Gut-selective sequestering agents for the treatment and prevention of autism and related disorders

Abstract

The present disclosure describes methods and compositions for the treatment of neurological disorders and related symptoms by the in vivo sequestration and excretion of microbial metabolites. These metabolites are related to neurological disorders such as autism and Parkinson's disease, as well as intestinal hyperpermeability (leaky gut) and gastrointestinal comorbidities associated with such disorders.

1 .- 14 . (canceled) 
     
     
         15 . A sequestrant composition for use in the treatment of a subject having a behavioral symptom of a neurological disorder associated with intestinal hyperpermeability or intestinal dysbiosis, comprising:
 a multiplicity of biocompatible particles and/or polymers which are non-absorbable by the digestive tract of the subject,   wherein the sequestrant composition binds to at least a fraction of at least one intestinal metabolite present in the digestive tract of the subject to form a sequestrant-metabolite complex, such that the sequestrant-metabolite complex is eliminated from the digestive tract, and   wherein the intestinal metabolite is associated with the development or presence of the behavioral symptom.   
     
     
         16 . The sequestrant composition of  claim 15  wherein:
 the sequestrant composition comprises activated carbon particles, a clay, an apatite or hydroxyapatite, a bentonite, a kaolin, a pectin, a cellulose polymer, a cellulose acetate polymer, a cellulose acetate propionate, an ion exchange resin, a cholestyramine polymer, a tetraethylenepentamine polymer, a phenolic resin, a boronic acid-presenting polymer, a catechin-presenting polymer, or a zeolite. 
 
     
     
         17 . The sequestrant composition of  claim 15  comprising:
 an AB-2004 preparation comprising spherical activated carbon particles having: 
 (a) a minimum average specific surface area determined by the Brunauer-Emmett-Teller (BET) method of at least 500 m 2 /g and a maximum average specific surface area determined by the Brunauer-Emmett-Teller (BET) method less than 4000 m 2 /g; and/or 
 (b) a minimum average particle diameter of at least 0.005 and a maximum average particle diameter of less than 1.5 mm. 
 
     
     
         18 . (canceled) 
     
     
         19 . The sequestrant composition of any one of  claims 15 - 18  wherein:
 the sequestrant composition is formulated for controlled release in the lower digestive tract. 
 
     
     
         20 . A method of treating a subject having a behavioral symptom of a neurological disorder associated with intestinal hyperpermeability or intestinal dysbiosis, comprising:
 administering to said subject a sequestrant composition which binds to at least a fraction of at least one intestinal metabolite present in the digestive tract of the subject to form a sequestrant-metabolite complex, such that the sequestrant-metabolite complex is eliminated from the digestive tract;   wherein the intestinal metabolite is associated with the development or presence of the behavioral symptom, and   wherein the sequestrant composition comprises a multiplicity of biocompatible particles which are non-absorbable by the digestive tract of the subject.   
     
     
         21 . The method of  claim 20  wherein:
 the neurological disorder is selected from the group consisting of: autism spectrum disorder, an anxiety disorder, Parkinson's Disease, Rett Syndrome, Fragile X Syndrome, Tuberous Sclerosis, Multiple Sclerosis, Alzheimer's Disease, Angelman Syndrome, Williams Syndrome, amyotrophic lateral sclerosis, leukodystrophies including Alexander Syndrome, alpha-synucleinopathies including Lewy Body Dementia, incidental Lewy body disease, Lewy body variant of Alzheimer's disease, multiple system atrophy, pure autonomic failure, or any combination thereof. 
 
     
     
         22 . The method of  claim 20  wherein:
 the behavioral symptom is selected from the group consisting of: tremors, paralysis, dyskinesia, repetitive behaviors, communicative symptoms, cognitive disorders, stereotyped behaviors, attachment to physical objects, aphasia, obsessive behaviors, unusual or inappropriate body language, gestures, and/or facial expressions and/or sensorimotor issues, lack of interest in other people, lack of empathy, difficulty grasping nonverbal cues, touch aversion, difficulty in socialization, speech delays, abnormal vocal tone or pitch, vocal repetition, perseveration, conversational difficulty, difficulty communicating needs or desires, inability to understand simple statements or questions, difficulties in processing language subtext, obsessive attachment to unusual objects, preoccupation, intolerance of changes in routine or environment, clumsiness, abnormal posture, odd ways of moving, fascination with particular objects, hyper- or hypo-reactivity to sensory input, and clinical irritability. 
 
     
     
         23 . The method of  claim 20  wherein:
 the neurological disorder is autism spectrum disorder and the behavioral symptom is selected from the group consisting of repetitive behaviors, communicative symptoms, stereotyped behaviors, and clinical irritability. 
 
     
     
         24 . The method of  claim 20  wherein:
 the subject does not have clinical anxiety or an anxiety disorder. 
 
     
     
         25 . The method of  claim 20  wherein:
 the subject does not have chronic kidney disease. 
 
     
     
         26 . The method of  claim 20  wherein: the intestinal metabolite is selected from the group consisting of: 4-ethylphenol (4-EP), 4-ethylphenylsulfate (4-EPS), p-cresol (PC), p-cresyl sulfate (PCS), 3-indoxyl sulfate, 3-hydroxy indole, coumaric acid, 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), 3-(3-hydroxyphenyl)propanoic acid, 3-(4-hydroxyphenyl)propanoic acid, 3-hydroxy hippuric acid (3HHA), 3-carboxy-4-methyl-5-propyl-2-furanoic acid (CMPF), 3-hydroxyphenyl acetic acid (3HPA), 4-hydroxyphenyl acetic acid, and 2-hydroxy-2-(4-hydroxyphenyl)acetic acid. 
     
     
         27 . The method of  claim 20  wherein:
 the intestinal metabolite is selected from the group consisting of: 4-ethylphenol (4-EP), 4-ethylphenylsulfate (4-EPS), p-cresol (PC), p-cresyl sulfate (PCS), 3-hydroxy indole, and 3-indoxyl sulfate. 
 
     
     
         28 . The method of  claim 20  wherein:
 the sequestrant composition comprises activated carbon particles, a clay, an apatite or hydroxyapatite, a bentonite, a kaolin, a pectin, a cellulose polymer, a cellulose acetate polymer, a cellulose acetate propionate, an ion exchange resin, a cholestyramine polymer, a tetraethylenepentamine polymer, a phenolic resin, a boronic acid-presenting polymer, a catechin-presenting polymer, or a zeolite. 
 
     
     
         29 . The method of  claim 20  wherein:
 the sequestrant composition comprises an AB-2004 preparation comprising spherical activated carbon particles having: 
 (a) a minimum average specific surface area determined by the Brunauer-Emmett-Teller (BET) method of at least 500 m 2 /g and a maximum average specific surface area determined by the Brunauer-Emmett-Teller (BET) method less than 4000 m 2 /g; and/or 
 (b) a minimum average particle diameter of at least 0.005 and a maximum average particle diameter of less than 1.5 mm. 
 
     
     
         30 . (canceled) 
     
     
         31 . The method of  claim 20 , further comprising monitoring intestinal metabolite levels of said subject during the course of treatment, or monitoring changes in the behavior of the subject. 
     
     
         32 . (canceled) 
     
     
         33 . The method of  claim 20 , wherein the composition is administered following the appearance of behavioral symptoms of the neurological disorder. 
     
     
         34 . The method of  claim 20 , wherein the composition is administered prior to the appearance of behavioral symptoms of the neurological disorder. 
     
     
         35 . The method  claim 20 , wherein the method is repeated as necessary to maintain reduced levels of intestinal metabolites relative to the levels identified prior to the first administration of the composition. 
     
     
         36 . The method of  claim 20 , wherein, for a given administration, the composition is different from a composition previously administered. 
     
     
         37 . (canceled) 
     
     
         38 . A method of reducing the amount of one or more intestinal metabolites from a subject having a behavioral symptom of a neurological disorder associated with intestinal hyperpermeability or intestinal dysbiosis, comprising:
 administering to said subject a sequestrant composition which binds to at least a fraction of at least one intestinal metabolite present in the digestive tract of the subject to form a sequestrant-metabolite complex, such that the sequestrant-metabolite complex is eliminated from the digestive tract;   wherein the intestinal metabolite is associated with the development or presence of the behavioral symptom, and   wherein the sequestrant composition comprises a multiplicity of biocompatible particles which are non-absorbable by the digestive tract of the subject.