Linking SETBP1-HD EEG Biomarkers to Clinical Profiles

Awardee: Caitlin Hudac

Institution: University of South Carolina

Grant Amount: $88,740.00

Funding Period: February 1, 2024 - January 31, 2025

---

Summary:

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.

Brain Penetrant Therapeutic Proteins for SETBP1 Haploinsufficiency Disorder

Awardee: Barbara Bailus

Institution: Keck Graduate Institute

Grant Amount: $45,832.00

Funding Period: February 1, 2023 - January 31, 2024

---

Summary:

SETBP1-HD is a neurodevelopmental disorder caused by a decreased amount of the SETBP1 protein, which plays a role in neuronal development, specifically in epigenetic modification. A potential treatment for this disorder would involve increasing SETBP1 levels in the brain. Several other disorders have been successfully treated by using a similar approach of directly providing the absent or reduced protein to the relevant tissue. This proposal aims to increase the levels of SETBP1 by creating novel therapeutic proteins that would have the ability to enter the brain from a peripheral injection through the use of a novel cell penetrating peptide (CPP). The CPP would act as a “keycard” to the brain allowing for the therapeutic proteins to enter. The CPP would make the potential treatment minimally invasive, titratable and with the ability to be removed if necessary. This proposal would test the therapeutic proteins in cellular models, with the aim to leverage this data to a future mouse study.

Deciphering the neurobiological pathways involved in heterogenous SETBP1 haploinsufficiency disorder using human brain organoids and transcriptomics

Awardees:

Simon E Fisher: Max Planck Institute for Psycholinguistics, The Netherlands

Maggie MK Wong: Max Planck Institute for Psycholinguistics, The Netherlands

Bregje W van Bon: Radboud University Medical Center, The Netherlands

Grant Amount: $45,832.00

Funding Period: February 1, 2023 - January 31, 2024

---

Summary:

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 moderate-to-severe speech and language impairments, wide variability in intellectual functioning, hypotonia, vision impairment, and behavioral problems such as attention/concentration deficits and hyperactivity. 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 utilize the informative tools that we have established in the laboratory to study the molecular and cellular pathways that are altered in SETBP1-haploinsufficiency disorder, and to understand how these relate to the clinical features of patients. Ultimately, we hope that analyses of SETBP1 (dys)function in the laboratory can help towards therapeutic development for the disorder.

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

---

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.

Toward Structure-based Drug-Discovery for SETBP1

Awardee: Jerome Baudry

Institution: The University of Alabama in Huntsville

Grant Amount: $45,733

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

---

Summary:

We will start the first drug discovery pipeline toward finding a pharmaceuticals that can counter the effect of SETBP1 mutations. We will use very powerful computers to predict how mutated SETBP1 interacts with its partners in the cell, and we will identify small molecules that can correct the problems.

REACT: a reversible knock-out mouse model to explore treatment strategies for the SETBP1 haploinsufficiency disease

Awardee: Rocco Piazza

Institution: University of Milano - Bicocca

Award Amount: $40,373

Funding Period: February 1, 2021 - January 31, 2022

---

Summary:

The SETBP1 gene is located on chromosome 18q21.1; it encodes for a protein of 1596 residues with a predicted molecular weight of 170 kD and a predominantly nuclear localization. Genetic abnormalities occurring in the SETBP1 gene are responsible for the onset of two different disorders: 1) SETBP1 haploinsufficiency (SH), a disorder characterized by varying degrees of intellectual disability, developmental as well as speech delays and caused by sub-megabase deletions occurring in SETBP1 locus. 2) Schinzel-Giedion Syndrome (SGS), a rare disease with multiple severe congenital malformations and fatal outcome, caused by de novo, single nucleotide SETBP1 mutations. The pathogenic mechanisms responsible for the onset of SH and SGS are probably tightly connected albeit opposite, as SH is caused by a decrease in SETBP1 protein while SGS is caused by its accumulation. The involvement of the central nervous system in both disorders suggests that SETBP1 itself plays a critical role in this context. Here, we propose to generate and to functionally validate a reversible knock-out mouse model for the SH syndrome. In this model, a blocking cassette flanked with loxP recombination sites would be inserted at intron level in the normal Setbp1 locus by homologous recombination, resulting in a mouse that is unable to express Setbp1 at normal level, therefore mimicking the human SH condition. Then, the usage of specific Cre mouse lines, where the recombinase is either expressed starting from the embryo, only in the adult, or is tamoxifen-inducible, would allow the removal of the blocking cassette and reactivation of the Setbp1 expression at normal levels.

The project herein presented will provide insightful information on the molecular consequences of the reactivation of SETBP1 protein in a knock-out/haploinsufficient model that mimic the SH syndrome. Our new in vivo model will constitute a valuable platform to dissect the molecular mechanisms at the basis of the brain damage following SETBP1 haploinsufficiency and, even more importantly, to study the effect of SETBP1 reactivation at different time-points during the life of the mouse model.

Neuromodulation of prefrontal circuits in a mouse model of SETBP1 disorder

Awardee: Audrey Brumback

Institution: The University of Texas at Austin

Award Amount: $40,373

Funding Period: February 1, 2021 - January 31, 2022

SETBP1 deficiency syndrome as an AKT modifer in human neurons

Awardee: Carl Ernst

Institution: McGill Uniersity (Douglas Hospital Research Institute)

Award Amount: $67,943