Research Grants

Dr Caitlin Hudac – Investigator

A better understanding of how the brain works in SETBP1 haploinsufficiency disorder (SETBP1-HD) will be helpful to predict what treatments will be most successful. We will collect data and build biological markers (or biomarkers”) that will capture how individuals with SETBP1-HD focus and learn about the world. Our biomarkers use electroencephalography (EEG) to record brain electricity across the head from over 100 recordings sites on a wet cap. We will collect data from an additional 25 participants with SETBP1-HD using mobile EEG data collection. Critically, this study will be the first to link these brain biomarkers to language, cognitive, and attention clinical profiles. This project will produce valid and reliable biomarkers that can be used as outcome measures to improve treatment and interventions and progress clinical trials.

Dr Barbara Bailus – Investigator

SETBP1-HD is a rare neurological disorder caused by insufficient levels of SETBP1 protein. The aim of this grant is to explore the potential to restore levels of SETBP1 through two different approaches. The first approach will aim to deliver SETBP1 protein into the brain using a novel delivery system that can function as a “keycard” to the brain. The second approach would use the CRISPR technology to increase the level of SETBP1 protein being made from the remaining copy of the gene. Both technologies will use the “keycard” delivery technology. The work will be done in human cells. If successful this could represent a potential therapeutic strategy for SETBP1-HD.

Prof Simon Fisher – Investigator

Dr Bregje van Bon – Co-Investigator

Maggie Wong – Researcher

SETBP1 haploinsufficiency disorder is a rare disorder caused by DNA changes that lead to a decreased amount of the SETBP1 protein. Individuals with SETBP1 haploinsufficiency disorder show expressive speech impairment, mild-moderate developmental delays, and a range of additional symptoms. To date, we still know little about how the SETBP1 protein works, and why insufficient amounts of this protein affect the human brain, leading to a disorder. Our research aims to study the molecular and cellular pathways that are altered in SETBP1-haploinsufficiency disorder, and for understanding how these relate to the clinical features of patients, using extensive informative tools including stem cells and brain organoids that we have already established in the laboratory. Ultimately, we hope that analyses of SETBP1 (dys)function in the laboratory can advance fundamental understandings of SETBP1 functions during brain development and help towards therapeutic development for the disorder.

Prof Angela Morgan – Investigator & Olivia Van Reyk – Research Assistant

Speech tracker builds on a previous SETBP1 study published recently, showing that speech and language development is a core challenge for children with SETBP1 haploinsufficiency disorder. In this new study, the speech and language team headed by Angela Morgan at the Murdoch Children’s Research Institute are examining speech and language over time. This data will help all of us better understand prognosis and help develop more targeted speech therapies for individuals with SETBP1 haploinsufficiency disorder.

Dr Trina Geye – Investigator

Dr Stephanie Robertson – Co-Investigator

This is a project developed by researchers/doctors and the families in the SETBP1-HD community. The SETBP1 Society president is a co-lead on the study. If you participate, you will be asked to complete standardized assessments. The data we collect will further our understanding of SETBP1 HD and provide evidence-based information and resources to the families. This project is a direct result of the parent experience surveys completed in 2021 and is a part of the community needs assessment.

Dr Maria Chahrour – Investigator

SETBP1 is a protein that binds to the genome and regulates gene expression. Mutations that lead to loss of half the amount of this protein cause SETBP1 haploinsufficiency disorder, characterized by intellectual disability, autism spectrum disorder, motor and language impairments, alongside an array of additional neurodevelopmental phenotypes. In this proposal, we investigate the cell-type specific role of SETBP1 in the brain and identify its interactors. We will utilize single-cell genomic technology on brain tissue from the established Setbp1indel mouse model which carries only half the amount of SETBP1 protein and thus models SETBP1 haploinsufficiency disorder. Results from our proposed studies will deepen understanding of how disruptions in this gene lead to disease and will inform the development of targeted therapies.

Dr Maria Aristizabal – Investigator

Dr Alexander Little – Co-Investigator

Our goal is to understand why decreased SETBP1 function leads to SETBP1 haploinsufficiency disorder (SETBP1-HD). To answer this question, we will generate a zebrafish model of the disorder using state-of-the-art genetic engineering methods to introduce mutations commonly observed in SETBP1-HD patients. This model will be examined for characteristics typical of SETBP1-HD patients and used to understand how these arise at the molecular levels, information critical for the future design and development of therapeutic interventions.

Dr Vanessa Fear – Investigator

SETBP1 haploinsufficiency disorder is caused by de novo mutations in SET binding Protein 1 (SETBP1). The clinical phenotype is characterized by intellectual disability, mild motor development delay, speech impairment, behavioral problems, hypotonia, vision impairment, and mild dysmorphic facial features. There is, however, a paucity of information on the molecular mechanisms leading to SETBP1-HD. Furthermore, whilst next generation sequencing rapidly identifies potential SETBP1 genetic variants many of these are novel with undetermined function in disease. Accordingly, these novel variants must be classified as a variant of uncertain significance (VUS) and the patient cannot receive a diagnosis. This study will utilize CRISPR gene editing and neuronal disease modelling to identify SETBP1 disorder disease-specific molecular pathways, to facilitate understanding of disease mechanism, and identify potential cellular targets for treatment. In addition, a SETBP1 VUS, will be assessed as disease pathogenic or benign, demonstrating the capacity of this methodology to facilitate SETBP1 haploinsufficiency patient diagnosis.

Dr Jerome Baudry

The project will be the first structure-based drug discovery approach to SETBP1 treatment. The project will 1) model a partial structure of the SETBP1 protein, especially the region around the degron motif and its nearby region. 2) characterize the interaction of the degron motif to the SCF- TrCP1 E3 ubiquitin ligase that binds SETBP1 for ubiquitination. 3) Perform virtual screening of chemicals databases to identify potential chemical modulators of the ubiquitin ligase/SETBP1 interaction.

Dr Audrey Brumback – Investigator

Children with neurodevelopmental disorders such as SETBP1 related disorder often have challenges in executive functioning – a broad set of abilities to focus attention, filter out distractions, control impulses, prioritize tasks, and to set and achieve goals. Most executive function skills rely on the a part of the brain called the prefrontal cortex. In the proposed work, we will use a mouse model to study how changes in the SETBP1 gene influence the activity of prefrontal cortex neurons. Understanding how prefrontal cortex neurons differ in their activity is an important step towards understanding why people with SETBP1 related disorder have so many challenges with executive functioning.

Dr Rocco Piazza – Investigator

Dr Alessandro Sessa – Co-Investigator

Dr Luca Mologni – Co-Investigator

Sub-megabase deletions occurring in SETBP1 locus are responsible for the onset of SETBP1 haploinsufficiency (SH), a disorder characterized by varying degrees of intellectual disability, developmental as well as speech delays. It is currently not known whether (i) SETBP1 haploinsufficiency is detrimental early during brain development and (ii) the correction of the SETBP1 levels is sufficient to revert the SH associated symptoms. This limits the possibility of thinking of new molecular therapies based on gene correction in symptomatic patients.
Here, we propose to generate and to functionally validate a reversible knock-out mouse model for the SH syndrome. The project herein presented will provide insightful information on the molecular consequences of the reactivation of SETBP1 protein in a knockout/haploinsufficient model that mimics the SH syndrome. Our in vivo model will constitute a valuable platform to dissect the molecular mechanisms at the basis of the brain damage following SETBP1 haploinsufficiency and to study the effect of SETBP1 reactivation at different time-points during the life of the mouse model.

Dr Carl Ernst – Investigator

For this project, we will model SETBP1 deficiency syndrome using brain-like cells that have been derived from people with SETBP1 loss-of-function mutations in one copy of the gene. We will investigate the interaction between SETBP1 and its binding partner SET and how this complex puts the brakes on a fundamental regulator in cells called PP2A. Our idea is that loss-of-function of SETBP1 leads to too much activity (partial loss of the braking system) of PP2A and it is this mechanism that leads to the symptoms consistent with disease. PP2A is a master switch which can activate and deactivate many proteins, and is a major target for therapeutic initiatives in cancer. Using molecules developed by scientists to target PP2A in unrelated cancer syndromes, we aim to test these drugs in SETBP1-deficient cells to determine if any can restore PP2A function to healthy levels. Our overall goal is to determine if any molecules are effective at re-establishing the brake on PP2A without major side effects.

Prof Dr Simon Fisher – Investigator
Dr Maggie Wong – Researcher

Dr Bregje van Bon
Co-Investigator

SETBP1 disorder is a rare disorder caused by DNA changes that lead to a decreased amount of the SETBP1 protein. Individuals with SETBP1 disorder show expressive speech impairment, mild-moderate developmental delays, and a range of additional symptoms. To date, only a few reports describing individuals with SETBP1 disorder have been published, and our understanding of the clinical features and likely outcomes is limited. In addition, we still know little about how the SETBP1 protein works, and why insufficient amounts of this protein affect the human brain, leading to a disorder. Our research aims to establish informative tools in the laboratory for studying the molecular and cellular pathways that are altered in SETBP1 disorder, and for understanding how these relate to the clinical features of patients. We plan to achieve these aims by 1) collecting fibroblasts and/or peripheral blood mononuclear cells (PBMCs) from patients with de novo heterozygous loss-of-function SETBP1 mutations and matched controls, 2) deriving and validating iPSCs (induced pluripotent stem cells) from patients and controls, 3) generating heterozygous SETBP1 knockout iPSC lines via CRISPR/Cas9 gene-editing, and 4) characterizing human cellular models carrying SETBP1 mutations. Ultimately, we hope that analyses of SETBP1 (dys)function in the laboratory can help towards therapeutic development for the disorder.