Awarded Grants

Awarded Grants

MDBR, CF Million Dollar Bike Ride MDBR, CF Million Dollar Bike Ride

Pharmacological strategies to target nonsense mutations in cystic fibrosis

Luis Juan Vicente Galietta

Fondazione Telethon - TIGEM

$54,718

Awardee: Luis Juan Vicente Galietta

Institution: Fondazione Telethon - TIGEM

Award Amount: $54,718

Final Report Lay Summary:

Cystic fibrosis (CF), one of most frequent and severe genetic diseases, affects multiple organs but

the consequences to the lungs are the most important ones for morbidity and mortality. The basic

defect in CF is the loss of function of CFTR, a plasma membrane chloride channel expressed in

various epithelial cell types. There are multiple types of CF-causing mutations that impair the

expression, maturation, and/or gating of CFTR protein. Importantly, some types of CFTR mutants

can be treated with drugs named correctors and potentiators. However, nonsense mutations, also

known as premature termination codons (PTCs), which cause the production of a truncated CFTR,

remain without an effective treatment. The overall goal of our project was to develop strategies to

target PTCs. In our experiments, cells expressing mutant CFTR were treated with combinations of

compounds acting at different levels on CFTR biosynthesis and function. We have identified the

most effective treatments for each mutation. In particular, we found that W1282X is the most

sensitive mutation with a large recovery mutant CFTR function, close to 30% of normal CFTR.

Y122X, G542X, and R1162X mutations could be also treated (10% of normal function) using

12 different combinations of compounds. In contrast, R553X mutation was particularly refractory to

pharmacological treatment. The results in our study will pave the way for future clinical trials in

which patients with specific mutations will be treated with the most appropriate compound

combinations.

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MDBR, MSUD Million Dollar Bike Ride MDBR, MSUD Million Dollar Bike Ride

A novel approach for identification of therapeutic leads to the Maple Syrup Urine Disease

Ehud Gazit

Tel Aviv University

$44,037

Awardee: Ehud Gazit

Institution: Tel Aviv University

Awarded Amount: $44,037

Final Report Summary:

We have recently shown that metabolites, as simple as single amino acids and nucleobases, can form amyloid-like structures, thus providing a novel paradigm for inborn error of metabolism (IEM) disorders. Here, we wish to explore a never-tested hypothesis suggesting that the systemic pathology following branched-chain amino acids (BCAAs) abnormally high levels in the blood, serum and urine of Maple Syrup Urine Disease (MSUD) patients may be related to the formation of amyloid-like structures. Our preliminary data provide a proof-of-concept for this hypothesis, indicating that BCAAs can form unique assemblies with amyloid-like characteristics. Therefore, we postulate that high levels of BCAAs can lead to the formation of toxic structures that in turn can be involved in the cytotoxicity observed in the disorder. This discovery can offer new prospects for understanding the complex etiologies of the disease and finding the proper treatment for MSUD patients. Here, we set out to utilize our unique expertise and knowledge in metabolite self-assembly and yeast models for IEMs to address fundamental issues concerning MSUD and for the identification of therapeutic leads.

In the scope of the MDBR project, we were able to successfully establish a unicellular yeast model as well as a multicellular organism nematode model for MSUD. Our data indicate that the MSUD models are sensitive to isoleucine supplied in the growth medium, implying the involvement of isoleucine accumulation and self-assembly in cell toxicity and the pathology of MSUD.

Our yeast model was successfully used as a platform for high throughput phenotypic screening of potential therapeutic agents to target metabolite aggregation. Compounds found to suppress the toxicity conferred by isoleucine feeding of the mutant strain in the screen were further characterized and validated in the yeast system. Yet, the compounds that were identified in the selected screen did not show a significant effect in the nematode model and the neuroblastoma cells and therefore could not be used as a potential treatment. Nevertheless, our successful pilot screen proves the strength of our platform and its future potential for the identification of novel treatment for MSUD patients.

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MDBR, FOP Million Dollar Bike Ride MDBR, FOP Million Dollar Bike Ride

Assessment of Disease Activity in FOP Patients using Electrical Impedance Myography

Jaymin Upadhyay

Boston Children's Hospital, Harvard Medical School

$40,208

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A working prototype of an in-home ionized calcium monitoring device using a paper-based ion-selective optode and an optical reader

Xuewei Wang, PhD

Virginia Commonwealth University

$149,019

Awardee: Xuewei Wang, PhD

Institution: Virginia Commonwealth University

Award Amount: $149,019

Funding Period: January 1, 2020 - December 31, 2020

Project Summary:

We are developing test strips for ionized calcium in finger-prick blood samples. One drop of blood can be easily introduced into the strip by patients. The optical response of the strip is recorded by a regular smartphone equipped with a customized app. The test can be finished within two minutes because of the fast sensor response. The concentration of ionized calcium can be accurately determined in a range of 0.1 to 5.0 mmol/L (0.4 to 20.0 mg/dL). There is no interference from other molecules and ions in the blood. Therefore, this new technology will enable the in-home measurement of calcium in the blood and allows the management of hypoparathyroidism by the patient themselves.

Final Summary:

Affordable and portable blood calcium sensors using a smartphone detector have been developed. These sensors empower patients to measure their calcium ion concentration at home using blood collected by fingerstick.

Publications:

R. Wang, X. Wang. Sensing of inorganic ions in microfluidic devices. Sensors and Actuators B: Chemical 2021, 329, 129171

R. Wang, Y. Zhou, N. Ghanbari Ghalehjoughi, Y. Mawaldi, X. Wang. Ion-Induced Phase Transfer of Cationic Dyes for Fluorescence-Based Electrolyte Sensing in Droplet Microfluidics. Analytical Chemistry, 2021

N. Ghanbari Ghalehjoughi, R. Wang, S. Kelley, X. Wang. Ultrasensitive Ionophore-Based Liquid Sensors for Colorimetric Ion Measurements in Blood. Analytical Chemistry, 2023, 95, 12564-12564

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Developing human pluripotent stem cells for investigation and treatment of hypoparathyroidism

Rene Maehr, PhD

Umass Medical School

$500,000

Awardee: Rene Maehr, PhD

Institution: Umass Medical School

Award Amount: $500,000

Funding Period: January 1, 2020 -December 31, 2020

Summary:

The parathyroid gland is critically involved in regulation of calcium homeostasis of the body. Hypoparathyroidism as encountered by parathyroid damage, hypoplasia, or as a result of thyroid and parathyroid surgery, results in chronic hypocalcemia and low-turnover bone disease. Human pluripotent stem cells could provide a virtually unlimited source of parathyroid-like cells with calcium level responsiveness, offering a unique opportunity for development of a cell replacement products capable of regulating calcium levels. To unlock human pluripotent stem cell-based treatment strategies, robust and safe stem cell differentiation protocols need to be established. Here, we propose to develop an approach that is based on human pluripotent stem cell differentiation according to a developmental roadmap, and cutting edge humanized mouse avatar models for functional evaluation of human parathyroid-like cells. We expect this rigorous approach to provide several high-impact resources, including a source of high-fidelity human parathyroid-like cells and novel mouse models for studying parathyroid function.

Publication:

Integration of single-cell transcriptomes and chromatin landscapes reveals regulatory programs driving pharyngeal organ development - Nature Communitcations

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In vitro differentiation of parathyroid cells from stem cells

Michael Mannstadt, MD

Massachusetts General Hospital/Harvard University

$1,000,000

Awardee: Michael Mannstadt, MD

Institution: Massachusetts General Hospital/Harvard University

Award Amount: $1,000,000

Funding Period: January 1, 2020 - December 31, 2021

Summary:

Parathyroid glands produce parathyroid hormone (PTH), which is necessary for regulating blood calcium and phosphate levels and maintaining bone health. Patients with insufficient parathyroid gland activity (hypoparathyroidism) can suffer from multiple symptoms caused by low blood calcium levels, including minor problems like muscle twitching or severe, life-threatening complications such as tetany and seizures. Conventional treatment with calcium and active vitamin D does not replace the functions of PTH and can lead to undesired long-term effects, such as kidney stones. PTH replacement therapy requires daily self-injections. 

Currently, testing of serum calcium involves a visit to a clinical laboratory, a blood draw, and a delay while the patient waits for a report of their test results. This delays dose adjustment and leads to hyper- or hypocalcemia.

The long-term goal of this proposal is to offer a regenerative therapy for patients with hypoparathyroidism using mature parathyroid cells differentiated from human stem cells.  With our collaborators from several institutions, including stem cell and developmental biologists, parathyroid surgeons, and specialists in microencapsulation of human stem cell-derived hormone-producing cells, we aim to define genetic mechanisms governing parathyroid cell fate specification during embryonic development.  We will target critical pathways using small molecule activators and inhibitors to facilitate parathyroid cell fate specification.  We will also test a novel microencapsulation technique for human parathyroid cells by transplantation in mice.

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MDBR, APBD Million Dollar Bike Ride MDBR, APBD Million Dollar Bike Ride

Gene Replacement Therapy for APBD

Berge Minassian

UT Southwestern Medical Center

$53,455

Awardee: Berge Minassian

Institution: UT Southwestern Medical Center

Award Amount: $53,455

Funding Period: February 1, 2019 - January 31, 2020

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