SETBP1 deficiency syndrome as an AKT modifer in human neurons

Awardee: Carl Ernst

Institution: McGill Uniersity (Douglas Hospital Research Institute)

Award Amount: $67,943

Dimethylspermine (Me2Spm) as a novel treatment approach to restore normal spermidine/spermine ratios in Snyder-Robinson Syndrome (SRS) models

Awardee: Robert A. Casero, Jr

Institution: Johns Hopkins School of Medicine

Grant Amount: $69,318

Rapid and unbiased in vivo screen for lead compounds that rescue STXBP1 dysfunction and subsequent in vitro validation in human neurons

Awardee: Matthijs Verhage

Institution: Rapid and unbiased in vivo screen for lead compounds that rescue STXBP1 dysfunction and subsequent in vitro validation in human neurons

Grant Amount: $69,588

Phenylbutyrate for STXBP1 Encephalopathy – A Pilot Study

Awardee: Zachary Grinspan

Institution: Weill Cornell Medicine

Grant Amount: $69,588

Towards new therapeutic treatments for the hyperinsulinism/hyperammonemia syndrome (HI/HA)

Awardee: Thomas Smith

Institution: University of Texas Medical Branch

Grant Amount: $72,014

What are the functional consequences of CDKL5 dysfunction in human neuronal cells?

Awardee: Nicole Van Bergen

Institution: Murdoch Children's Research Institute

Award Amount: $55,898

Testing the efficacy of new pharmaceutical candidates for APBD

Awardee: Or Kakhlon

Institution: Research Fund of the Hadassah Medical Organization

Award Amount: $52,509

Gene Therapy for Adult Polyglucosan Body Disease (APBD)

Awardee: Baodong Sun

Institution: Duke University

Award Amount: $51,209

Pericyte contractility in CADASIL

Awardee: Fabrice Dabertrand

Institution: University of Colorado Denver Anschutz Medical Campus

Award Amount: $81,951

Clonal activation of lymph node stromal cells in unicentric Castleman Disease

Awardee: Ivan Maillard

Institution: University of Pennsylvania

Award Amount: $51,358

Targeting retinoid traffic for treatment of CRB1-CRUMB1 degenerative retinal disorders

Awardee: Konstantin Petrukhin

Institution: Columbia University Medical Center

Grant Amount: $44,037

Pharmacological strategies to target nonsense mutations in cystic fibrosis

Awardee: Luis Juan Vicente Galietta

Institution: Fondazione Telethon - TIGEM

Award Amount: $54,718

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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.

Publications:

Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene

Generation and Characterization of a Collagen VI Muscular Dystrophy Zebrafish Model for Drug Screening

Awardee: Robert Bryson-Richardson

Institution: Monash University

Award Amount: $91,176

Testing Niemann-Pick C proteostasis therapeutics on human iPSC derived neurons

Awardee: Mark Schultz

Institution: Regents of the University of Michigan

Awarded Amount: $61,637

Adaptive Optics imaging in follow-ups of choroideremia patients after gene therapy

Awardee: Katarina Stingl

Insitutional: University Eye Hospital Tübingen, Germany

Awarded Amount: $61,079

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

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.

A study of the correlation between gait abnormalities, activity monitoring parameters, CMTPeds and a biomarker in children with Charcot-Marie-Tooth disease

Awardee: Sylvia Ounpuu

Institution: Connecticut Children's Medical Center

Award Amount: $60,330

Characterisation of CRB1 patient human iPSC-derived retinal organoids to set-up potency assays for gene therapy

Awardee: Jan Wijnholds

Institution: Leiden University Medical

Award Amount: $40,177

Pre-malignant Clonal Evolution in Telomere Biology Disorders (TBD)

Awardee: Daria Babushok

Institution: University of Pennsylvania

Award Amount: $62,664

Do osteoclasts mediate bone marrow fibrosis in fibrous dysplasia?

Awardee: Julia Charles

Institution: Brigham and Women's Hospital, Harvard Medical School

Award Amount: $54,663