Editorial
Making progress in autism drug discovery
Expert Opin. Drug Discov. Downloaded from informahealthcare.com by The University of Manchester on 10/13/14 For personal use only.
Kathryn K Chadman 1.
Introduction
New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
2.
Expert opinion
Currently, there are still just two medications approved by the U.S. FDA to treat the irritability that is often found in children with autism spectrum disorder (ASD). Furthermore, there are no drugs approved that treat the core symptoms of ASD. And while many drugs have had good outcomes in preclinical animal models, they have been met with very little success in human clinical trials. There are several factors likely contributing to this problem starting with the heterogeneity within the ASD phenotype. It is therefore important that researchers develop their knowledge about the neurobiological basis of ASD as well as possible subgroups within the disorder, based on either specific behavioral profiles or biological pathways. Furthermore, the development of valid biological markers will allow researchers to use more than parent or teacher reports to determine if a treatment is effective. This author believes that there a good chance of finding effective pharmacological treatments for the core symptoms of ASD with this increased knowledge of the biology and etiology. Keywords: arbaclofen, autism, IGF-1, oxytocin, pharmacotherapy Expert Opin. Drug Discov. [Early Online]
1.
Introduction
The estimated prevalence of autism spectrum disorder (ASD), based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), has recently increased again [1], highlighting the need for treatment options for the core symptoms of this disorder. The 5th edition of the DSM (DSM-5) has revised the diagnostic criteria for ASD, eliminating the different disorders such as Asperger’s disorder and pervasive developmental delay not otherwise specified and bringing all persons with the same core symptoms into one designation, ASD. The new diagnostic criteria are persistent deficits in social communication and interaction and restricted or repetitive patterns of behavior, interests or activities with symptoms arising before the age of 3 years. Despite the outstanding research that has been done on ASD, there are still no pharmacological interventions that target the core symptoms. Unfortunately, there are few clinical trials with sufficient sample sizes for information on the effects of treatments across a wide range of people with ASD. Behavioral intervention remains the most effective treatment, and little research has been done pairing pharmacotherapy with behavioral therapy. Drugs with promising preclinical data in general are not performing well in clinical trials. There are many reasons that may account for the disconnection between preclinical models and clinical trials. There is likely a greater heterogeneity in the human ASD population represented in clinical trials than is accounted for in a single animal model system. The variety of ASD phenotypes within a given group of people may contribute to the lack of success in small-scale trials as there may not be enough subjects with similar underlying biology to respond to any given treatment. Another potential area for improvement are the outcome measures for many clinical trials that rely heavily on parent report, as objective clinical endpoints or biomarkers are not well defined for ASD. The length 10.1517/17460441.2014.962511 © 2014 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X All rights reserved: reproduction in whole or in part not permitted
1
Expert Opin. Drug Discov. Downloaded from informahealthcare.com by The University of Manchester on 10/13/14 For personal use only.
K. K. Chadman
of treatment may also be a factor because the expectation that 6 or 12 weeks of any therapy will undo years of ASD pathology is unlikely. All of these potential factors may be underlying the lack of success in clinical trials. Researchers are aware of these issues and are taking steps to address them. Excellent research is being conducted to look for biomarkers for subgroups within ASD that may have similar biology and therefore may respond similarly to a medication. Despite these limitations, there are several drugs being tested in the clinic for the core symptoms of ASD. These medications have a wide range of targets including the hormone oxytocin as well as the more traditional targets, neurotransmitter receptors, including glutamate, GABA, acetylcholine and norepinephrine. Oxytocin Oxytocin is a 9 amino acid hormone made in the hypothalamus and secreted by the pituitary gland that has both central and peripheral actions. The central actions of oxytocin are thought to enhance the perception of social stimuli by making social stimuli more salient. When administered orally, oxytocin is digested before it is absorbed. It is also unlikely to cross the blood--brain barrier. To get around the drug delivery limitations for oxytocin, intranasal administration is in the early stages of investigation. It has been shown that oxytocin can pass through the nasal pathway into the cerebrospinal fluid, bypassing the blood--brain barrier, within 10 min of administration and the increase in oxytocin continues to increase for 80 min [2]. Based on several small clinical trials, intranasal oxytocin may be effective in treating the social communication deficits found in ASD [3-5]. These promising early studies indicate the need for larger-scale clinical trials. 1.1
Metabotropic glutamate antagonists and GABA agonists
1.2
One of the prevailing theories for the neurobiology underlying ASD is a disturbance during synaptic maturation leading to an imbalance between the excitatory and inhibitory neurotransmission, with increased excitation. Many of the known genetic causes of ASD lead to protein changes converging in the synapse that either directly or indirectly affect local dendritic protein synthesis [6]. Drugs that reduce excitation such as antagonists at the metabotropic glutamate receptors or increase inhibition such as agonists at GABA receptors are expected to lower excitation levels and possibly restore some balance and have therapeutic benefit. Arbaclofen (STX209) is a GABA (B) receptor agonist that was examined in a clinical trial for the symptoms of Fragile X syndrome. Arbaclofen is the R stereoisomer of baclofen, a drug already approved to treat muscle spasticity and already has been evaluated for safety. Overall arbaclofen treatment did not cause statistically significant improvement in the primary endpoints of the study, though there was some reduction in social avoidance and improvements in other social and behavior skills [7]. 2
More studies are planned to measure specific secondary endpoints that were promising in the initial trial. IGF-1 One new area of research is with IGF-1. Brain development is altered in ASD and the growth hormone/IGF-1 axis is involved in several aspects of brain development including myelination and neurogenesis. IGF-1 has not been studied extensively in children with ASD, but there is evidence for higher levels of IGF-1 in blood [8] and lower levels in cerebrospinal fluid [9,10]. The therapeutic profile for IGF-1 has already been established in children as recombinant IGF-1, also known as mecasermin, was approved by the FDA in 2005 for use in children with IGF-1 deficiency or growth hormone gene deletion [11]. There are several ongoing clinical trials examining the effect of IGF-1 to treat the core symptoms of ASD in children with ASD and SHANK3 deficiency (Phelan-McDermid Syndrome; 22q13 Deletion Syndrome) (ClinicalTrials.gov). 1.3
Other targets There several other pharmacological targets being evaluated to treat the symptoms of ASD. The hormone melatonin is important for neurodevelopment and the establishment of circadian rhythms and its physiology is disrupted in ASD, and there is some evidence that melatonin has therapeutic potential, but randomized clinical trials are needed [12]. Other therapeutic targets that are being clinically evaluated include acetylcholinesterase and the mammalian target of rapamycin. 1.4
2.
Expert opinion
The ultimate goal of this research is to use pharmacological agents to improve quality of life for people with ASD by lessening the severity of the core symptoms to improve social communication and behavior and reduce restricted interests and repetitive behaviors. To achieve this goal, a better understanding of the underlying biology of ASD and the etiology during neurodevelopment will be necessary. Also, clinical trials will need to examine much larger groups of individuals with ASD in order to fractionate subgroups of ASD by either behavioral or biological phenotypes. The biological phenotypes may be based on different genetic mutations that affect the same final common pathways. Whereas determining subgroups based on behavioral phenotypes will use the severity of the individual core symptoms and/or what other syndromes are also present such as anxiety, obsessive-compulsive disorder or epilepsy. And with so much heterogeneity in the ASD population defining the criteria for subgroups is not a trivial task, it is going to take a significant effort by many researchers using the same criteria to generate the phenotypic profiles that are specific enough for subgroups but not as general as the overall ASD phenotype. It is unclear at present whether the genetic and behavioral subgroups will include the same people as there may be variation in behavior symptom severity
Expert Opin. Drug Discov. (2014) 9(12)
Expert Opin. Drug Discov. Downloaded from informahealthcare.com by The University of Manchester on 10/13/14 For personal use only.
Making progress in autism drug discovery
among people with similar changes in same pathway and vice versa. It will be easier to interpret and look for treatments for subgroups where insults to a specific biological pathway lead to a similar behavioral phenotype. Or if it is found that specific behavioral phenotypes have similarities in etiology. But this is likely only to account for a small portion of people; the reality is that there will probably be a lot of variety of behavioral symptoms in the physiological subgroups and vice versa. The hope is that patterns will emerge as we begin to parse out the subgroups about how biology and behavior interact. As more people with ASD are put into subgroups, the information about the phenotypes that define the subgroups will greatly enhance the field of ASD research. Better endpoints for clinical trials are needed in ASD research. Subgroups will be defined by specific biological or behavioral characteristics that may provide these endpoints. When drugs are examined within a specific subgroup with a known common marker, the effects of the drugs on these markers hopefully will be more straightforward. New avenues will open up and potentially lead to discovery and use of objective biomarkers in addition to behavioral reports as. Subgroups with specific markers will also improve preclinical research. Animal models will be able to be examined using the same biomarkers that define the human subgroup. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
2.
3.
4.
.
CDC. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years ---Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2010. MMWR Morb Mortal Wkly Rep 2014;63(SS02):1-21 Born J, Lange T, Kern W, et al. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci 2002;5(6):514-16 Watanabe T, Abe O, Kuwabara H, et al. Mitigation of sociocommunicational deficits of autism through oxytocininduced recovery of medial prefrontal activity: a randomized trial. JAMA Psychiatry 2014;71(2):166-75 Gordon I, Vander Wyk BC, Bennett RH, et al. Oxytocin enhances brain function in children with autism. Proc Natl Acad Sci USA 2013;110(52):20953-8 Intranasal oxytocin appears to make social stimuli more salient.
5.
6.
7.
..
8.
9.
Following that, the efficacy of any treatment in the animal model will more likely predict the drug effect in humans. It is also expected that as the subgroups are defined, diagnosis of the subgroups will also improve, potentially allowing for diagnosis at earlier ages. This is critical for pharmacological treatment because by the time ASD is diagnosed the changes in the brain have already occurred. Drug treatments will have a chance to be more effective if they can be administered during development while the neurons in the brain are still organizing. Pharmacological research in ASD is still evolving along with our knowledge of the disorder. ASD is the result of very complex interactions during development between genes and the environment. As we learn more about the etiology of ASD and how it may differ within the disorder, it will give us new tools to find drug treatments for the core symptoms.
Declaration of interest KK Chadman has been supported by the New York State Office for Persons with Development Disabilities. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Domes G, Heinrichs M, Kumbier E, et al. Effects of intranasal oxytocin on the neural basis of face processing in autism spectrum disorder. Biol Psychiatry 2013;74(3):164-71 Kleijer KTE, Schmeisser MJ, Krueger DD, et al. Neurobiology of autism gene products: towards pathogenesis and drug targets Psychopharmacology (Berl.). 2014;231(6):1037-62 Berry-Kravis EM, Hessl D, Rathmell B, et al. Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, phase 2 trial. Sci Transl Med 2012;4(152):152ra127 Though deemed unsuccessful for specific endpoints, arbaclofen lead to improvements in sociability. Mills JL, Hediger ML, Molloy CA, et al. Elevated levels of growth-related hormones in autism and autism spectrum disorder. Clin Endocrinol (Oxf.) 2007;67(2):230-7 Riikonen R, Makkonen I, Vanhala R, et al. Cerebrospinal fluid insulin-like
Expert Opin. Drug Discov. (2014) 9(12)
growth factors IGF-1 and IGF-2 in infantile autism. Dev Med Child Neurol 2006;48(9):751-5 10.
Vanhala R, Turpeinen U, Riikonen R. Low levels of insulin-like growth factor-I in cerebrospinal fluid in children with autism. Dev Med Child Neurol 2001;43(9):614-16
11.
Fintini D, Brufani C, Cappa M. Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency. Ther Clin Risk Manag 2009;5(3):553-9
12.
Tordjman S, Najjar I, Bellissant E, et al. Advances in the research of melatonin in autism spectrum disorders: literature review and new perspectives. Int J Mol Sci 2013;14(10):20508-42
Affiliation Kathryn K Chadman Research Scientist, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10302, USA E-mail: [email protected]
3
Making progress in autism drug discovery
Expert Opin. Drug Discov. Downloaded from informahealthcare.com by The University of Manchester on 10/13/14 For personal use only.
Kathryn K Chadman 1.
Introduction
New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
2.
Expert opinion
Currently, there are still just two medications approved by the U.S. FDA to treat the irritability that is often found in children with autism spectrum disorder (ASD). Furthermore, there are no drugs approved that treat the core symptoms of ASD. And while many drugs have had good outcomes in preclinical animal models, they have been met with very little success in human clinical trials. There are several factors likely contributing to this problem starting with the heterogeneity within the ASD phenotype. It is therefore important that researchers develop their knowledge about the neurobiological basis of ASD as well as possible subgroups within the disorder, based on either specific behavioral profiles or biological pathways. Furthermore, the development of valid biological markers will allow researchers to use more than parent or teacher reports to determine if a treatment is effective. This author believes that there a good chance of finding effective pharmacological treatments for the core symptoms of ASD with this increased knowledge of the biology and etiology. Keywords: arbaclofen, autism, IGF-1, oxytocin, pharmacotherapy Expert Opin. Drug Discov. [Early Online]
1.
Introduction
The estimated prevalence of autism spectrum disorder (ASD), based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), has recently increased again [1], highlighting the need for treatment options for the core symptoms of this disorder. The 5th edition of the DSM (DSM-5) has revised the diagnostic criteria for ASD, eliminating the different disorders such as Asperger’s disorder and pervasive developmental delay not otherwise specified and bringing all persons with the same core symptoms into one designation, ASD. The new diagnostic criteria are persistent deficits in social communication and interaction and restricted or repetitive patterns of behavior, interests or activities with symptoms arising before the age of 3 years. Despite the outstanding research that has been done on ASD, there are still no pharmacological interventions that target the core symptoms. Unfortunately, there are few clinical trials with sufficient sample sizes for information on the effects of treatments across a wide range of people with ASD. Behavioral intervention remains the most effective treatment, and little research has been done pairing pharmacotherapy with behavioral therapy. Drugs with promising preclinical data in general are not performing well in clinical trials. There are many reasons that may account for the disconnection between preclinical models and clinical trials. There is likely a greater heterogeneity in the human ASD population represented in clinical trials than is accounted for in a single animal model system. The variety of ASD phenotypes within a given group of people may contribute to the lack of success in small-scale trials as there may not be enough subjects with similar underlying biology to respond to any given treatment. Another potential area for improvement are the outcome measures for many clinical trials that rely heavily on parent report, as objective clinical endpoints or biomarkers are not well defined for ASD. The length 10.1517/17460441.2014.962511 © 2014 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X All rights reserved: reproduction in whole or in part not permitted
1
Expert Opin. Drug Discov. Downloaded from informahealthcare.com by The University of Manchester on 10/13/14 For personal use only.
K. K. Chadman
of treatment may also be a factor because the expectation that 6 or 12 weeks of any therapy will undo years of ASD pathology is unlikely. All of these potential factors may be underlying the lack of success in clinical trials. Researchers are aware of these issues and are taking steps to address them. Excellent research is being conducted to look for biomarkers for subgroups within ASD that may have similar biology and therefore may respond similarly to a medication. Despite these limitations, there are several drugs being tested in the clinic for the core symptoms of ASD. These medications have a wide range of targets including the hormone oxytocin as well as the more traditional targets, neurotransmitter receptors, including glutamate, GABA, acetylcholine and norepinephrine. Oxytocin Oxytocin is a 9 amino acid hormone made in the hypothalamus and secreted by the pituitary gland that has both central and peripheral actions. The central actions of oxytocin are thought to enhance the perception of social stimuli by making social stimuli more salient. When administered orally, oxytocin is digested before it is absorbed. It is also unlikely to cross the blood--brain barrier. To get around the drug delivery limitations for oxytocin, intranasal administration is in the early stages of investigation. It has been shown that oxytocin can pass through the nasal pathway into the cerebrospinal fluid, bypassing the blood--brain barrier, within 10 min of administration and the increase in oxytocin continues to increase for 80 min [2]. Based on several small clinical trials, intranasal oxytocin may be effective in treating the social communication deficits found in ASD [3-5]. These promising early studies indicate the need for larger-scale clinical trials. 1.1
Metabotropic glutamate antagonists and GABA agonists
1.2
One of the prevailing theories for the neurobiology underlying ASD is a disturbance during synaptic maturation leading to an imbalance between the excitatory and inhibitory neurotransmission, with increased excitation. Many of the known genetic causes of ASD lead to protein changes converging in the synapse that either directly or indirectly affect local dendritic protein synthesis [6]. Drugs that reduce excitation such as antagonists at the metabotropic glutamate receptors or increase inhibition such as agonists at GABA receptors are expected to lower excitation levels and possibly restore some balance and have therapeutic benefit. Arbaclofen (STX209) is a GABA (B) receptor agonist that was examined in a clinical trial for the symptoms of Fragile X syndrome. Arbaclofen is the R stereoisomer of baclofen, a drug already approved to treat muscle spasticity and already has been evaluated for safety. Overall arbaclofen treatment did not cause statistically significant improvement in the primary endpoints of the study, though there was some reduction in social avoidance and improvements in other social and behavior skills [7]. 2
More studies are planned to measure specific secondary endpoints that were promising in the initial trial. IGF-1 One new area of research is with IGF-1. Brain development is altered in ASD and the growth hormone/IGF-1 axis is involved in several aspects of brain development including myelination and neurogenesis. IGF-1 has not been studied extensively in children with ASD, but there is evidence for higher levels of IGF-1 in blood [8] and lower levels in cerebrospinal fluid [9,10]. The therapeutic profile for IGF-1 has already been established in children as recombinant IGF-1, also known as mecasermin, was approved by the FDA in 2005 for use in children with IGF-1 deficiency or growth hormone gene deletion [11]. There are several ongoing clinical trials examining the effect of IGF-1 to treat the core symptoms of ASD in children with ASD and SHANK3 deficiency (Phelan-McDermid Syndrome; 22q13 Deletion Syndrome) (ClinicalTrials.gov). 1.3
Other targets There several other pharmacological targets being evaluated to treat the symptoms of ASD. The hormone melatonin is important for neurodevelopment and the establishment of circadian rhythms and its physiology is disrupted in ASD, and there is some evidence that melatonin has therapeutic potential, but randomized clinical trials are needed [12]. Other therapeutic targets that are being clinically evaluated include acetylcholinesterase and the mammalian target of rapamycin. 1.4
2.
Expert opinion
The ultimate goal of this research is to use pharmacological agents to improve quality of life for people with ASD by lessening the severity of the core symptoms to improve social communication and behavior and reduce restricted interests and repetitive behaviors. To achieve this goal, a better understanding of the underlying biology of ASD and the etiology during neurodevelopment will be necessary. Also, clinical trials will need to examine much larger groups of individuals with ASD in order to fractionate subgroups of ASD by either behavioral or biological phenotypes. The biological phenotypes may be based on different genetic mutations that affect the same final common pathways. Whereas determining subgroups based on behavioral phenotypes will use the severity of the individual core symptoms and/or what other syndromes are also present such as anxiety, obsessive-compulsive disorder or epilepsy. And with so much heterogeneity in the ASD population defining the criteria for subgroups is not a trivial task, it is going to take a significant effort by many researchers using the same criteria to generate the phenotypic profiles that are specific enough for subgroups but not as general as the overall ASD phenotype. It is unclear at present whether the genetic and behavioral subgroups will include the same people as there may be variation in behavior symptom severity
Expert Opin. Drug Discov. (2014) 9(12)
Expert Opin. Drug Discov. Downloaded from informahealthcare.com by The University of Manchester on 10/13/14 For personal use only.
Making progress in autism drug discovery
among people with similar changes in same pathway and vice versa. It will be easier to interpret and look for treatments for subgroups where insults to a specific biological pathway lead to a similar behavioral phenotype. Or if it is found that specific behavioral phenotypes have similarities in etiology. But this is likely only to account for a small portion of people; the reality is that there will probably be a lot of variety of behavioral symptoms in the physiological subgroups and vice versa. The hope is that patterns will emerge as we begin to parse out the subgroups about how biology and behavior interact. As more people with ASD are put into subgroups, the information about the phenotypes that define the subgroups will greatly enhance the field of ASD research. Better endpoints for clinical trials are needed in ASD research. Subgroups will be defined by specific biological or behavioral characteristics that may provide these endpoints. When drugs are examined within a specific subgroup with a known common marker, the effects of the drugs on these markers hopefully will be more straightforward. New avenues will open up and potentially lead to discovery and use of objective biomarkers in addition to behavioral reports as. Subgroups with specific markers will also improve preclinical research. Animal models will be able to be examined using the same biomarkers that define the human subgroup. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
2.
3.
4.
.
CDC. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years ---Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2010. MMWR Morb Mortal Wkly Rep 2014;63(SS02):1-21 Born J, Lange T, Kern W, et al. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci 2002;5(6):514-16 Watanabe T, Abe O, Kuwabara H, et al. Mitigation of sociocommunicational deficits of autism through oxytocininduced recovery of medial prefrontal activity: a randomized trial. JAMA Psychiatry 2014;71(2):166-75 Gordon I, Vander Wyk BC, Bennett RH, et al. Oxytocin enhances brain function in children with autism. Proc Natl Acad Sci USA 2013;110(52):20953-8 Intranasal oxytocin appears to make social stimuli more salient.
5.
6.
7.
..
8.
9.
Following that, the efficacy of any treatment in the animal model will more likely predict the drug effect in humans. It is also expected that as the subgroups are defined, diagnosis of the subgroups will also improve, potentially allowing for diagnosis at earlier ages. This is critical for pharmacological treatment because by the time ASD is diagnosed the changes in the brain have already occurred. Drug treatments will have a chance to be more effective if they can be administered during development while the neurons in the brain are still organizing. Pharmacological research in ASD is still evolving along with our knowledge of the disorder. ASD is the result of very complex interactions during development between genes and the environment. As we learn more about the etiology of ASD and how it may differ within the disorder, it will give us new tools to find drug treatments for the core symptoms.
Declaration of interest KK Chadman has been supported by the New York State Office for Persons with Development Disabilities. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Domes G, Heinrichs M, Kumbier E, et al. Effects of intranasal oxytocin on the neural basis of face processing in autism spectrum disorder. Biol Psychiatry 2013;74(3):164-71 Kleijer KTE, Schmeisser MJ, Krueger DD, et al. Neurobiology of autism gene products: towards pathogenesis and drug targets Psychopharmacology (Berl.). 2014;231(6):1037-62 Berry-Kravis EM, Hessl D, Rathmell B, et al. Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, phase 2 trial. Sci Transl Med 2012;4(152):152ra127 Though deemed unsuccessful for specific endpoints, arbaclofen lead to improvements in sociability. Mills JL, Hediger ML, Molloy CA, et al. Elevated levels of growth-related hormones in autism and autism spectrum disorder. Clin Endocrinol (Oxf.) 2007;67(2):230-7 Riikonen R, Makkonen I, Vanhala R, et al. Cerebrospinal fluid insulin-like
Expert Opin. Drug Discov. (2014) 9(12)
growth factors IGF-1 and IGF-2 in infantile autism. Dev Med Child Neurol 2006;48(9):751-5 10.
Vanhala R, Turpeinen U, Riikonen R. Low levels of insulin-like growth factor-I in cerebrospinal fluid in children with autism. Dev Med Child Neurol 2001;43(9):614-16
11.
Fintini D, Brufani C, Cappa M. Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency. Ther Clin Risk Manag 2009;5(3):553-9
12.
Tordjman S, Najjar I, Bellissant E, et al. Advances in the research of melatonin in autism spectrum disorders: literature review and new perspectives. Int J Mol Sci 2013;14(10):20508-42
Affiliation Kathryn K Chadman Research Scientist, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10302, USA E-mail: [email protected]
3
