Mouse Model for Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS) (NR2F1 gene mutation)

Awardee: Carlie Monnier

Foundation: NR2F1 Foundation / COMBINEDBrain

Funding Period: May 13, 2022

Mouse Model for SLC13A5 Epilepsy (Citrate Transporter Disorder)

Awardee: Tanya Brown

Foundation: TESS Research Foundation

Funding Period: May 13, 2022

Mouse Model for SCN1A Gain of Function (ultra-early onset Dravet syndrome)

Awardee: Ethan Goldberg

Insitution: CHOP

Funding Period: May 13, 2022

Utilizing patient iPSC-derived neurons to determine the functional consequences of longer cilia in CDKL5 Deficiency Disorder (CDD)

Awardee: Mustafa Sahin, MD PhD

Institution: Boston Children’s Hospital

Award Amount: $149,241

Funding Period: May 1, 2022 - April 31, 2023

Computational drug repurposing for CDKL5 Deficiency Disorder

Awardee: Diego Di Bernardo, PhD

Institution: Telethon Institute of Genetics and Medicine

Award Amount: $150,000

Funding Period: May 1, 2022 - April 31, 2023

Rescuing functional defects in a zebrafish model of CDKL5 deficiency: Contribution to the identification of therapeutic target

Awardee: M. Leonor Cancela, PhD

Institution: University of Algarve

Award Amount: $141,338

Funding Period: May 1, 2022 - April 31, 2023

A functional genomics approach to dissect the molecular bases of CDKL5 Deficiency Disorder

Awardee: Davide Cacchiarelli, PhD

Institution: Telethon Institute of Genetics and Medicine

Award Amount: $150,000

Funding Period: May 1, 2022 - April 31, 2023

Hematopoietic stem cell gene therapy as a therapeutic approach for CDKL5 Deficiency Disorder

Awardee: Joseph Anderson, PhD

Institution: University of California, Davis

Award Amount: $150,000

Funding Period: May 1, 2022 - April 31, 2023

Identifying Unmet Care and Communication Needs of Families Affected by Complex Lymphatic Anomalies

Awardee: Bryan Sisk

Institution: Washington University School of Medicine

Grant Amount: $53,460

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

Complex lymphatic anomalies (CLAs) are a group of rare disorders associated with abnormal lymphatic development that arise in infants and children. These disorders can be disfiguring, painful, and even life-threatening. In our clinical experiences, families affected by CLAs have described multiple barriers to care and communication, such as difficulty accessing care from CLA experts, persistent uncertainty about the diagnosis and long-term consequences, insufficient information to guide decisions, and the necessity of persistent parental advocacy to ensure the child receives adequate medical care. However, no researchers have explored or categorized the needs or barriers experienced by these families. Without this critical information, we cannot provide guidance to clinicians, patients, parents, or advocacy groups on how to best support these families to overcome care and communication challenges. Furthermore, this foundational knowledge is necessary to support the development of interventions and systemic changes to improve care for these families. In this study, we will characterize the care and communication needs of families affected by CLAs and identify resources and coping strategies from the perspectives of parents using qualitative semi-structured interviews (Aim 1). We will also assess the psychosocial wellbeing of parents and the quality of communication using survey methodology (Aim 2). To disseminate findings and seek feedback from the CLA community (Aim 3), we will host separate interactive webinars with the Lymphangiomatosis and Gorham’s Disease Alliance (LGDA) and the Chan-Zuckerberg Institute (CZI) Lymphatic Researchers Network. These findings will be essential to improve care and ensure that scientific discoveries translate to actual clinical benefits for families affected by CLAs.

Novel, point of care biomarker to detect pre-clinical flares for people living with fibrodysplasia ossificans progressiva (FOP)

Awardee: Nezihi Murat Karabacak

Institution: Massachusetts General Hospital

Grant Amount: $64,000

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

Fibrodysplasia ossificans progressiva (FOP) is a severely debilitating condition with no accurate and clinically applicable biomarkers or imaging approaches. Our overall goal is to develop a novel, non-invasive assay to detect the initiation and progression of FOP. We will define a series of novel blood-based biomarkers specific for monitoring heterotopic ossification predicated in people living with FOP. As a result, we will establish an innovative way to detect and evaluate progression and monitor treatment outcomes for this disease process.

Understanding the role of inflammation in MPSIIIA disease to identify therapeutic approaches for older patients without treatment options

Awardee: Brian Bigger

Institution: University of Manchester

Grant Amount: $64,015

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

Many older patients with mucopolysaccharide diseases are ineligible for new treatment trials, and those with brain disease, such as type IIIA, have no current treatments available. To address this gap, we want to explore in the mouse model of MPSIIIA, the observed decline in cognition that follows repeated rounds of viral infection in patients and has been described in many dementias. Our aim is to first see if these effects can be recapitulated in the MPSIIIA mouse model, and later to develop novel immunotherapies to treat it. There are several drugs already available that may be re-purposable to this end, potentially offering rapid relief for MPS patients from behavioural and cognitive aspects of disease

CNS disease severity assessment with quantitative neuroimaging

Awardee: Igor Nestrasil

Institution: University of Minnesota

Grant Amount: $64,645

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

This project aims to find the underpinnings of brain magnetic resonance imaging (MRI) clinical/radiological severity in mucopolysaccharidosis type I (MPS I) and relate these findings to quantitative MRI outcomes. These links may ease the process of the central nervous system (CNS) disease severity assessment in the clinical setting.

Rescue of STXBP1 encephalopathies with small molecules in mouse models in vivo

Awardee: Jacqueline Burré

Institution: Weill Medical College of Cornell University

Grant Amount: $80,070

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

Mutations in STXBP1 lead to nerve cell dysfunction in the brain due to a reduction in functional STXBP1 amount. We had previously identified three small molecules (4-phenylbutyrate and two novel compounds) that restore nerve cell function in cultured mouse nerve cells and in live worm disease models. Yet, if and to what extent these small molecules revert the dysfunction in a brain remains unknown. Plus, it remains unclear if there is a critical period for when treatment needs to start, necessitating studies in a mouse model. We have established a mouse line with half of STXBP1 amount and are in the process of generating two additional mouse lines with missense mutations in STXBP1. We will use these mouse models of STXBP1 disorder to test the effect of our three small molecules in living animals. We will measure changes in seizure frequency, learning and memory, anxiety, hyperactivity and general movement, in addition to brain structure and development. To reveal if there is a critical period for when treatment needs to be started, we will determine the efficiency of the three small molecules in reversing the identified dysfunction when given to mice in utero, to newborn mice or to adolescent mice. Our study is significant because it further dissects the disease mechanism in a living animal, and because of its translational importance. Importantly, our studies will go hand-in-hand with the on-going 4-phenylbutyrate clinical trial at Weill Cornell Medicine, to achieve the most effect with the least amount of drug.

A novel mouse model for developing therapeutic approaches of STXBP1 encephalopathy

Awardee: Mingshan Xue

Institution: Baylor College of Medicine

Grant Amount: $80,070

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

STXBP1 encephalopathy is a severe neurodevelopmental disorder caused by heterozygous pathogenic variants in syntaxin-binding protein 1 (STXBP1). Both protein haploinsufficiency and dominant-negative mutations were identified as the disease mechanisms. Models of haploinsufficiency have been developed and validated and are currently being used to test potential disease-modifying therapies. However, dominant-negative mutations may require therapeutic approaches that are different from those for haploinsufficiency. Mammalian models carrying dominant-negative mutations are currently lacking. Thus, this project aims to develop and validate a new mouse model carrying a dominant-negative missense variant to fill this critical gap. This model will provide a new tool for preclinical evaluations of different therapies of STXBP1 encephalopathy and lead to a better understanding of the disease pathogenesis.

CXCL13 as a novel biomarker and therapeutic target in idiopathic multicentric Castleman disease

Awardee: David Fajgenbaum

Institution: University of Pennsylvania

Grant Amount: $64,205

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

Idiopathic multicentric Castleman disease (iMCD) is a poorly understood disorder involving lymphoproliferation and multiple organ failure due to a cytokine storm often involving interleukin-6 (IL-6). Its causes, key immune cell types, signaling pathways, and cytokines involved in the disease are poorly understood. Diagnosis is challenging due to lack of a positive diagnostic biomarker and management is suboptimal due to a lack of indicators of response and novel therapeutic approaches. Annual US incidence is ~1000 individuals of all ages, and 5-year survival is estimated at 65-75%. Few treatment options exist beyond cytotoxic chemotherapies for the 50-66% of patients who do not respond to the only FDA-approved therapy, siltuximab, which blocks IL-6. Advances in discovering treatments, diagnostic biomarkers, and indicators of response to siltuximab are critically needed. We recently identified the chemokine CXCL13 as a potential, novel biomarker and therapeutic target in iMCD. CXCL13 is critical to maintaining lymph node morphology as well as developing appropriate adaptive immune responses, both of which are abnormal in iMCD. In a pilot study, we found that CXCL13 is the most elevated circulating cytokine in iMCD patients and that CXCL13 expression is increased in iMCD lymph node tissue (Pierson et al, AJH, 2018). Proteomic profiling of serum from 88 iMCD patients revealed CXCL13 to be the most elevated cytokine compared to healthy controls and, further, it decreases rapidly in siltuximab responders upon administration but remains elevated in siltuximab non-responders (unpublished). The overall goal of this project is to investigate CXCL13 as a possible diagnostic biomarker, indicator of response to therapy, and/or therapeutic target for iMCD. These goals directly align with one of the top priority research questions outlined on the RFA (“What is the role of CXCL13 in iMCD?”). The specific aims of this project are to (1) quantify CXCL13 expression in iMCD lymph node tissue to assess the diagnostic applicability of this test for iMCD and to determine the cellular source of CXCL13, (2) quantify CXCL13 levels in serum to determine a threshold for serum CXCL13 as a potential diagnostic test or a clinical indicator biomarker of response to siltuximab, and (3) assess the in vitro effects of CXCL13 on circulating immune cells from iMCD patients. These studies will improve understanding of iMCD biology and may translate into more effective and personalized therapies and biomarkers that will have a transformative impact. Thank you for your consideration.

Leveraging proteostasis to improve Niemann-Pick C gene therapy

Awardee: Mark Schultz

Institution: Regents of the University of Michigan

Grant Amount: $50,010

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

Niemann-Pick C is a genetically inherited disease caused by an abnormal accumulation of cholesterol. This cholesterol build-up commonly occurs due to a defect in a gene called NPC1. In Niemann-Pick C mouse models, adding back a fully functional NPC1 gene via gene therapy improves but does not fully correct the disease. Here we will leverage the information we have gained on protein folding to significantly increase the efficacy of Niemann-Pick C gene therapy.

Natural History of the Hyperinsulinism Hyperammonemia Syndrome – A Multi-center Observational Study Incorporating Patient-centered Data through the HI Global Registry

Awardee: Elizabeth Rosenfeld

Institution: Children's Hospital of Philadelphia

Grant Amount: $73,045

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

Congenital hyperinsulinism (HI) is a rare genetic disorder that causes low blood sugar. The second most common genetic form of hyperinsulinism is the hyperinsulinism hyperammonemia (HI/HA) syndrome. Individuals with HI/HA syndrome develop low blood sugar after fasting and after eating protein-rich foods. HI/HA syndrome is also associated with high blood concentrations of ammonia, characteristic seizures, and learning and behavioral problems. Low blood sugar in HI/HA syndrome is treated with dietary modification and a medication called diazoxide, Studies have shown that the severity of low blood sugar in other (ie: non-HI/HA) forms of HI treated with diazoxide can improve with time – many individuals are able to discontinue diazoxide, or decrease the dose, as they age. There have been isolated reports documenting resolution of low blood sugar and seizures in individuals with HI/HA syndrome. However, studies describing the typical trajectory of disease over time in HI/HA syndrome are lacking. Closing this knowledge gap is an important first step toward individualizing therapy, establishing standards of care, and improving patient outcomes. We propose a multi-center, multimodal approach to describe the natural history of the HI/HA syndrome. Data will be obtained through both medical chart review and telephone interview of patients with HI/HA syndrome followed by the Hyperinsulinism Centers at the Children’s Hospital of Philadelphia and Cook Children's Health Care System. The HI Global Registry will additionally be utilized as a source for collection of detailed, patient-level data. Primary outcomes will include the frequency of diazoxide discontinuation and seizure resolution in individuals with HI/HA syndrome. The relationship between these outcomes and other assessed patient characteristics will be explored. We will also explore the utility of this multi-prong approach to examine the natural history of different HI subtypes. Ultimately, by combining clinical data and patient perspectives, we aim to develop a deeper understanding of the natural history of the HI/HA syndrome that will lead to improved patient outcomes.

Evaluating the Effects of Selected Small-Molecules on a Zebrafish Model of TBCK Syndrome

Awardee: Gerald B. Downes

Institution: University of Massachusetts Amherst

Grant Amount: $50,400

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

TBCK Syndrome is a rare, poorly understood, severe neurological disease. In 2016 multiple publications first reported that mutations in the TBCK gene result in a progressive loss of muscle tone, intellectual disability, characteristic facial features, drug resistant epilepsy, and a high incidence of childhood or adolescent mortality. Outside of managing symptoms, there are currently no treatments to slow the progression of the disease. Animal models are often a key step towards better understanding a disease and developing new therapeutics, however there are currently no published animal models of TBCK Syndrome. Zebrafish are a widely used disease model due to several advantageous features, which also make this an excellent system to evaluate or screen for new therapeutic drugs. My laboratory is establishing a zebrafish model of TBCK Syndrome, and we have already created multiple tbck mutant lines and identified a phenotype. Our goals here are to continue characterizing the effects of tbck mutation on the zebrafish nervous system and to evaluate whether any of three different small-molecules, already FDA approved or known to be safe for human consumption, decrease the severity of tbck-mutant phenotypes. The completion of this project will establish a foundation to use zebrafish for small-molecule screens and help determine whether any of these compounds should be further investigated as a treatment for TBCK Syndrome.

Identify genetic regulatory circuitry driving the development of rapamycin tolerance

Awardee: Yan Tang

Institution: Brigham and Women's Hospital

Grant Amount: $73,491

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

Rapamycin (and its analogues, rapalogs) are the only effective treatment for TSC-associated diseases, including lymphangioleiomyomatosis (LAM). However, rapalogs can only stabilize lung function in LAM, but lung function continues to decline upon treatment cessation. It’s of paramount importance to understand the mechanisms of why and how LAM cells can survive rapamycin treatment and regrow after treatment cessation. Our single cell RNA-seq analysis of five LAM and six AML (angiomyolipoma, kidney manifestation of TSC) samples identified a subset population of LAM/AML cells with elevated stemness and dormancy programs, two typical features of drug tolerant/resistant tumor persister cells. These cells exhibited stabilized tumor cell phenotypes upon rapamycin treatment, including maintaining high expression of many TSC marker genes, suggesting a rapamycin tolerance mechanism. To identify drivers of development of rapamycin tolerance in a heterogeneous population, we have adopted a high-complex barcoding lineage tracing system that enables simultaneous assessing of each cell’s origin/lineage and transcriptomic/epigenomic profiles at single cell level. This novel approach will enable us to identify lineage-specific drivers for the development of rapamycin tolerance.

Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis and treatment.

Awardee: Vanessa Fear

Institution: Telethon Kids Institute, University of Western Australia

Grant Amount: $45,733

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

SETBP1 haploinsufficiency disorder presents with intellectual disability, speech impairment and development delay, among other symptoms. There is little information regarding SETBP1 haploinsufficiency disorder and the cellular pathways that lead to disease. This study will use CRISPR gene editing and stem cell neural disease modelling to elucidate cellular pathways that contribute to SETBP1 haploinsufficiency disorder, and identify new treatments.