiety in a subject diagnosed with Autism Spectrum Disorders (ASD), Rett Syndrome (RTT), or Fragile X Syndrome, by administering to the subject a therapeutically effective amount of a peripherally-restricted GABA A agent, wherein the GABA A agent is not isonipecotic acid, gamma-amino butyric acid (GABA), isoguvacine, homotaurine, acetylaminopropane sulfonate, trans-amino-4-crotonic acid (TACA), 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol (THIP), 5-oxo-zaleplon, tiagabine, 3-((aminoiminomethyl) thio)-2-propenoic acid (ZAPA), L-838,417, or stiripentol.
2. The method of claim 1 , wherein the GABA A agent is a GABA A receptor agonist.
3. The method of claim 1 , wherein the GABA A agent is a positive allosteric modulator of the GABA A receptor.
4. The method of claim 1 , wherein said subject is a human.
5. The method of claim 1 , wherein the GABA A agent is trans-aminocyclopentane-3-carboxylic acid.
6. The method of claim 2 , wherein the GABA A receptor agonist is N-methyl isoguvacine, acetylaminopropane sulfonate, homohypotaurine, β-guanidinopropionic acid, trans-aminocyclopentane-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
7. The method of claim 2 , wherein the GABA A receptor agonist is a compound of Formula (I):
or a pharmaceutically acceptable salt or tautomer thereof;
wherein R is selected from the group consisting of acetyl, or a group of the general Formula (Ia):
where R′ is C 1 -C 8 alkyl, phenyl, phenyl substituted in the 4 position with halogen, C 1 -C 4 alkoxy, or C 1 -C 4 alkyl; or phenylalkyl in which the phenyl group may be substituted in the 4-position with halogen, C 1 -C 4 alkoxy, or C 1 -C 4 alkyl.
8. The method of claim 3 , wherein the positive allosteric modulator of the GABA A receptor is selected from the group consisting of 5-nitro-alpha-oxo-N-(1R)-phenylethyl1-1H-indole-3-acetamide (TCS 1205), 5-nitro-alpha-oxo-N-(1R)-phenylethyl1-1H-indole-3-acetamide, 5-oxo-zaleplon, homo-β-proline, 5-fluoro-2-[4-fluoro-3-[8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-3-yl]phenyl]benzonitrile (TP 003), and [1-[(Z)-2-chloro-2-(2,4-dichlorophenyl)vinyl]-1H-1,2,4-triazole] (loreclezole).
9. The method of claim 1 , wherein the subject has been diagnosed with ASD.
10. The method of claim 1 , wherein the subject has been diagnosed with RTT.
11. The method of claim 1 , wherein the subject has been diagnosed with Fragile X Syndrome.
12. The method of claim 1 , wherein the subject is characterized as having a deficiency in Mecp2, Gabrb3, or Shank3.
13. The method of claim 1 , wherein the subject is characterized has having abnormal habituation to aversive stimuli.
Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Sep 26, 2022
From: OREFICE, LAUREN L.
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 061207/0438 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Sep 26, 2022
From: GINTY, DAVID D.
To: HOWARD HUGHES MEDICAL INSTITUTE
Reel/Frame 061207/0449 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Sep 26, 2022
From: HOWARD HUGHES MEDICAL INSTITUTE
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 061207/0452 →
Continuity (4)
Continuation
16308422
Provisional Application
62421807
· Nov 14, 2016
Provisional Application
62347260
· Jun 8, 2016
References Cited (245)
US 3243427A
· Recder et al.
· 1966
[cited by applicant]
US 3516988A
· Schmitt
· 1970
[cited by applicant]
US 3862149A
· Cortel et al.
· 1975
[cited by applicant]
US 4065451A
· McCaully et al.
· 1977
[cited by applicant]
US 4122265A
· Jaunin
· 1978
[cited by applicant]
US 4382938A
· Kaplan et al.
· 1983
[cited by applicant]
US 4460592A
· Kaplan et al.
· 1984
[cited by applicant]
US 4492695A
· Kaplan et al.
· 1985
[cited by applicant]
US 4820834A
· Evans et al.
· 1989
[cited by applicant]
US 4879293A
· Hiraga et al.
· 1989
[cited by applicant]
US 5618824A
· Schmidt et al.
· 1997
[cited by applicant]
US 5776930A
· Lynch, Jr. et al.
· 1998
[cited by applicant]
US 5786357A
· Young et al.
· 1998
[cited by applicant]
US 6927290B2
· Miki et al.
· 2005
[cited by applicant]
US 7456173B2
· Jerussi et al.
· 2008
[cited by applicant]
US 8980887B2
· Yang et al.
· 2015
[cited by applicant]
US 9586890B2
· Statsyuk et al.
· 2017
[cited by applicant]
US 20060084806A1
· Sridharan et al.
· 2006
[cited by applicant]
US 20070015810A1
· Cuberes
· 2007
[cited by applicant]
US 20080312279A1
· Warren
· 2008
[cited by examiner]
US 20100150944A1
· Hilbush et al.
· 2010
[cited by applicant]
US 20110046090A1
· Barlow
· 2011
[cited by examiner]
US 20120095217A1
· Ritter et al.
· 2012
[cited by applicant]
US 20140066504A1
· Hochman
· 2014
[cited by applicant]
US 20150313913A1
· Catterall et al.
· 2015
[cited by applicant]
US 20220233133A1
· Ginty et al.
· 2022
[cited by applicant]
CN 103933036A
· 2014
[cited by applicant]
EP 0167919A2
· 1986
[cited by applicant]
WO WO1996031210A1
· 1996
[cited by applicant]
WO WO9749690A1
· 1997
[cited by applicant]
WO WO1999051594A1
· 1999
[cited by applicant]
WO WO2002028831A1
· 2002
[cited by applicant]
WO WO03051274A2
· 2003
[cited by applicant]
WO WO2004106310A1
· 2004
[cited by applicant]
WO WO2008003044A2
· 2008
[cited by applicant]
WO WO2008022396A1
· 2008
[cited by applicant]
WO WO2010017047A1
· 2010
[cited by applicant]
WO WO2013154712A1
· 2013
[cited by applicant]
WO WO2014100438A1
· 2014
[cited by applicant]
WO WO2014123909A1
· 2014
[cited by examiner]
WO WO2014138791A1
· 2014
[cited by applicant]
WO WO2015013715A2
· 2015
[cited by applicant]
WO WO2015052076A1
· 2015
[cited by applicant]
WO WO2017214442A1
· 2017
[cited by applicant]
WO WO2018114663A1
· 2018
[cited by applicant]
WO WO2019103658A2
· 2019
[cited by applicant]
WO WO2020237043A1
· 2020
[cited by applicant]
More GABA for Autism and Epilepsy? Not so Simple, Epiphany, An Alternative Reality for Classic Autism—Based on Today's Science, Wednesday Dec. 23, 2015, available at https://www.epiphanyasd.com/2015/12/more-gaba-for-aut…
[cited by examiner]
Braat et al., Neuron 86, Jun. 3, 2015, 1119-1130.
[cited by examiner]
Cascio et al., Somatosensory processing in neurodevelopmental disorders, J. Neurodevelop. Disord. (2010) 2:62-69.
[cited by examiner]
Orefice et al., Peripheral Mechanosensory Neuron Dysfunction Underlies Tactile and Behavioral Deficits in Mouse Models of ASDs, Cell, Jul. 14, 2016;166(2):299-313.
[cited by examiner]
Drasbek et al., THIP, a hypnotic and antinociceptive drug, enhances an extrasynaptic GABAA receptor-mediated conductance in mouse neocortex. Cereb Cortex. Aug. 2006;16(8):1134-41. doi: 10.1093/cercor/bhj055. Epub Oct. 1…
[cited by applicant]
Hoehn-Saric, Effects of THIP on chronic anxiety. Psychopharmacology (Berl). 1983;80(4):338-41. doi: 10.1007/BF00432116.
[cited by applicant]
Olmos-Serrano et al., The GABA(A) receptor agonist THIP ameliorates specific behavioral deficits in the mouse model of fragile X syndrome. Dev Neurosci. 2011;33(5):395-403. doi: 10.1159/000332884. Epub Nov. 8, 2011.
[cited by applicant]
Pardridge, Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab. Nov. 2012;32(11):1959-72. doi: 10.1038/jcbfm.2012.126. Epub Aug. 29, 2012.
[cited by applicant]
Paulson et al., Blood-brain barrier transfer and cerebral uptake of antiepileptic drugs. Clin Pharmacol Ther. Oct. 1982;32(4):466-77. doi: 10.1038/clpt.1982.190.
[cited by applicant]
Extended European Search Report for Application No. 20779891.9, mailed Nov. 21, 2022.
[cited by applicant]
Extended European Search Report for Application No. 20810565.0, mailed Jun. 29, 2023.
[cited by applicant]
Boitano et al., Structure activity studies of a novel cytotoxic benzodiazepine. Bioorg Med Chem Lett. Oct. 6, 2003;13(19):3327-30. doi: 10.1016/s0960-894x(03)00683-8.
[cited by applicant]
No Author Listed, Pubchem CID 3393. Flurazepam compound summary. Entered Mar. 25, 2005. 81 pages.
[cited by applicant]
No Author Listed, Caplus Chemical Abstracts Service for U.S. Pat. No. 9,586,890. 2017. 3 pages.
[cited by applicant]
Ogata et al., 5-Aryl-1,5-dihydro-2H-1,4-benzodiazepin-2-one derivatives as antianxiety agents. J Med Chem. Jun. 1977;20(6):776-81. doi: 10.1021/jm00216a008.
[cited by applicant]
Pavlovsky et al., Synthesis and anticonvulsant activity of 3-alkoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-ones. Pharmaceutical Chemistry Journal. 2012; 46(9): 540-545. DOI: 10.1007/s11094-012-0842-9.
[cited by applicant]
Roland et al., Quinazolines et benzodiazépines-1,4. LX1) Imidazo[5,1-c]benzodiazépines-1,4. 1973; 56(7):2569-2583. Helvetica Chimica Acta. Retrieved from the Internet: URL: https://api.wiley.com/onlinelibrary/tdm/v1/art…
[cited by applicant]
Waszczak et al., GABAergic actions of THIP in vivo and vitro: a comparison with muscimol and GABA. Eur J Pharmacol. Jul. 11, 1980;65(1):21-9. doi: 10.1016/0014-2999(80)90204-6.
[cited by applicant]
Partial Supplementary European Search Report, mailed Jan. 24, 2020, in connection with Application No. EP 17811036.7.
[cited by applicant]
European Search Report, mailed Jun. 24, 2020, in connection with Application No. EP 17811036.7.
[cited by applicant]
Invitation to Pay Additional Fees, mailed Sep. 11, 2017, in connection with Application No. PCT/US2017/036621.
[cited by applicant]
International Search Report and Written Opinion, mailed Nov. 9, 2017, in connection with Application No. Application No. PCT/US2017/036621.
[cited by applicant]
International Preliminary Report on Patentability, mailed Oct. 29, 2018, in connection with Application No. PCT/US2017/036621.
[cited by applicant]
Extended European Search Report for Application No. 19806972.6, mailed Feb. 9, 2022.
[cited by applicant]
International Search Report and Written Opinion, mailed Jul. 25, 2019, in connection with Application No. PCT/US2019/033581.
[cited by applicant]
International Preliminary Report on Patentability, mailed Dec. 3, 2020, in connection with Application No. PCT/US2019/033581.
[cited by applicant]
Partial European Search Report, mailed Sep. 16, 2021, in connection with Application No. 19810786.4.
[cited by applicant]
Extended European Search Report, mailed Dec. 20, 2021, in connection with Application No. 19810786.4.
[cited by applicant]
Invitation to Pay Additional Fees, mailed Jul. 19, 2019, in connection with Application No. PCT/US2019/034390.
[cited by applicant]
International Search Report and Written Opinion, mailed Sep. 19, 2019, in connection with Application No. PCT/US2019/034390.
[cited by applicant]
International Preliminary Report on Patentability, mailed Dec. 10, 2020, in connection with Application No. PCT/US2019/034390.
[cited by applicant]
Invitation to Pay Additional Fees, mailed Jun. 4, 2020, in connection with Application No. PCT/US2020/024564.
[cited by applicant]
International Search Report aand Written Opinion, mailed Jul. 28, 2020, in connection with Application No. PCT/US2020/024564.
[cited by applicant]
International Preliminary Report on Patentability, mailed Oct. 7, 2021, in connection with Application No. PCT/US2020/024564.
[cited by applicant]
International Search Report aand Written Opinion, mailed Aug. 17, 2020, in connection with Application No. PCT/US2020/033984.
[cited by applicant]
International Preliminary Report on Patentability, mailed Dec. 2, 2021, in connection with Application No. PCT/US2020/033984.
[cited by applicant]
[No Author Listed] Caplus Registry No. 1616667-55-0. Carbamic acid, N,N-diethyl-, 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl ester entered STN: Jul. 23, 2014.
[cited by applicant]
[No Author Listed] Caplus Registry No. 952499-50-2. [1,2-a]pyridine-3-acetamide, 6,8-dichloro-2-(4-chlorophenyl)-N-[2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]ethyl]-N-(phenylmethyl)- Entered STN: Nov. 6, 2007.
[cited by applicant]
[No Author Listed] Caplus Registry No. 952499-71-7. Carbamic acid, N-[2-[[2-[6,8-dichloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]acetyl](phenylmethyl)amino]ethyl]-, 1,1-dimethylethyl ester. Entered STN: Nov. 6, 20…
[cited by applicant]
[No Author Listed] Caplus Registry No. 952499-78-4. 1,2-a]pyridine-3-acetamide, N-(2-aminoethyl)-6,8-dichloro-2-(4-chlorophenyl)-N-(phenylmethyl). Entered STN: Nov. 6, 2007.
[cited by applicant]
[No Author Listed] PubChem. 4-Methyl-1-{[2-(4-chlorophenyl)-imidazo[1,2-a]pyridin-3-yl]-methylcarbonyl}-piperazine. Accessed Jul. 11, 2019; created Feb. 8, 2017; modified Jul. 10, 2019. https://pubchem.ncbi.nlm.nih.gov/…
[cited by applicant]
[No Author Listed] PubChem. Compound Summary for SID 319566201. Available Date Dec. 8, 2016; [Retrieved on Jul. 2, 2019]. Retrieved from the internet. https://pubchem.ncbi.nlm.nih.gov/substance/319566201.
[cited by applicant]
[No Author Listed] Pubmed-CID: 13068199. Create Date: Feb. 8, 2007. pp. 1-7.
[cited by applicant]
[No Author Listed] Pubmed-CID: 19842214. Create Date: Dec. 5, 2007. pp. 1-7.
[cited by applicant]
[No Author Listed] Pubmed-CID: 4506. Create Date: Mar. 25, 2005. pp. 1-47.
[cited by applicant]
[No Author Listed] Pubmed-CID: 614001. Create Date: Mar. 27, 2005. pp. 1-11.
[cited by applicant]
[No Author Listed], Cas RN: 2098817-47-9. 2017. 3 pages.
[cited by applicant]
Abrahams et al., Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet. May 2008;9(5):341-55. doi: 10.1038/nrg2346.
[cited by applicant]
Agudo et al., Achieving regio- and enantioselectivity of P450-catalyzed oxidative CH activation of small functionalized molecules by structure-guided directed evolution. Chembiochem. Jul. 9, 2012;13(10):1465-73. doi: 10…
[cited by applicant]
Akyol et al., Generating somatic mosaicism with a Cre recombinase-microsatellite sequence transgene. Nat Methods. Mar. 2008;5(3):231-3.
[cited by applicant]
Amaral et al., The amygdala and autism: implications from non-human primate studies. Genes Brain Behav. Oct. 2003;2(5):295-302.
[cited by applicant]
Amaral, The amygdala, social behavior, and danger detection. Ann N Y Acad Sci. Dec. 2003;1000(1):337-47.
[cited by applicant]
Anagnostou et al., Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial. Mol Autism. Dec. 2012;3(1):16.
[cited by applicant]
Antoine et al., Increased Excitation-Inhibition Ratio Stabilizes Synapse and Circuit Excitability in Four Autism Mouse Models. Neuron. Feb. 20, 2019;101(4):648-61.
[cited by applicant]
Bader et al., Neurophysiological findings in the Rett syndrome, I: Emg, conduction velocity, EEG and somatosensory-evoked potential studies. Brain Dev. Jan. 1, 1989;11(2):102-9.
[cited by applicant]
Baio et al., Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years—Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. MMWR Surveill Summ. Apr. 27, 2018; 67(6): 1-23.
[cited by applicant]
Banerjee et al., Impairment of cortical GABAergic synaptic transmission in an environmental rat model of autism. Int J Neuropsychopharmacol. Jul. 2013;16(6):1309-18. doi: 10.1017/S1461145712001216. Epub Dec. 11, 2012.
[cited by applicant]
Berge et al., Pharmaceutical salts. J Pharm Sci. Jan. 1977;66(1):1-19.
[cited by applicant]
Bhattacherjee et al., Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome. Proceedings of the National Academy of Sciences. Aug. 15, 2017; 114(33): E6952-E6961.
[cited by applicant]
Bowery et al., Isoguvacine, isonipecotic acid, muscimol and N-methyl isoguvacine on the GABA receptor in rat sympathetic ganglia. Experientia. Sep. 15, 1978;34(9):1193-5. doi: 10.1007/BF01922953.
[cited by applicant]
Bowery et al., Characteristics of GABAB receptor binding sites on rat whole brain synaptic membranes. Br J Pharmacol. Jan. 1983; 78(1): 191-206.
[cited by applicant]
Boyle et al., The behavioral phenotype of FMR1 mutations. Am J Med Genet C Semin Med Genet. Nov. 15, 2010; 154(4): 469-76.
[cited by applicant]
Braat et al., The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders. Neuron. Jun. 3, 2015;86(5):1119-30.
[cited by applicant]
Braff et al., Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl.). Jul. 2001;156(2-3):234-58. doi: 10.1007/s002130100810.
[cited by applicant]
Brandt et al., Impaired peripheral somatosensory function in children with Prader-Willi syndrome. Neuropediatrics. Jun. 1998; 29(30): 124-6.
[cited by applicant]
Carlton et al., Peripheral GABA(A) receptors: evidence for peripheral primary afferent depolarization. Neuroscience. Jul. 1, 1999; 93(2): 713-22.
[cited by applicant]
Cascio et al., Tactile Perception in Adults with Autism: a Multidimensional Psychophysical Study. J Autism Dev Disord. Jan. 2008;38(1):127-37. doi: 10.1007/s10803-007-0370-8. Epub Apr. 6, 2007.
[cited by applicant]
Cascio, Somatosensory processing in neurodevelopmental disorders. J Neurodev Disord. Jun. 2010;2(2):62-9.
[cited by applicant]
Cellot et al., GABAergic signaling as therapeutic target for autism spectrum disorders. Front Pediatr. Jul. 8, 2014;2:70.
[cited by applicant]
Chen et al., Presynaptic GABAergic inhibition regulated by BDNF contributes to neuropathic pain induction. Nature communications. Oct. 30, 2014; 5: 5331.
[cited by applicant]
Cheng et al., Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (150) of an enzymatic reaction. Biochem. Pharmacol. Dec. 1973; 22(23):3099-3108.
[cited by applicant]
Choi et al., The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science. Feb. 26, 2016; 351(6276): 933-9.
[cited by applicant]
Coury et al., Use of psychotropic medication in children and adolescents with autism spectrum disorders. Pediatrics. Nov. 1, 2012; 130(Suppl 2): S69-76.
[cited by applicant]
Crozier et al.,MrgD activation inhibits KCNQ/M-currents and contributes to enhanced neuronal excitability. The Journal of neuroscience : the official journal of the Society for Neuroscience. Apr. 18, 2007; 27(16): 4492-…
[cited by applicant]
Dalai et al., Exploring selectivity requirements for peripheral versus central benzodiazepine receptor binding affinity: QSAR modeling of 2-phenylimidazo[1,2-a]pyridine acetamides using topological and physicochemical d…
[cited by applicant]
Dawes et al., Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent Excitability. Neuron. Feb. 21, 2018; 97(4):806-22.
[cited by applicant]
Denora et al., 2-Phenyl-imidazo[1,2-a]pyridine compounds containing hydrophilic groups as potent and selective ligands for peripheral benzodiazepine receptors: synthesis, binding affinity and electrophysiological studie…
[cited by applicant]
Dorrn et al.,Developmental sensory experience balances cortical excitation and inhibition. Nature. Jun. 2010; 465(7300): 932-6.
[cited by applicant]
Downs et al., Linking MECP2 and pain sensitivity: the example of Rett syndrome. Am J Med Genet A. May 2010; 152(5): 1197-205.
[cited by applicant]
Du et al., Local GABAergic signaling within sensory ganglia controls peripheral nociceptive transmission. J Clin Invest. May 1, 2017; 127(5): 1741-56.
[cited by applicant]
Enna et al., The role of GABA in the mediation and perception of pain. Adv Pharmacol. Jan. 1, 2006; 54: 1-27.
[cited by applicant]
Erickson et al.,STX209 (arbaclofen) for autism spectrum disorders: an 8-week open-label study. J Autism Dev Disord. Apr. 1, 2014; 44(4): 958-64.
[cited by applicant]
Fier et al., Synthesis and late-stage functionalization of complex molecules through C-H fluorination and nucleophilic aromatic substitution. J Am Chem Soc. Jul. 16, 2014;136(28):10139-47. doi: 10.1021/ja5049303. Epub J…
[cited by applicant]
Filice et al. Reduction in parvalbumin expression not loss of the parvalbumin-expressing GABA interneuron subpopulation in genetic parvalbumin and shank mouse models of autism. Mol Brain. Dec. 2016; 9: 10.
[cited by applicant]
Flegel et al., RNA-Seq Analysis of Human Trigeminal and Dorsal Root Ganglia with a Focus on Chemoreceptors. PLoS One. Jun. 12, 2015; 10(6): e0128951.
[cited by applicant]
Fukuda et al.,Delayed maturation of neuronal architecture and synaptogenesis in cerebral cortex of Mecp2-deficient mice. J Neuropathol Exp Neurol. Jun. 1, 2005; 64(6): 537-44.
[cited by applicant]
Gebhardt et al., Maturation of prepulse inhibition (PPI) in childhood: Maturation of PPI in childhood. Psychophysiology. Apr. 2012;49(4):484-8. doi: 10.1111/j.1469-8986.2011.01323.x. Epub Dec. 16, 2011.
[cited by applicant]
Golombok et al.,Cognitive impairment in long-term benzodiazepine users. Psychol Med. May 1988; 18(2): 365-74.
[cited by applicant]
Groeneveld et al., Measuring blood-brain barrier penetration using the NeuroCart, a CNS test battery. Drug Discov Today Technol. Jun. 1, 2016; 20: 27-34.
[cited by applicant]
Guastella et al. The effects of a course of intranasal oxytocin on social behaviors in youth diagnosed with autism spectrum disorders: a randomized controlled trial. J Child Psychol Psychiatry. Apr. 2015; 56(4): 444-52.
[cited by applicant]
Gudex, Adverse effects of benzodiazepines. Soc Sci Med. Jan. 1, 1991; 33(5): 587-96.
[cited by applicant]
Guetzoyan et al., Flow chemistry synthesis of zolpidem, alpidem and other GABA agonists and their iological evaluation through the use of in-line frontal affinity chromatography. Chemical Science. 2013; 4(2): 764-69.
[cited by applicant]
Gupta et al., Quantitative structure-activity relationship studies on some nonbenzodiazepine series of compounds acting at the benzodiazepine receptor. Bioorg Med Chem. Nov. 1998;6(11):2213-8. doi: 10.1016/s0968-0896(98…
[cited by applicant]
Guy et al., A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet. Mar. 2001;27(3):322-6.
[cited by applicant]
Haas et al., Peripheral nerve findings in Rett syndrome. J Child Neurol. Jan. 1988; 3(1_Suppl): S25-30.
[cited by applicant]
Hadjikhani et al., Bumetanide for autism: more eye contact, less amygdala activation. Sci Rep. Feb. 26, 2018; 8(1): 3602.
[cited by applicant]
Hagerman et al., Neuropathy as a presenting feature in fragile X- associated tremor/ataxia syndrome. Am J Med Genet A. Oct. 1, 2007; 143(19): 2256-60.
[cited by applicant]
Han et al. SHANK3 Deficiency Impairs Heat Hyperalgesia and TRPV1 Signaling in Primary Sensory Neurons. Neuron. Dec. 21, 2016; 92(6): 1279-93.
[cited by applicant]
Hanack et al., GABA blocks pathological but not acute TRPV1 pain signals. Cell. Feb. 12, 2015; 160(4): 759-770.
[cited by applicant]
Hanson et al., Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different. J Med Chem. Nov. 27, 2008;51(22):7243-52. doi: 10.1021/jm800889m.
[cited by applicant]
Hasegawa et al., Analyzing somatosensory axon projections with the sensory neuron-specific Advillin gene. The Journal of neuroscience : the official journal of the Society for Neuroscience. Dec. 26, 2007; 27(52): 14404-…
[cited by applicant]
Hashemi et al., The Number of Parvalbumin-Expressing Interneurons Is Decreased in the Medial Prefrontal Cortex in Autism. Cereb Cortex. Mar. 1, 2017; 27(3): 1931-43.
[cited by applicant]
He et al.,Critical period inhibition of NKCC1 rectifies synapse plasticity in the somatosensory cortex and restores adult tactile response maps in fragile X mice. Mol Psychiatry. Nov. 2019; 24(11):1732-47.
[cited by applicant]
Hill et al.,3H-baclofen and 3H-GABA bind to bicuculline-insensitive GABA B sites in rat brain. Nature. Mar. 1981; 290(5802): 149-152.
[cited by applicant]
Howes et al., Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. J Psychopharmacol. Jan. 2018; 32(1): 3-29.
[cited by applicant]
Hubel et al., The period of susceptibility to the physiological effects of unilateral eye closure in kittens. The Journal of physiology. Feb. 1, 1970; 206(2): 419-36.
[cited by applicant]
Janak et al.,From circuits to behaviour in the amygdala. Nature. Jan. 2015; 517(7534): 284-92.
[cited by applicant]
Jaramillo et al., Novel Shank3 mutant exhibits behaviors with face validity for autism and altered striatal and hippocampal function. Autism Res. Jan. 2017; 10(1): 42-65.
[cited by applicant]
Jellinger et al.,Neuropathology of Rett syndrome. Acta Neuropathol. Mar. 1, 1988; 76(2): 142-58.
[cited by applicant]
Jevtovic-Todorovic et al., Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. The Journal of neuroscience: the official journal o…
[cited by applicant]
Jiao et al. A key mechanism underlying sensory experience-dependent maturation of neocortical GABAergic circuits in vivo. Proceedings of the National Academy of Sciences. Jul. 19, 2011; 108(29): 12131-6.
[cited by applicant]
Kanner, Autistic disturbances of affective contact. Nerv Child. 1943; 2: 217-250.
[cited by applicant]
Khalfa et al., Peripheral auditory asymmetry in infantile autism. Eur J Neurosci. Feb. 2001; 13(3): 628-32.
[cited by applicant]
King et al.,Lack of efficacy of citalopram in children with autism spectrum disorders and high levels of repetitive behavior: citalopram ineffective in children with autism. Arch Gen Psychiatry. Jun. 1, 2009; 66(6): 583…
[cited by applicant]
Kodish et al., Pharmacotherapy for anxiety disorders in children and adolescents. Dialogues in clinical neuroscience. Dec. 2011; 13(4): 439-452.
[cited by applicant]
Kohl et al., Prepulse Inhibition of the Acoustic Startle Reflex in High Functioning Autism. PLoS One. Mar. 18, 2014;9(3):e92372. doi: 10.1371/journal.pone.0092372. eCollection 2014.
[cited by applicant]
Konig et al., Integrator or coincidence detector? The role of the cortical neuron revisited. Trends Neurosci. Apr. 1, 1996; 19(4): 130-7.
[cited by applicant]
Krishnan et al., MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex. Proceedings of the National Academy of Sciences. Aug. 25, 2015; 112(34): E4782-91.
[cited by applicant]
Krogsgaard-Larsen et al., A new class of GABA agonist. Nature. 1977; 268: 53-55.
[cited by applicant]
Krogsgaard-Larsen et al., Structure-activity studies on the inhibition of GABA binding to rat brain membranes by muscimol and related compounds. J Neurochem. Jun. 1978; 30(6): 1377-82.
[cited by applicant]
Krogsgaard-Larsen et al., THIP, isoguvacine, isoguvacine oxide, and related GABA agonists. Adv Biochem Psychopharmacol. 1981; 29: 69-76.
[cited by applicant]
Kuznetsov et al., Synthesis of cyclic |1-5,7 amino alcohols with cholinolytic properties. Zhurnal Obshchei Khimii [Russian Journal Of Organic Chemistry]. Jan. 1, 1959; 29: 2421-2428.
[cited by applicant]
Laquintana et al., N-Benzyl-2-(6,8-dichloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-N-(6-(7-nitrobenzo[c][1,2,5]oxadiazol-4-ylamino)hexyl)acetamide as a New Fluorescent Probe for Peripheral Benzodiazepine Receptor…
[cited by applicant]
Lau et al., Temporal control of gene deletion in sensory ganglia using a tamoxifen-inducible Advillin-Cre-ERT2 recombinase mouse. Mol Pain. Dec. 21, 2011; 7: 1744-8069.
[cited by applicant]
Lemonnier et al., Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders. Transl Psychiatry. Mar. 2017; 7(3): e1056.
[cited by applicant]
Levy et al., The effect of the GABA antagonists bicuculline and picrotoxin on primary afferent terminal excitability. Brain research. Aug. 11, 1972; 43(1): 171-80.
[cited by applicant]
Lopez-Mendoza et al., Visible light/Ir(III) photocatalytic initiation of xanthate-based radical-chain reactions: Xanthate group transfer and oxidative addition to aromatic systems. Tetrahedron. Apr. 2018; 74(38):5494-55…
[cited by applicant]
Lozano et al., Modulation of the GABAergic pathway for the treatment of fragile X syndrome. Neuropsychiatr Dis Treat. Sep. 16, 2014;10:1769-79. doi: 10.2147/NDT.S42919. eCollection 2014.
[cited by applicant]
Lyst et al., Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. Nature neuroscience. Jul. 2013; 16(7): 898-902.
[cited by applicant]
Maddox et al., The Accuracy of the ADOS-2 in Identifying Autism among Adults with Complex Psychiatric Conditions. J Autism Dev Disord. Sep. 2017;47(9):2703-2709. doi: 10.1007/s10803-017-3188-z.
[cited by applicant]
Madsen et al., Increased Prepulse Inhibition and Sensitization of the Startle Reflex in Autistic Children: Sensorimotor gating in autistic children. Autism Res. Feb. 2014;7(1):94-103. doi: 10.1002/aur.1337. Epub Oct. 4,…
[cited by applicant]
Mammen et al., Infant Avoidance during a Tactile Task Predicts Autism Spectrum Behaviors in Toddlerhood. Infant Ment Health J. Nov. 2015; 36(6): 575-87.
[cited by applicant]
Marin, Interneuron dysfunction in psychiatric disorders. Nat Rev Neurosci. Feb. 2012; 13(2): 107-120.
[cited by applicant]
Mazurek et al., Anxiety, sensory over-responsivity, and gastrointestinal problems in children with autism spectrum disorders. J Abnorm Child Psychol. Jan. 1, 2013; 41(1): 165-76.
[cited by applicant]
Mei et al., Adult restoration of Shank3 expression rescues selective autistic-like phenotypes. Nature. Feb. 2016; 530(7591): 481-4.
[cited by applicant]
Nadeau et al., Treatment of comorbid anxiety and autism spectrum disorders. Neuropsychiatry. Dec. 2011;1(6):567-78.
[cited by applicant]
Nelson et al., Excitatory/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders. Neuron. Aug. 19, 2015; 87(4): 684-98.
[cited by applicant]
No Author Listed, Annex to ESOP (EP19810786). Jan. 1, 2021. 84 pages.
[cited by applicant]
Obradovic et al., Silencing the alpha2 subunit of gamma-aminobutyric acid type A receptors in rat dorsal root ganglia reveals its major role in antinociception posttraumatic nerve injury. Anesthesiology. Sep. 1, 2015; 1…
[cited by applicant]
Oginsky et al., Hyperexcitability of Mesencephalic Trigeminal Neurons and Reorganization of Ion Channel Expression in a Rett Syndrome Model. J Cell Physiol. May 2017; 232(5): 1151-64.
[cited by applicant]
Orefice et al., Targeting Peripheral Somatosensory Neurons to Improve Tactile-Related Phenotypes in ASD Models. Cell. Aug. 8, 2019;178(4):867-886.e24. doi: 10.1016/j.cell.2019.07.024.
[cited by applicant]
Orefice, Peripheral Somatosensory Neuron Dysfunction: Emerging Roles in Autism Spectrum Disorders. Neuroscience. Oct. 1, 2020;445:120-129. doi: 10.1016/j.neuroscience.2020.01.039. Epub Feb. 6, 2020.
[cited by applicant]
Page et al.,GABA(B) receptors inhibit mechanosensitivity of primary afferent endings. The Journal of neuroscience : the official journal of the Society for Neuroscience. Oct. 1, 1999; 19(19): 8597-8602.
[cited by applicant]
Pajouhesh et al., Medicinal chemical properties of successful central nervous system drugs. NeuroRx. Oct. 1, 2005; 2(4): 541-553.
[cited by applicant]
Peca et al., Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature. Apr. 2011; 472(7344): 437-442.
[cited by applicant]
Peixoto et al., Early hyperactivity and precocious maturation of corticostriatal circuits in Shank3B(−/−) mice. Nature neuroscience. May 2016; 19(5): 716-24.
[cited by applicant]
Perche et al., Early Retinal Defects in Fmr1(−/y) Mice: Toward a Critical Role of Visual Dys-Sensitivity in the Fragile X Syndrome Phenotype? Front Cell Neurosci. Apr. 6, 2018; 12: 96.
[cited by applicant]
Phelan et al., The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome). Mol Syndromol. 2011; 2(3-5): 186-201.
[cited by applicant]
Price et al., Fragile X mental retardation protein (FMRP) and the spinal sensory system. Results Probl Cell Differ. 2012; 54, 41-59.
[cited by applicant]
Ray et al., Comparative transcriptome profiling of the human and mouse dorsal root ganglia: an RNA-seq-based resource for pain and sensory neuroscience research. Pain. Jul. 2018; 159(7): 1325-1345.
[cited by applicant]
Romermann et al., Multiple blood-brain barrier transport mechanisms limit bumetanide accumulation, and therapeutic potential, in the mammalian brain. Neuropharmacology. May 1, 2017; 117: 182-94.
[cited by applicant]
Roy et al., QSAR modeling of peripheral versus central benzodiazepine receptor binding affinity of 2-phenylimidazo[1,2-a]pyridineacetamides using optimal descriptors calculated with Smiles. QSAR Comb Sci. 2007; 26(4): 4…
[cited by applicant]
Rudolph et al., Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes. Nat Rev Drug Discov. Sep. 2011; 10(9): 685-97.
[cited by applicant]
Salamon, Conners Scale for ADHD Assessment. WebMD. Jul. 12, 2020. available at https://www.webmd.com/add-adhd/childhood-adhd/conners-rating-scale#-:text=The%20Conners%20rating%20scale%20is, %2C%20home%20Iife%2C%20and%20…
[cited by applicant]
Samanta et al., Search for Structural Requirements of2-Phenylimidazo[1,2-a]pyridineacetamide Analogs to Im prove Affinity and Selectivity towards Central and/or Peripheral Benzodiazepine Receptors. Internet Electronic J…
[cited by applicant]
Schultz et al., Sensory hypersensitivity predicts repetitive behaviours in autistic and typically-developing children. Autism : the international journal of research and practice. May 2019; 23(4): 1028-41.
[cited by applicant]
Shank et al., Ion and temperature effects on the binding of gamma-aminobutyrate to its receptors and the high-affinity transport system. J. Neurochem. Jun. 1990;54(6):2007-15.
[cited by applicant]
Silverman et al., Behavioural phenotyping assays for mouse models of autism. Nat Rev Neurosci. Jul. 2010;11(7):490-502. doi: 10.1038/nrn2851.
[cited by applicant]
Simons et al., Early experience of tactile stimulation influences organization of somatic sensory cortex. Nature. Apr. 1987; 326(6114): 694-7.
[cited by applicant]
Sohal et al., Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature. Jun. 2009; 459(7247): 698-702.
[cited by applicant]
Swerdlow et al., Sensorimotor gating of the startle reflex: what we said 25 years ago, what has happened since then, and what comes next. J Psychopharmacol. Nov. 2016;30(11):1072-1081. doi: 10.1177/0269881116661075. Epu…
[cited by applicant]
Tata et al., Lack of cognitive recovery following withdrawal from long-term benzodiazepine use. Psychol Med. Feb. 1994; 24(1): 203-13.
[cited by applicant]
Tomassy et al. Developmental abnormalities of cortical interneurons precede symptoms onset in a mouse model of Rett syndrome. J Neurochem. Oct. 2014; 131(1): 115-27.
[cited by applicant]
Tomchek et al., Sensory processing in children with and without autism: a comparative study using the short sensory profile. Am J Occup Ther. Mar. 1, 2007; 61(2): 190-200.
[cited by applicant]
Torres et al., Autism: the micro-movement perspective. Front Integr Neurosci. Jul. 24, 2013;7: 32.
[cited by applicant]
Trapani et al., Structure-activity relationships and effects on neuroactive steroid synthesis in a series of 2-phenylimidazo[1,2-a]pyridineacetamide peripheral benzodiazepine receptors ligands. J Med Chem. Jan. 13, 2005…
[cited by applicant]
Trapani et al., Synthesis and binding affinity of 2-phenylimidazo[1,2-alpha]pyridine derivatives for both central and peripheral benzodiazepine receptors. A new series of high-affinity and selective ligands for the peri…
[cited by applicant]
Tuccinardi et al., A virtual screening study of the 18 kDa translocator protein using pharmacophore models combined with 3D-QSAR studies. ChemMedChem. Oct. 2009;4(10):1686-94. doi: 10.1002/cmdc.200900254.
[cited by applicant]
Usoskin et al., Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nature neuroscience. Jan. 2015; 18(1): 145-53.
[cited by applicant]
Veenstra-Danderweele et al., Arbaclofen in Children and Adolescents with Autism Spectrum Disorder: A Randomized, Controlled, Phase 2 Trial. Neuropsychopharmacology. Jun. 2017; 42(7): 1390-8.
[cited by applicant]
Voos et al., Autistic traits are associated with diminished neural response to affective touch. Soc Cogn Affect Neurosci. Apr. 2013;8(4):378-86. doi: 10.1093/scan/nss009. Epub Jan. 20, 2012.
[cited by applicant]
Wang et al., Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism. The Journal of Clinical Investigation. May 1, 2017; 127(5): 1978-90.
[cited by applicant]
Watanabe et al., Disruption of the epilepsy KCNQ2 gene results in neural hyperexcitability. J Neurochem. Jul. 2000; 75(1): 28-33.
[cited by applicant]
Wiesel et al., Extent of recovery from the effects of visual deprivation in kittens. Journal of neurophysiology. Nov. 1, 1965; 28(6): 1060-72.
[cited by applicant]
Wiggins et al., Brief report: sensory abnormalities as distinguishing symptoms of autism spectrum disorders in young children. J Autism Dev Disord. Jul. 1, 2009; 39(7): 1087-91.
[cited by applicant]
Womelsdorf et al., Dynamic circuit motifs underlying rhythmic gain control, gating and integration. Nature neuroscience. Aug. 2014; 17(8): 1031-9.
[cited by applicant]
Wright, Cognition and behavior: Sensory sensitivity tied to autism, Oct. 10, 2012, available at https://www.spectrumnews.org/news/cognition-and-behavior-sensory-sensitivity-tied-to-autism/.
[cited by applicant]
Yatawara et al., The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: a randomized clinical crossover trial. Mol Psychiatry. Sep. 2016; 21(9): 1225-31.
[cited by applicant]
Yi et al., Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons. Science. May 6, 2016; 352(6286): aaf2669.
[cited by applicant]
Zeilhofer et al., Fast synaptic inhibition in spinal sensory processing and pain control. Physiological reviews. Jan. 2012; 92(1): 193-235.
[cited by applicant]
Zheng et al., Suppression of KCNQ/M (Kv7) potassium channels in dorsal root ganglion neurons contributes to the development of bone cancer pain in a rat model. Pain. Mar. 1, 2013; 154(3): 434-48.
[cited by applicant]
Zikopoulos et al., Altered neural connectivity in excitatory and inhibitory cortical circuits in autism. Front Hum Neurosci. Sep. 27, 2013; 7: 609.
[cited by applicant]
U.S. Appl. No. 18/790,038, filed Jul. 31, 2024, Ginty et al.
[cited by applicant]
U.S. Appl. No. 18/782,829, filed Jul. 24, 2024, Ginty et al.
[cited by applicant]