Clonal activation of lymph node stromal cells in unicentric Castleman Disease

Awardee: Ivan Maillard

Institution: University of Pennsylvania

Award Amount: $51,358

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

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

Mechanistic and Therapeutic Studies of Fibrous Dysplasia Craniofacial Defects

Awardee: Yingzi Yang

Institution: Harvard Medical School

Award Amount: $54,663

Assessment of Disease Activity in FOP Patients using Electrical Impedance Myography

Awardee: Jaymin Upadhyay

Institution: Boston Children's Hospital, Harvard Medical School

Award Amount: $40,208

Publications:

Diminished muscle integrity in patients with fibrodysplasia ossificans progressiva assessed with at-home electrical impedance myography

Synthetic CT Assessment of Lesions in Children With Rare Musculoskeletal Diseases