For Scientists

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2024 Awardees

Seeking Potential Treatment for X-Linked 63 Intellectual Disability

Don Kong, PhD | Department of Pediatrics

Intellectual disability (ID) is a severe developmental disease, affecting 1-3% of human population. Given the
complex and heterogeneous causes of it, effective prevention or treatment of ID are still largely missing. In this
proposal, we found that a lipid enzyme, ACSL4, whose mutations were identified in human patients of ID, plays
an important role on the interface of lipid metabolism and brain development, and its dysregulation in the brain
contributes to the development of ID. We propose to employ multiple state-of-the-art technologies with both
neuron-specificity and high-throughput analysis to assess promising treatment method of this disease.

Identifying NDD Mechanisms and Treatments in Human Brain

Emily K. Osterweil, PhD | Alexander Rotenberg, MD, PhD | Department of Neurology
Zhigang He, PhD | F.M. Kirby Neurobiology Center

The proposed research will study how the gene mutations linked to neurodevelopmental disorders
Fragile X Syndrome (FMR1), SYNGAP1-related intellectual disability, and Phelan-McDermid
Syndrome (SHANK3) disrupt brain function and identify new targets for drug development. We will
develop a new model system using human brain slices from surgery patients to assess the effects of
gene mutation on brain activity, protein production, and gene expression. This information is currently
only available from mouse models. The goal is to use this unique human model to identify new disease
mechanisms and therapeutic targets for these currently untreatable neurodevelopmental disorders.

Development of Antisense Oligonucleotides to Durably Treat Usher Syndrome Type 1b

Gwenaelle Geleoc, PhD | Stephanie Mauriac, PhD | Department of Otolaryngology

The goal of this project is to develop two innovative treatments for patients carrying mutations in MYO7A gene (USH1B). For this purpose, we will use (1) antisense oligonucleotides (ASOs), a promising class of drugs, already approved by the FDA and that can correct gene splicing, and a (2) vectorized form of ASOs, a novel technic to durably treat patient and avoid repeated injections in the eyes and the ears. These approaches will be tested in vitro in different cell lines and in inner ear and retinal organoids generated from control and mutant human iPSCs. This proposal will chart a path for individualized ASO therapies for USH1B patients.

2023 Awardees

Translational Biomarkers and Therapeutic Development for Very Young Children Diagnosed with Autism Spectrum Disorder and Co-occurring Anxiety

Susan Faja, PhD and Katherine Driscoll, PhD | Division of Developmental Medicine

This study has the broad goal of evaluating new tools that could be used to improve the clinical care of autistic preschoolers who have co-occurring anxiety diagnoses. It plans to test four measures of the physical response to stressful situations because they have been validated in older autistic and neurotypical children, are feasible for autistic preschoolers, and provide an objective way to measure elevated anxiety prior to intervention or reduced anxiety following intervention. It will collect these measures before intervention to examine whether baseline scores predict intervention response, one month later to ensure that they provide a reliable measure of functioning, and after a behavioral intervention to examine whether changes in scores correspond to intervention response. It will use a behavioral intervention, Being Brave, that has been successfully used to reduce anxiety with autistic preschoolers to examine the four potential measures of anxiety response and regulation.

Discovery of Exosome-Based Biomarkers of Brain Development in Preterm Infants

Christopher Elitt, MD, PhD | Department of Neurology
Zhigang He, PhD | F.M. Kirby Neurobiology Center

Premature birth is a major problem is the United States and worldwide, disproportionally impacting Black and Brown families. Infants born early are at high risk for brain injuries, particularly injuries to the cells (oligodendrocytes) that later produce the insulation (myelin) around the wires in the brain. There is increasing evidence that nutritional deficits may underlie some of these injuries. A major problem is identifying babies in the Neonatal Intensive Care Units who have abnormal brain development from insufficient nutrition or other insults. This study proposes a new approach to discover biomarkers using tiny bubbles (exosomes) that are released by all cells into the blood. The exosomes contain information from the original cell (DNA, RNA, protein) providing a window into brain development. This study has recruited nearly 50 very preterm infants with blood, urine and breast milk samples, as well as obtained a picture of their brain (MRI) when they left the hospital. It will isolate exosomes, count the number of copies of every RNA (instructions from genes to make proteins) and then determine associations of these RNAs with zinc intake, blood zinc concentrations, brain development and body growth. These experiments are likely to discover biomarkers that can be introduced rapidly into the NICU, as well as identify novel genes or pathways critical for brain development and brain injury in preterm infants.

Identifying Novel Network-based EEG Biomarkers of Drug-Resistant and Surgery-Resistant Epilepsy in Children

Eleonora Tamilia, PhD | Division of Newborn Medicine
Alexander Rotenberg, MD, PhD | Department of Neurology

One of the most effective treatments for children with drug resistant epilepsy (DRE) is brain surgery for the removal of the brain area(s) that cause them to have seizures. However, most children with DRE spend precious years trying ineffective drugs while continuing to experience uncontrolled seizures. It would be ideal if we could make the diagnosis of DRE as soon as a patient experience their first seizure/s: However, it is quite unknown how to recognize DRE in a child that presents seizures until the lengthy process of trying several ASMs.
Based on this premise, the first aim of this study is to test whether we can identify drug resistant epilepsy (DRE) using the scalp EEG data recorded very early in the course of the disease, by developing a new methodology that focuses on understanding the brain network. For children with DRE, a significant challenge is to understand whether they will actually benefit from brain surgery or not, since not all patients with DRE can become seizure free with brain surgery. Thus, a second aim of this is to predict whether a patient will benefit from brain surgery by analyzing scalp EEG data recorded before surgery. To this purpose, a new methodology is proposed that estimates whether the area/s of the brain that cause the seizures can be fully targeted during brain surgery (and thus stop the seizures) or not.

Developing Splice-Modulating ASO Strategies For CDKL5 Deficiency Disorder

Timothy Yu, MD, PhD | Division of Genetics and Genomics
Heather Olson, MD, MS | Department of Neurology

Antisense oligonucleotides (ASOs) are promising drugs comprised of 15-20 nucleotide snippets of chemically modified RNA molecules that can be customized to modulate specific gene-splicing patterns for treating genetic disorders. The goal of this project is to develop ASO therapeutic strategy for CDKL5 deficiency disorder (CDD), a severe developmental and epileptic encephalopathy with no established disease modifying therapies. The present authors found at least 20 patients carrying CDKL5 mutations within in-frame exons beyond the kinase domain that are skippable, and more within exons that could be skipped with a combined exon skipping strategy to maintain the reading frame. This study will develop and test ASOs to rescue CDKL5 pathogenic variants by inducing in-frame exon deletions. Successful completion of this project will provide a foundation for launching new interventional clinical trials for CDD.

2022 Awardees

EEG Biomarkers of Preferential Psychostimulant Treatment Response in Children with ADHD.

Anne Arnett, PhD and Eugenia Chan, MD, PhD | Division of Developmental Medicine

This study aims to identify electroencephalography (EEG) and event related potential (ERP) biomarkers of preferential response to two commonly prescribed psychostimulants, among treatment-naïve children with attention deficit hyperactivity disorder (ADHD). The results of this investigation will improve understanding of individual differences in neurobiological mechanisms of ADHD and provide preliminary data for a large-scale clinical trials aimed at developing a precision medicine care model for pharmacological treatment of ADHD.

Circadian Biology of EHMT1 and Sleep-associated Neurodevelopmental Collapse in Kleefstra Syndrome.

Jonathan Lipton, MD, PhD and Siddharth Srivastava, MD | Department of Neurology

The goal of this study is to establish a collaborative translational pipeline to investigate the mechanistic bases for sleep dysfunction in the neurodevelopmental disorder (NDD) Kleefstra Syndrome (KS). It will implement a combination of patient derived cells, circadian rhythm studies, cell biology and biochemistry coupled with clinical assessments of a clinical cohort with Kleefstra Syndrome to investigate the molecular mechanisms by which mutations in the EHMT1 enzyme result in circadian rhythm disruption, and address an important gap in knowledge in child neurology that has eluded mechanistic understanding and therapeutic development.

Novel tools for selective and reversible modulation of neuronal gene expression and brain activity

Xin Tang, PhD | Department of Neurosurgery

This study aims to pioneer a novel approach of silencing brain activities focally and reversibly through injection of small molecule compounds that increase Kir2.1 expression. It seeks to develop two high-throughput screening-compatible assays that are sensitive and robust in detecting endogenous Kir2.1 expression levels in neurons, and will provide a proof-of-concept for a novel focal molecular therapy that has considerable clinical promise to support personalized surgical planning, by enabling clinicians to identify the precise anatomical loci that are safe for surgical removal and efficacious for treating diseases such as epilepsy.

2021 Awardees

Development of Mechanism-Based Therapeutics for Kabuki Syndrome (KS).

Maxwell G. Heiman, PhD and Olaf Bodamer, MD, PhD | Division of Genetics and Genomics

The goal of this study is to leverage Kabuki Syndrome (KS) patient sample repositories and innovative KS animal models to screen a collection of 10,000 drugs and identify those that ameliorate KS symptoms. This will be the first step in providing families with a drug therapy targeted specifically to treating this disorder.

Translational Gene Therapy for DFNB16 Hearing Loss Patients

Jeffrey R. Holt, PhD and Olga Shubina-Oleinik, PhD | F.M. Kirby Neurobiology Center at Boston Children’s Hospital

This study aims to develop methods that allow gene sequences to be divided into two components for delivery into the sensory cells of the inner ear, focusing on the large STRC gene, a common cause hereditary hearing loss in humans. The researchers will test the strategy in human inner ear cells generated from stem cells, anticipating this strategy will help with development of new treatments for genetic hearing loss.

Atlas based Analysis of Abnormalities in Brain Microstructure in Fetuses with Congenital Heart Disease (CHD)

Camilo Jaimes, MD | Department of Radiology

This study will utilize a technique called diffusion MRI to evaluate the brains of fetuses with Congenital Heart Disease. The goal of this project is to create automated and semi-automated image processing pipelines that make this technology scalable and accessible. To do this, the researchers propose the creation of the first set of fetal specific anatomic labels which can be propagated to individual subjects using computational neuroimaging technology. This will allow comparison of large groups of patients, without manually segmenting each individual. The rich anatomic detail of these segmentations will allow identification of emergent differences which can be used to study prenatal brain development in fetuses with a wide array of clinical indications.

Identifying EEG-Based Biomarkers of Language and Cognitive Development in Down Syndrome (DS) and Fragile X Syndrome (FXS)

Carol L. Wilkinson, MD, PhD | Division of Developmental Medicine
Nicole Baumer, MD, MEd | Department of Neurology

This study will collect EEG data from preschool-aged children with Down Syndrome and compare them to typically developing children and as children with Fragile X Syndrome. EEG-markers that are found in this study could be used as an objective way to look at developmental prognosis and will help the development of effective behavioral and medication therapies.