Methods and assays for treating subjects with shank3 deletion, mutation or reduced expression

Abstract

Methods and assays are disclosed for treating subjects with 22q13 deletion syndrome or SHANK3 deletion or duplication, mutation or reduced expression, where the methods comprise administering to the subject insulin-like growth factor 1 (IGF-1), IGF-1-derived peptide or analog, growth hormone, an AMPAkine, a compound that directly or indirectly enhances glutamate neurotransmission, including by inhibiting inhibitory (most typically GABA) transmission, or an agent that activates the growth hormone receptor or the insulin-like growth factor 1 (IGF-1) receptor, or a downstream signaling pathway thereof.

1 . A method for treating a subject with 22q13 deletion syndrome or SHANK3 deletion or duplication, SHANK3 mutation or reduced expression of SHANK3, the method comprising administering to the subject insulin-like growth factor 1 (IGF-1), an active IGF-1 fragment including the tripeptide (1-3)IGF-1 or an analog thereof, growth hormone, an AMPAkine, or a compound that enhances glutamate neurotransmission, in an amount and manner effective to treat a subject with 22q13 deletion syndrome or SHANK3 deletion or duplication, mutation or reduced expression. 
     
     
         2 .- 4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the analog of (1-3)IGF-1 is selected from the group consisting of (1-3)IGF-1 amide, (1-3)IGF-1 stearate, Gly-Pro-D-glutamate, glycine-proline-threonine (Gly-Pro-Thr), glycine-glutamic acid-proline (Gly-Glu-Pro), glutamic acid-glycine-proline (Glu-Gly-Pro), and glutamic acid-proline-glycine (Glu-Pro-Gly). 
     
     
         6 . The method of  claim 1 , wherein IGF-1, IGF-1-derived peptide or analog, growth hormone, AMPAkine, compound that enhances glutamate neurotransmission, or agent is administered locally. 
     
     
         7 . The method of  claim 1 , wherein IGF-1, IGF-1-derived peptide or analog, growth hormone, AMPAkine, compound that enhances glutamate neurotransmission, or agent is administered systemically. 
     
     
         8 . A method for screening for agents for treating a subject with 22q13 deletion syndrome or SHANK3 deletion or duplication, mutation or reduced expression, the method comprising determining whether or not the agent enhances long-term potentiation or increases glutamate transmission, wherein an agent that enhances long-term potentiation or increases glutamate transmission is a candidate for treating a subject with 22q13 deletion syndrome or SHANK3 deletion or duplication, mutation or reduced expression, whereas an agent that does not enhance long-term potentiation or increase glutamate transmission is not a candidate for treating a subject with 22q13 deletion syndrome or SHANK3 deletion or duplication, mutation or reduced expression. 
     
     
         9 . The method of  claim 8 , wherein the method is carried out using a mouse with a disruption in one copy of SHANK3. 
     
     
         10 .- 11 . (canceled) 
     
     
         12 . The method of  claim 8 , wherein the method is carried out using a brain slice preparation. 
     
     
         13 . The method of  claim 12 , wherein the brain slice is from an animal with a disruption of one at least one copy of SHANK3. 
     
     
         14 . The method of  claim 1 , wherein the subject is human. 
     
     
         15 . The method of  claim 14 , wherein the subject has autism, Asperger syndrome, autism spectrum disorder, pervasive developmental disorder, mental retardation, hypotonia, speech deficits, or a developmental delay and/or defect. 
     
     
         16 . The method of  claim 1 , wherein IGF-1, IGF-1-derived peptide or analog, growth hormone, AMPAkine, compound that enhances glutamate neurotransmission, or agent alleviates one or more of hypotonia; a motor deficit; absent speech; increased tolerance to pain; thin, flaky toenails; poor thermoregulation; chewing non-food items; teeth grinding; autistic behaviors; tongue thrusting; hair pulling; and aversion to clothes. 
     
     
         17 . The method of  claim 1 , wherein the compound that enhances glutamate neurotransmission inhibits an inhibitory neurotransmitter. 
     
     
         18 . The method of  claim 17 , wherein the inhibitory neurotransmitter is GABA. 
     
     
         19 . A method for treating a subject with 22q13 deletion syndrome or SHANK3 deletion or duplication, SHANK3 mutation or reduced expression of SHANK3, the method comprising administering to the subject insulin-like growth factor 1 (IGF-1) or an active IGF-1 fragment including the tripeptide (1-3)IGF-1 or an analog thereof, in an amount and manner effective to treat a subject with 22q13 deletion syndrome or SHANK3 deletion or duplication, mutation or reduced expression, wherein the subject has autism spectrum disorder, autism, Asperger syndrome, pervasive developmental disorder, mental retardation, hypotonia, a speech deficit, or a developmental delay and/or defect. 
     
     
         20 . (canceled)