Pilot Project Award

 

The Pilot Project award is given to a Boston Children’s Hospital faculty member to support new high risk/high yield projects that require development of preliminary data or proof of concept studies in order to attract longer-term funding from the National Institute of Health and other mainstream funding agencies. One-year research proposals for up to $50,000 (inclusive of overhead at the current philanthropic fund rate) will be considered with competitive renewal for a second year a possibility.


2020 Pilot Project Awardees

Heather Olson, MD, MS
Project title: Genetic variants in inflammatory epilepsy: Rasmussen Encephalitis and FIRES

Rasmussen Encephalitis (RE) and Febrile Infection Epilepsy Syndrome (FIRES) are two rare devastating disorders that occur in children resulting in a severe seizure disorder not responding to medications along with additional neurological deficits. Additional deficits may include learning and behavioral problems, muscle weakness, and swallowing or vision difficulties for example. The underlying cause for these disorders is unknown. This pilot study seeks to investigate underlying genetic causes for these two rare and severe disorders with inflammatory components. Understanding the underlying biology could lead to better treatments in the future.

Amy O'Connell, MD, PhD
Project title: T Cell Receptor Repertoire Sequencing Enhances Specificity of Newborn Screening for SCID in Premature Infants

Infants born prematurely have abnormal development of several organ systems, leading to orphan diseases of the eyes (retinopathy of prematurity), lungs (chronic lung disease), and other systems. Our research has shown that some premature infants may also develop a disease of their immune system, specifically impacting the development of their T cells. Some former premature babies have low numbers of T cells, but it’s hard to know if the function of the T cells is impaired because the traditional tests are not accurate in premature infants. For this pilot study, we will use a technique that assesses how many diverse T cell receptors are in a blood sample from these infants. If T cells are functioning normally, there will be a diverse set/repertoire of these receptors. This will help us to determine whether some premature infants have abnormal T cell development due to their prematurity. It may also improve newborn screening for another orphan disease, severe combined immunodeficiency (SCID), by giving us an easier way to check T cell activity during prematurity, as traditional tests often give false positive results in premature infants.

Anne O'Donnell, MD, PhD
Project title: Investigating the contribution of non-coding genetic changes to unsolved cases

Despite improvements in our ability to read the human genome, our understanding of how changes in the genome impact human disease remains limited. For example, although we know that disease-causing genetic changes can be located throughout the genome, current genetic testing is largely limited to only 1% of the human genome, which is the portion that codes for proteins. By contrast, genetic changes in the other 99% of the genome that alter when and where these proteins are produced are routinely ignored during genetic testing due to our poor ability to interpret their functional impact. This limitation hampers our ability to diagnose and provide targeted therapies for our patients. In this proposal, we aim to improve the diagnosis of patients with rare disorders by leveraging a novel method that determines whether a genetic change alters when and where a protein is produced, thereby enabling the interpretation of genetic variants in the other 99% of the genome. We aim to evaluate nine cases that have been enrolled through the Manton Center using this approach to help identify any genetic alterations underlying their disease.

2018 Pilot Project Awardees:

Alice Lee, PhD and Boxun Zhao, PhD
Project title: Pathogenic structural variant identification and splicing defect correction

Advances in next-generation sequencing have revolutionized the diagnosis of genetic diseases; however, there remains a significant fraction of genetic diseases that are not linked to causal mutations, in part because it is challenging to study some structural variants with current sequencing technologies and conventional analytical pipelines. This points to an urgent need for specialized variant calling tools, as well as long-read or linked-read sequencing approaches to elucidate the full spectrum of genomic variants. We propose to undertake an investigation of structural variants as underexplored sources of DNA variation that likely underlie a large portion of unresolved genetic cases. We will systematically identify pathogenic structural variants and characterize their effects on gene transcripts. This research will advance our understanding of the importance of structural variants as a mechanism underlying orphan diseases and will facilitate the development of novel diagnoses and therapeutics.

Anne Fulton, MD and Lucia Ambrosio, MD, PhD
Project title: Translational Read-Through Inducing Drugs (TRIDS) to treat Inherited Retinal Disorders (IRDs)

This project centers on utilizing read-through therapy to identify compounds that may affect inherited retinal disorders (IRDs), each of which is an orphan disease. Read-through is a gene-based therapeutic approach for hereditary diseases caused by premature termination codon (PTCs) mutations, based on the discovery that small molecules, known as TRIDs (translational read-through inducing drugs), enable the translation machinery to suppress a nonsense codon and extend the nascent peptide chain; consequently, these molecules contribute in the full-length protein synthesis. In collaboration with BCH Translational Lab, Dr. Ambrosio plans to create patient-specific cell lines — from skin-derived fibroblasts and EBV-transformed lymphoblastoid cells from peripheral blood mononuclear cells — of patients with the rare syndromic ciliopathy, Bardet Biedl syndrome (BBS), as well as healthy controls. These banked specimens will be the cellular material to test several TRIDs she has selected. After treatment with TRIDs, mRNA, proteins, and a specific functional assay for markers for cilia will be evaluated. The results in BBS subjects and controls will be compared to demonstrate a successful read-through process as restoration of the proteins' transcription.