Awarded Grants

Awarded Grants

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Congenital hyperinsulinism models for novel drug discovery

Michael Kalwat

Indiana Biosciences Research Institute

$70,200.00

Awardee: Michael Kalwat

Institution: Indiana Biosciences Research Institute

Grant Amount: $70,200.00

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

Summary:

Patients with congenital hyperinsulinism (HI) are in a continual battle to regulate their blood glucose levels. HI is caused by genetic mutations that lead to inappropriately high insulin levels in the blood. Insulin is normally released from beta cells within the pancreas only after meals when blood glucose is elevated. However, in HI these cells are dysfunctional and release too much insulin even when glucose levels are low. The only FDA-approved drug for HI, diazoxide, has side-effects and some patients are unresponsive. Therefore, new treatments need to be developed. To accomplish this requires the creation of new methods that allow us to test drugs on cells which mimic the human disease. In our project, we will create a human beta cell model that mimics HI and we will test new drugs to determine their ability to suppress insulin release and their mechanisms of action. Our project is broken into two Aims. In Aim 1, we will create a human β-cell line that expresses a mutant version of a gene found in HI. We will use this line alongside normal β-cells to test our new drug compounds. In Aim 2, we will collaborate with a medicinal chemist to improve the effectiveness of our top candidate compound and we will perform experiments to identify exactly which proteins are involved in our drug’s actions. We anticipate that the success of this project will propel our lab’s progress in HI research and enable us to develop improved model systems and make discoveries that will benefit HI patients.

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Implementing detection of low-level mosaic variants from blood samples in hyperinsulinism to improve diagnosis

Sarah Flanagan

University of Exeter Medical School

$70,920.00

Awardee: Sarah Flanagan

Institution: University of Exeter Medical School

Grant Amount: $70,920.00

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

Summary:

A genetic diagnosis improves treatment and management of hyperinsulinsm; however, currently ~40% of children referred for genetic testing do not receive a genetic diagnosis. One reason for these missed diagnoses is that some children have mosaic variants, which cannot be detected by standard DNA sequencing. Mosaic variants occur during development so will only be present in some tissues, which is why they are hard to detect in genetic testing of blood samples. Our preliminary data identified 8 patients with previously undetected mosaic variants. Our study will develop these methods for detecting mosaic variants so that they can be included in diagnostic genetic testing for hyperinsulinsm worldwide.

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

Elizabeth Rosenfeld

Children's Hospital of Philadelphia

$73,045

Awardee: Elizabeth Rosenfeld

Institution: Children's Hospital of Philadelphia

Grant Amount: $73,045

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

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.

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Maximising the Utilisation of the Hyperinsulinism Global Registry (HIGR) [Max HIGR]

Indraneel Banerjee

University of Manchester, Royal Manchester Children's Hospital

$73,190

Awardee: Indraneel Banerjee

Institution: University of Manchester, Royal Manchester Children's Hospital

Award Amount: $73,190

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

Summary:

The HI Global Registry (HIGR) is a unique rare disease patient registry developed by Congenital Hyperinsulinism International. This international online registry that gathers important information on different types and treatments for low sugars due to hyperinsulinism. The completion of HIGR relies on parents and families uploading their child's required details. Our proposed study "Maximizing the Utility of HIGR" (MaxHIGR) aims to build on the opportunity to add medical grade information to existing parent reported HIGR information, thereby joining up clinical and parent perspectives in the search towards better understanding and improved treatment for HI. MaxHIGR will lay the basis for HIGR to evolve into a registry that will tell us about the natural history of disease, which treatments are better and have less side effects and how we can improve the quality of life of children and families living with HI.

Final Report Summary:

MaxHIGR has brought international co laborators to agree on a common data colection to replicate natural history of Congenital Hyperinsulinism. MaxHIGR required close co laboration across time zones around the world, while adapting to a a common set of rules for data entry. The form is now currently being integrated into an online tool for use in a pilot study. This study has been delayed to accommodate in person patient-clinician consultations that had been set back due to the pandemic.

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Bihormonal Bionic Pancreas for the Treatment of Diabetes Post-Pancreatectomy in Individuals with Congenital Hyperinsulinism – A Pilot Study

Diva De Leon-Crutchlow

University of Pennsylvania/Children's Hospital of Philadelphia

$87,109

Awardee: Diva De Leon-Crutchlow

Institution: University of Pennsylvania/Children's Hospital of Philadelphia

Award Amount: $87,109

Funding Period: January 1, 2018 - December 31, 2018

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