Methods and compositions for reducing tactile dysfunction and anxiety associated with autism spectrum disorder, Rett syndrome, and Fragile X syndrome
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.
1. A method of reducing tactile dysfunction in a subject diagnosed with Autism Spectrum Disorders (ASD), Rett Syndrome (RTT), or Fragile X Syndrome, by administering to the subject a GABA A agent having reduced blood brain barrier (BBB) permeability, wherein the GABA A agent is not 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 GABAA 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 isonipecotic acid.
6. The method of claim 1 , wherein the subject has been diagnosed with ASD.
7. The method of claim 1 , wherein the subject has been diagnosed with RTT.
8. The method of claim 1 , wherein the subject has been diagnosed with Fragile X Syndrome.
9. The method of claim 2 , wherein the GABAA receptor agonist is N-methyl isoguvacine, homohypotaurine, β-guanidinopropionic acid, or trans-aminocyclopentane-3-carboxylic acid.
10. The method of claim 3 , wherein the positive allosteric modulator of the GABA A receptor is 5-nitro-alpha-oxo-N-(1R)-phenylethyl]-1H-indole-3-acetamide (TCS 1205), homo-β-proline, isonipecotic acid, TP 003 (5-fluoro-2-[4-fluoro-3-[8-fluoro-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-3-yl]phenyl]benzonitrile), loreclezole [1-[(Z)-2-chloro-2-(2,4-dichlorophenyl)vinyl]-1H-1,2,4-triazole], or an agonist of Formula (I), or a pharmaceutically acceptable salt or tautomer thereof:
where 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 such as benzyl or phenylethyl 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.
11. The method of claim 1 , wherein the tactile dysfunction is tactile hyposensitivity.
12. The method of claim 1 , wherein the tactile dysfunction is tactile hypersensitivity.
13. The method of claim 12 , wherein the tactile hypersensitivity is characterized by loss of GABA A receptor-mediated presynaptic inhibition (PSI) of low-threshold mechanosensory neuron (LTMR) inputs to the spinal cord.
14. The method of claim 12 , wherein the tactile hypersensitivity is characterized by hyperexcitability of LTMRs.
15. The method of claim 1 , wherein the subject is characterized as having reduced presynaptic GABAA receptors on LTMR terminals in the dorsal horn of the spinal cord.
16. The method of claim 1 , wherein the subject is characterized as having a deficiency in Mecp2, Gabrb3, or Shank3.