Individuals with a mutation in ASH1L exhibit symptoms of profound autism, as well as several medical comorbidities. Building on this fellow’s expertise in pre-clinical models of ASH1L-related autism, the fellow will advance to a natural history study of human patients with this mutation, and their families. In addition, the fellow will collect EEG data from families and identify potential biomarkers of this gene mutation. These are critical steps that enable future drug development and seizure treatment. When the study is complete, the findings have potential to guide development of new drugs to treat symptoms of profound autism, including those with and without an ASH1L mutation.
Building a Clinical Trial Pipeline for Profound Autism
Executive functioning is the ability to manage daily life, follow directions and handle emotions — and has been reported to be significantly impaired in individuals with ASD. This project will take advantage of an existing longitudinal study to examine the specific role and active ingredients of early intervention from ages 2-4 on executive functioning. The fellow will also examine whether demographic factors, including race and ethnicity, play a role in the effectiveness of the intervention.
The UBE3A gene is thought to be responsible for Dup15q Syndrome, one of the genetically derived autism spectrum disorders (ASD). Despite its clinical importance, we know very little about UBE3A distribution in the human brain. Most researchers assume it closely mirrors that of the rodent brain. This lack of knowledge could be catastrophic if the distribution of UBE3A in the human brain is improperly inferred from rodent studies and leads to inappropriate delivery and treatment strategies for autism. To assure the safe targeting of therapeutic approaches to normalizing UBE3A levels in individuals with Dup15q Syndrome, this fellow will study UBE3A developmental expression in the closest proxy we can get to the human brain – the brain of the rhesus monkey.
Given the historically higher prevalence of white males in autism research studies, many autism diagnostic and outcome instruments have not been specifically validated in people of color or in females. This study will recruit women and individuals from racially and ethnically diverse communities to understand how a measure of treatment outcome, called the BOSCC (Brief Observation of Social Communication Change), can be used more effectively in these communities.
Many autism referrals in low-resource settings originate from community mental health care clinics. Unfortunately, many mental health care providers are not trained in autism interventions and do not have the appropriate resources to provide support to parents or provide parent training for early developmental interventions. This fellow will work directly with ABA agencies that contract with Medicaid to determine how clinicians can better support parents participating in parent- mediated interventions.
Hypersensitivity to auditory stimuli, including even regular sounds and voices, is seen in a high percentage of people with autism. This project will expand on existing research at Vanderbilt looking at brain activity in autistic and non-autistic individuals with different levels of sound tolerance to understand the factors that play a role in the brain’s response to noise.
Early intervention is vital for children on the autism spectrum but is often only available after a formal diagnosis. Because of the COVID- 19 pandemic, many assessments are now conducted online. This change has sometimes occurred without studying whether modifications made to support online assessments affect the outcomes of the assessments. Researchers at the University of Massachusetts Boston, the University of Washington, Rush University Medical Center, and Michigan State University recently adapted an assessment protocol (the Communication Play Protocol; CPP), to be conducted as an online assessment of ASD (RISE-CPP). ASF’s funding will allow researchers to determine if clinicians can diagnose ASD online using the RISE-CPP protocol as accurately as they can using traditional in-person assessments. An online version has the advantages of possibly reaching a more diverse community and improving opportunities for early intervention.
Quality of Life (QoL) outcome measures have traditionally excluded autistic individuals with minimal verbal ability or cognitive disability. The Patient-Reported Outcomes Measurement Information System (PROMIS®) Autism Battery – Lifespan (PAB-L) is a
recently developed instrument to measure autistic QoL across the lifespan. Although PAB-L has been shown to be an acceptable QoL measure in autism, nonverbal people with cognitive disability were underrepresented among participants in the original validation studies. This grant will expand the research on the PAB-L to examine whether it is appropriate in those with profound autism, and also determine what changes, if any, should be made to effectively measure quality of life in this underserved population.
Up to 90% of people with autism experience GI distress. Although these symptoms often occur in children and adults, there is a lack of research focused on addressing GI dysfunction in autistic adults. A current study is gathering input from a group of autistic adults in order to develop a set of recommendations for improving GI health in adults. This grant will provide funding to expedite data collection, analysis, and dissemination of the outcomes of this study so that results can be seen up to a year earlier. These recommendations will shape future research by prioritizing the most relevant GI concerns identified by autistic adults and interdisciplinary collaborators, leading to the development of better treatments and overall approaches to GI health in people with autism.
Even in cases of autism with a known genetic mutation, there can be differences in the presentation of symptoms, which is also known as “phenotypic heterogeneity.” One way to measure this variability across individuals with autism is by examining brainwave patterns. Earlier research in people with Fragile X Syndrome has shown that individuals have different patterns of brainwave activity, which may predict their response to treatments. Building on this research, the fellow will collect cells from individuals with Fragile X Syndrome and turn them into neurons. These cells will then be tested for their own electrical activity, validating the brainwave data collected earlier. This study will then take the research a step further by examining if and how different therapeutics affect these neurons in different ways, leading to more targeted therapeutics.
Genetic testing is recommended for all children with autism. However, many children receive test results that reveal mutations in genes that have not yet been associated with autism. Unfortunately, these variants of uncertain significance can cause confusion and problems for parents seeking clinical diagnoses and support. This study will utilize machine learning to integrate genetic findings with the child’s attainment of key developmental milestones, because often milestone delays are associated with rare genetic disorders. Eventually, this research could lead to a brief, low-cost clinical prediction tool that increases the diagnostic certainty of genetic testing in autism.
Despite awareness that depression is common in autistic people, the mental health of minimally verbal (MV) autistic adults has received inadequate attention. Part of the problem is the lack of valid tools to assess depression in MV autistic adults. This study will investigate the utility and appropriateness of using surveys administered by a caregiver around depression and will gather information about behaviors that caregivers believe reflect low mood or depression. This project addresses a gap in mental health supports for MV autistic adults and will assist clinicians in determining which tools should be used for people with autism who show signs of depression but cannot verbally communicate their feelings.