For Scientists

2026 Awardees

Using Human Induced Pluripotent Stem Cell (hiPSC)-Derived Neurons and Organoids from TSC Individuals with Integrated Functional Imaging and Transcriptomics to Define Rescue Mechanisms

Wardiya Afshar-Saber, PhD | Department of Neurology

Tuberous sclerosis complex (TSC) is a genetic condition that affects brain development and is commonly associated with seizures, autism, and learning and behavioral difficulties. Current treatments mainly target a pathway called mTOR, which is overactive in TSC. While these treatments can help reduce seizures partially,they do not improve the cognitive and behavioral symptoms that most affect daily life. Research from our lab shows that brain cells from individuals with TSC also have problems with energy production, and communication between neurons, issues that are not fixed by current therapies. Thus, new treatment approaches are urgently needed. Cannabidiol (CBD), an FDA-approved drug for TSC-related seizures, may help by working through different pathways. However, CBD affects many systems in the body, which can cause side effects. To develop safer and more effective treatments, we need to understand how CBD works in brain cells. In this project, we will use stem cell technology to generate human brain cells from individuals with TSC. These cells can be studied in the lab as neurons and as three-dimensional brain organoids that better mimic brain function. We will use advanced imaging and genetic analysis to measure how these cells function and respond to treatment. Our goal is to learn exactly how CBD helps brain cells work better. With that understanding, we can create new medicines that keep CBD’s benefits while causing fewer side effects. This work is conducted in partnership with specialized teams in human neuron modeling and drug development, helping ensure that discoveries can move quickly toward clinical impact. Ultimately, this work aims to improve not only seizure control but also the cognitive and behavioral outcomes that matter most to individuals with TSC and their families.

Investigating Somatic Mosaicism in Cerebral Palsy (Preclinical Research)

Alissa D’Gama, MD, PhD | Division of Newborn Medicine, Department of Pediatrics       

Siddharth Srivastava, MD | Department of Neurology         

Weston Northam, MD | Department of Neurosurgery                                                     

Cerebral palsy is the most common childhood-onset motor disability, affecting up to 4 in 1000 children in the United States, and is associated with significant morbidity, caregiver burden, and healthcare costs. In some cases referred to as non-cryptogenic CP, clear risk factors for CP are identified around the time of birth, such as being born prematurely. In other cases referred to as cryptogenic CP, which account for approximately 20% of cases, no clear risk factors are identified, raising suspicion for an underlying genetic disorder. This proposal will use cutting-edge sequencing and analysis methods to identify genetic changes that occur during fetal development that may cause CP. By identifying new genetic causes of CP, this study will inform precision diagnosis, identify targets for future precision therapies, and contribute to our understanding of the pathophysiology of CP.

The ‘Hydrogen In neonatal Encephalopathy’ (HIE) Trial: A Pilot

Brian Kalish, MD | Division of Newborn Medicine, Department of Pediatrics

P. Ellen Grant, MD | Department of Radiology

John Kheir, MD | Department of Cardiology

Each year, hundreds of thousands of newborns worldwide suffer hypoxic-ischemic encephalopathy (HIE), a type of brain injury caused when a baby’s brain is deprived of oxygen around the time of birth. HIE is often due to sudden emergencies such as umbilical cord compression, placental separation, or uterine rupture. The only proven treatment is therapeutic hypothermia, in which a baby’s body is cooled for 72 hours after birth to slow ongoing brain cell damage. Despite this treatment, roughly half of affected infants still die or develop lasting disabilities. This study tests whether breathing a small amount of hydrogen gas (2% H2) alongside standard treatment can better protect the newborn brain. When oxygen is cut off and then restored, the body produces harmful molecules called free radicals that damage cells; hydrogen gas neutralizes these molecules by reacting with them to form water. In the Hydrogen In neonatal Encephalopathy (HIE) Trial, babies born at or near full term with signs of moderate or severe HIE will be randomly assigned to receive either hydrogen gas plus standard cooling, or standard cooling alone. Because HIE is a time-critical emergency, enrollment will occur rapidly under special federal emergency research regulations. We will enroll 63 babies across multiple hospitals, measuring whether hydrogen can be reliably and safely delivered for 72 hours, how it affects blood biomarkers of brain injury and inflammation, and whether MRI brain scans show less injury in treated infants. If successful, this trial will directly support a larger study to confirm whether hydrogen saves lives and prevents disability, which may offer a low-cost, widely available treatment that could help newborns around the world.

Development and Testing of Wake Quality Biomarkers in CNS Hypersomnolence Disorders

Kiran Maski, MD, MPH | Department of Neurology

Children and teenagers with CNS Disorders of Hypersomnolence such as idiopathic hypersomnia and narcolepsy experience severe daytime sleepiness that interferes with school and daily life. Though current treatments such as traditional stimulants and oxybates reduce daytime sleepiness, patients still complain of not feeling fully awake and struggling with “brain fog”. New medications targeting a brain chemical called orexin are in development. Orexin is the master regulator of wake state, but researchers currently have no reliable, objective way to measure whether a child’s wakefulness improves with treatment. Currently, only subjective questionnaires exist such as the Epworth Sleepiness Scale, and patients have long emphasized these surveys do not capture their full disease burden. This study develops and tests two objective measures of wakefulness quality for use in future clinical trials. The first is a brain wave (EEG) measure taken during quiet wakefulness throughout the day of sleep testing, capturing how alert the brain before and after timed rest opportunities is at the neurological level. The second is a 5-minute attention and reaction time test measuring sustained focus. We will study these measures in 20 youth with CNS Disorders of Hypersomnolence and 20 healthy youth during daytime sleep study testing. Additionally, we will examine wake brain wave patterns captured during retrospective sleep studies in over 200 children in an existing sleep database. Our early data show that children with idiopathic hypersomnia have measurably different brain wave patterns and more attention lapses compared to controls, with differences growing larger as the testing day progresses, consistent with patient experience. By establishing these objective markers of wakefulness quality, this research will equip future clinical trials with the tools needed to rigorously test whether new wake promoting medications help children with CNS Disorders of Hypersomnolence feel and function better.

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.

Pilot Research Grant Application

For detailed application instructions for the TNC Pilot Research Grants, please download the PDF guidelines >