Alkaline phosphatase agents for treatment of neurodevelopmental disorders

Abstract

The present invention relates, inter alia, to compositions and methods, including therapeutic alkaline phosphatases that find use in the treatment or prevention of various neurodevelopmental diseases or disorders.

1 . A method of treating or preventing a neurodevelopmental disorder in a subject in need thereof comprising, administering to the subject an alkaline phosphatase (AP)-based agent. 
     
     
         2 . The method of  claim 1 , wherein the AP-based agent is a mammalian or bacterial alkaline phosphatase. 
     
     
         3 . The method of  claim 2 , wherein the bacterial AP has catalytic activity comparable to that of mammalian AP. 
     
     
         4 . The method of  claim 2 , wherein the mammalian alkaline phosphatase is selected from intestinal alkaline phosphatase (IAP), placental alkaline phosphatase (PLAP), germ cell alkaline phosphatase (GCAP), and tissue non-specific alkaline phosphatase (TNAP). 
     
     
         5 . The method of any of the above claims, wherein the AP-based agent is intestinal alkaline phosphate (IAP). 
     
     
         6 . The method of any of the above claims, wherein the neurodevelopmental disorder is selected from autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder. 
     
     
         7 . The method of  claim 1 , wherein the neurodevelopmental disorder is ASD. 
     
     
         8 . The method of  claim 7 , wherein the treatment or prevention of ASD comprises reduction or elimination of one or more of social withdrawal, averted gaze, inability to make eye contact, repetitive behaviors, obsessions, anxiety, stereotyped movements, attention deficit, hyperactivity, depression, a reclusive personality, and the inability to understand feelings. 
     
     
         9 . The method of any of the above claims, wherein the subject is a pregnant woman. 
     
     
         10 . The method of  claim 9 , wherein the pregnant woman is afflicted with one or more of gastrointestinal dysbiosis, obesity, metabolic syndrome, gut-mediated systemic inflammation, and leaky gut. 
     
     
         11 . The method of any of  claims 1 - 8 , wherein the subject is an unborn child or newly born child, and optionally wherein the mother of said child is afflicted with one or more of gastrointestinal dysbiosis, obesity, metabolic syndrome, gut-mediated systemic inflammation, and leaky gut. 
     
     
         12 . The method of any of the above claims, wherein the AP-based agent is administered orally. 
     
     
         13 . The method of any of the above claims, wherein the AP-based agent is IAP selected from human IAP (hIAP), calf IAP (cIAP), and bovine IAP (bIAP), or variants thereof. 
     
     
         14 . The method of any of the above claims, wherein the AP-based agent comprises an amino acid sequence having at least 95%, or 97%, or 99% sequence identity with any one of SEQ ID NOs: 1-11 and 17-18. 
     
     
         15 . The method of any of the above claims, wherein the AP-based agent is bIAP II or a variant thereof. 
     
     
         16 . The method of any of the above claims, wherein the AP-based agent comprises an amino sequence having at least 95% sequence identity with SEQ ID NO: 2 (bIAP II). 
     
     
         17 . The method of any of the above claims, wherein the AP-based agent comprises an amino sequence having at least 97% sequence identity with SEQ ID NO: 2 (bIAP II). 
     
     
         18 . The method of any of the above claims, wherein the AP-based agent comprises the amino sequence of SEQ ID NO: 2 (bIAP II). 
     
     
         19 . The method of  claim 7 , wherein the AP-based agent comprises the amino sequence of SEQ ID NO: 2 (bIAP II). 
     
     
         20 . The method of any of the above claims, wherein the AP-based agent is bIAP IV or a variant thereof. 
     
     
         21 . The method of any of the above claims, wherein the AP-based agent comprises an amino sequence having at least 95% sequence identity with SEQ ID NO: 3 (bIAP IV). 
     
     
         22 . The method of any of the above claims, wherein the AP-based agent comprises an amino sequence having at least 97% sequence identity with SEQ ID NO: 3 (bIAP IV). 
     
     
         23 . The method of any of the above claims, wherein the AP-based agent comprises the amino sequence of SEQ ID NO: 3 (bIAP IV). 
     
     
         24 . The method of  claim 7 , wherein the AP-based agent comprises the amino sequence of SEQ ID NO: 3 (bIAP IV). 
     
     
         25 . The method of any of the above claims, wherein the AP-based agent comprises a specific activity of at least about 100 U/mg to about 20,000 U/mg. 
     
     
         26 . The method of any of the above claims, wherein the AP-based agent is stable and/or active in the GI tract, in one or more of the mouth, esophagus, stomach, duodenum, small intestine, jejunum, ileum, large intestine, colon, cecum, and rectum. 
     
     
         27 . The method of any of the above claims, wherein the AP-based agent is substantially active at a pH of about 6.0 to about 12. 
     
     
         28 . The method of any of the above claims, wherein the AP-based agent is stable in chyme. 
     
     
         29 . Use of an AP-based agent for the treatment or prevention of a neurodevelopmental disorder in a subject in need thereof. 
     
     
         30 . The use of an AP-based agent for the preparation of a medicament for the treatment or prevention of a neurodevelopmental disorder in a subject in need thereof. 
     
     
         31 . A method of treating or preventing autism spectrum disorder (ASD) in an unborn child or newly born child in need thereof comprising, administering to the mother of said unborn child or newly born child an alkaline phosphatase (AP)-based agent,
 wherein the mother is afflicted with one or more of gastrointestinal dysbiosis, obesity, metabolic syndrome, gut-mediated systemic inflammation, and leaky gut, and   wherein the AP-based agent comprises an amino acid sequence having at least 97% sequence identity with SEQ ID NO: 2 or SEQ ID NO: 3.