Over the past 12 or so years, estimates of the incidence of autism spectrum disorder (ASD) have risen dramatically. In 2007 it was reported that one in 150 children had a diagnosis of autism, a number that a 2018 Centers for Disease Control report now puts at a stunning one in 59. Einstein has a long tradition of performing cutting-edge work in the clinic and the laboratory on autism. The highly esteemed neurologist and autism expert Dr. Isabelle Rapin (d. 2017) began her professional career here in 1958, and practiced as a physician-scientist until her retirement in 2016. Her legacy lives on as scientists, physicians, and clinicians at Einstein-Montefiore vigorously strive to understand and address the problems associated with autism.

Although autism can be recognized as early as 18 months of age, diagnosing autism can be a challenge even for the experienced clinician, and an accurate diagnosis is often significantly delayed by years. Age of ASD diagnosis nationally remains at 4–5 years of age, and 8+ years of age in traditionally underserved populations. Here at the Rose F. Kennedy Children’s Evaluation and Rehabilitation Center (CERC), the outstanding efforts of Lisa Shulman, M.D., and the RELATE program (Rehabilitation, Evaluation, and Learning for Autistic Infants and Toddlers at Einstein) have led to a far-earlier age of diagnosis compared to the national average for the same socioeconomic and racial/ethnic demographic. This has significant implications for prognosis, since early intervention is key to an optimal outcome.

When a diagnosis is received, a search on the Internet presents caregivers with an overwhelming number of treatment options. Scientists at Einstein are working to understand which therapies are effective and which are best suited to specific patient characteristics within this heterogeneous neurodevelopmental condition. Ongoing clinical trials include testing whether pharmaceutical interventions such as cannabidivarin and balovaptan reduce severe irritability, performed by Eric Hollander, M.D., and his group, and testing the efficacy of sensory-integration therapy for problem behaviors in autism, being done by Sophie Molholm, Ph.D., and colleagues, and of social interventions, being studied by Dr. Shulman and colleagues. A number of therapeutic approaches are already known to be helpful. At the Rose F. Kennedy CERC, where some 300 children with autism are seen for weekly therapy, and across the broader scope of the Children’s Hospital at Montefiore and affiliated clinics, evidence-based treatment options include speech/language and feeding therapies, social-skills groups, occupational and physical therapies, behavioral interventions such as applied behavioral analysis, augmentative communication training, seizure control, and special-care dentistry for those with sensory reactivity during dental procedures.

Genetics play a significant causal role in autism, whether due to inherited risk or de novo mutations. Getting to the bottom of the genetics of autism will allow scientists to better understand the affected neurobiological pathways, which is an important step in the development of novel targeted treatments. Both Dr. Shulman’s and Dr. Molholm’s groups are involved in multisite collection of DNA samples from individuals with autism. The highly diverse ethnic and racial makeup of the East Bronx and the surrounding area contributes to a more-representative pool of data for use in studying the genetic basis of autism. While autism is thought to have largely complex polygenic (and epigenetic) etiologies, sometimes the disorder can be caused by single-gene mutations. These monogenic syndromic cases can be highly informative about possible causative molecular pathways in idiopathic autism because they link a single gene to behavioral outcomes. Neuroscientist Dr. Jordan is studying inherited haploinsufficiency in the ANKS1B gene, which is associated with increased risk of autism and other neurodevelopmental conditions such as speech apraxia and ADHD. He is using quantitative proteomics in genetically modified mice, as well as induced pluripotent stem cells from affected individuals, to understand the molecular mechanisms underlying autism and other neurodevelopmental phenotypes associated with ANKS1B haploinsufficiency. It is widely hypothesized that impaired inhibitory interneuronal function leads to an imbalance of excitation/inhibition in cortical network activity in autism, but how this plays out is not well understood. Neuroscientist Renata Batista-Brito, Ph.D., and her team are making headway on this front by studying the role of inhibitory interneuronal processing on brain development in mice. She hypothesizes that disruption of MEF2C, another gene associated with autism, in a specific subset of inhibitory neurons will impair synaptic transmission and compromise cortical network activity and processing of sensory information. There is growing reason to think that impaired cerebellar connectivity plays a role in some cases of autism; Dr. Khodakhah is testing this thesis, applying his expertise on the cerebellum to investigating cerebellar circuit function, including connections between cerebellum and reward centers that respond to social interactions in the ventral tegmentum, in genetic mouse models of autism.

While animal models are critical to gaining detailed knowledge of the molecular pathways and neuropathology underling autism, it is a uniquely human condition that we wish to understand. Dr. Molholm and John Foxe, Ph.D., are using noninvasive electrical brain imaging combined with measures of cognitive function and clinical behaviors in children and adults with autism to study links between brain function and clinical phenotype, and to develop biomarkers of autism. Their work focuses on a range of perceptual-cognitive processes that may contribute to the autism phenotype, including predictive processing, attention, and multisensory integration. Clinicians working with individuals with autism play a key role in noting and then systematically charting facets of the autism phenotype. A number of Einstein-Montefiore clinicians are active on this front. Shlomo Shinnar, M.D., Ph.D., Maria Valicenti-McDermott, M.D., and colleagues, for example, have documented increased incidence of sleep and gastrointestinal problems in this pediatric population; occupational therapist Elizabeth Ridgway, O.T.D., is applying her experience to contribute to research on impaired sensory integration; and clinicians at the Human Clinical Phenotyping Core of the RFK IDDRC, overseen by neuropsychologist Juliana Bates, Ph.D., use clinical and neuropsychological assessments to characterize the cognitive and clinical phenotypes of research participants with autism.

The above represents just a sampling of the exciting clinical and research efforts at Einstein-Montefiore that are focused on autism. If you want to know more, check out the resources below, and look to future editions of the RFK IDDRC newsletter and to the RFK IDDRC website (http://www.einstein.yu.edu/centers/iddrc/) to learn about the latest developments as they unfold.

Key Projects

Cannabidivarin (CBDV) vs. Placebo in Children with Autism Spectrum Disorder (ASD)

Funded by the DOD CDMRP Autism Research Program. The expected study duration is April 12, 2019 to June 30, 2021.

ABSTRACT: There is a clear unmet need for new therapeutics to treat irritability in children with ASD that do not have the metabolic and weight adverse event profiles of the currently approved treatments. Cannabidivarin (CBDV) is a nonpsychoactive phytocannabinoid and a safe variant of Cannabidiol (CBD). It has no appreciable tetrahydrocannabinol (THC) [less than 0.01%], has been shown to have no impact on weight or metabolism, and improves both social and cognitive functioning in animal models of idiopathic and syndromal autism (Fragile X, Rett Syndrome, Angelman Syndrome). The CDC currently estimates 1 in 59 children have ASD. ASD is characterized by deficits in social communication, irritability, repetitive behaviors, impulsivity, temper tantrums, and high caregiver burden. Currently, the only FDA-approved medications for symptoms of ASD are aripiprazole and risperidone, both of which are indicated for irritability in pediatric ASD. These medications are effective but are associated with considerable side effects with long term treatment in this chronic developmental disorder, including weight gain, metabolic syndrome and the risk of type 2 diabetes, prolactin elevation and growth of breast tissue, extrapyramidal symptoms and the risk of tardive dyskinesia. The anticonvulsant divalproex sodium (valproate/VPA) also significantly reduces irritability and repetitive behaviors in individuals with ASD. Although VPA is efficacious for pediatric epilepsy and some symptoms of ASD, it also has significant side effects, including weight gain, sedation and nausea. CBDV, like VPA, is effective in the treatment of pediatric epilepsy, and ASD mouse models demonstrate potential mechanisms for treatment with CBDV, including potential therapeutic effects on repetitive behaviors, irritability, sociability, and quality of life, and the capacity to reduce inflammation. This study aims to examine the efficacy and safety of cannabidivarin (CBDV) with a primary aim of studying its effect on irritability in children with ASD.

STUDY DESIGN: This is a 12-week randomized, double-blind study of CBDV vs. placebo in 100 child and adolescent subjects aged 5 to 18 years with a diagnosis of ASD.
Clinical Trials: https://clinicaltrials.gov/ct2/show/NCT03202303

Intranasal Oxytocin vs. Placebo in Children with Prader-Willi Syndrome (PWS)

Funded by the FDA. The expected study duration is April 11, 2018 to February 11, 2020.

RATIONALE: Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder caused by lack of expression of paternally derived imprinted material on chromosome 15q11-q13. PWS is characterized by mild to moderate intellectual disabilities, repetitive/compulsive behaviors and rigidity, social cognition deficits and severe hypotonia at birth, followed by the onset of hyperphagia later in life. Obesity is responsible for the majority of the morbidity and mortality associated with PWS, and compulsive eating behaviors are most responsible for diminishing the quality of life for caregivers and family members. Oxytocin has been implicated in the pathophysiology of PWS and there have been small studies of intranasal oxytocin (IN-OXT) in this population. To date, however, studies have not been adequately powered to detect significance in target symptoms of hyperphagia and associated symptoms of individuals with PWS. The primary goal of this study is to examine the safety and efficacy of IN-OXT on hyperphagia, as measured by the Hyperphagia Questionnaire-Clinical Trails, from baseline to week 8. Currently, there are no effective treatments available to manage hyperphagia in patients with PWS.

STUDY DESIGN: This is an 8-week double-blind, randomized study in 50 children with PWS aged 5-17. Participation involves 5 in-person visits to our program and two telephone-call visits. Travel expenses will be reimbursed to participating families.
Clinical Trails: https://clinicaltrials.gov/ct2/show/NCT03197662

Long-term Antipsychotic Pediatric Safety Trial (LAPS)

Funded by the Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The expected study duration is January 10, 2019 to September 10, 2021.

RATIONALE: There have been several studies in children evaluating the relationship between atypical antipsychotics and weight gain. However, these studies are limited to a relatively small number of participants (30-300) for relatively short periods of time (3-18 months). The studies that directly compare different antipsychotics to one another have very small samples of individuals on some agents, limiting their ability to detect differences in smaller groups. The purpose of this study is to evaluate the long-term pathologic weight changes associated with multi-year risperidone or aripiprazole therapy in 3 - <18-year-old children, who have varying durations of prior antipsychotic drug exposure. This is critical because children appear to have greater vulnerability to antipsychotic-associated weight gain than adults, and obesity has significant effects on morbidity and mortality.

STUDY DESIGN: This is a muli-center, observational study that will include approximately 350 children being treated with risperidone and 350 children being treated with aripiprazole. The participants’ personal physicians will continue to prescribe their medications over the course of the study. Assessments will occur every six months at in-person visits, for 2 years.
Clinical Trials: https://clinicaltrials.gov/ct2/show/NCT03522168

aV1ation: A Study to Investigate the Efficacy and Safety of Balovaptan in Participants with Autism Spectrum Disorder (ASD)

Sponsored by Hoffmann-La Roche. The expected study duration is November 21, 2016 - July 6, 2021.

RATIONALE: To date, few studies have investigated the effect of pharmacological treatments on the social and communication deficits in ASD and no agent has received marketing approval for treating these core symptoms. Currently in the US, the only two approved medications for ASD are the atypical antipsychotics risperidone and aripiprazole, which only target irritability associated with ASD, but not the core symptoms. There is no pharmacological treatment available for the social and communication deficits in individuals with ASD and as a consequence there is a high unmet medical need for effective pharmacological therapies in the treatment of core symptoms in ASD. Balovaptan is a drug that drug blocks a hormone receptor (vasopressin 1a) in the brain that is linked to socialization, stress, anxiety, and aggression. Balovaptan has the potential to be the first pharmacotherapy to help improve core socialization and communication symptoms of ASD, and it has been granted Breakthrough Therapy Designation by the FDA.

STUDY DESIGN: This is a multi-center, randomized, double-blind, 24-week study to investigate the efficacy, safety, and pharmacokinetics of Balovaptan in children and adolescents aged 5-17 years with ASD who are high functioning (IQ >=70). After the participant completes the 24-week double-blind phase of the study, he/she will have the option to receive balovaptan in open treatment for 52 weeks.
Clinical Trails: https://clinicaltrials.gov/ct2/show/NCT02901431

oRBiting: A Study to Evaluate Scales for Repetitive and Restricted Behaviors in Children, Adolescents, and Adults With Autism Spectrum Disorder (ASD)

Sponsored by Hoffmann-La Roche. The expected study duration is August 13, 2018 to November 30, 2019.

RATIONALE: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and social interaction and presence of repetitive patterns of behaviors, interests, or activities. In addition to these core deficits, individuals with ASD may suffer from a range of co-morbid conditions and associated behavioral problems, including irritability, depression or anxiety, attention deficits, obsessive compulsive symptoms, seizures and sleep disruption. Restricted and repetitive behaviors (RRBs) are core diagnostic features of ASD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). At present, no pharmacological treatment has been approved by FDA to treat the core deficits of ASD, and currently available approved drugs (risperidone and aripiprazole) address only associated behavioral problems (used for the treatment of irritability associated with ASD). Nonpharmacological treatments have been developed to address the core symptoms; however, clear efficacy has been difficult to demonstrate in large controlled clinical trials and they are time consuming and costly. Accordingly, there is a high unmet medical need for pharmacological treatments of these core symptoms of the disorder. RRBs constitute a broad range of behaviors, including simple motor stereotypies as well as more complex ritualized and rigid behaviors, compulsions, and restricted interests that vary in frequency, intensity, and duration. Although there is an extensive literature on RRBs in subjects with ASD, the instruments available and widely used to assess these behaviors in clinical trials are not fully understood or have limitations to assess change in these behaviors, in particular in clinical trials. This study is observational and seeks to characterize different scales to measure repetitive and restricted behaviors in different ASD sub-populations over time. The study will also to explore the use of digital biomarkers. The results from this study will inform the planning and setup of subsequent drug interventional studies in programs aimed to treating restrictive and repetitive behaviors in ASD.

STUDY DESIGN: This is a 12-week study that includes 4 in-person visits to our program. The participant will also receive a smart watch and a smart phone. The smart watch will be used to monitor repetitive movements that the participant may exhibit. The smart phone will be used at home to play games that assess cognition, social skills and speech.
Clinical Trails: https://clinicaltrials.gov/ct2/show/NCT03611075

Research Laboratories

Clinical Resources