Understanding RASopathies to better inform diagnosis and treatment.

Awardee: Vanessa Fear

Institution: The University of Western Australia

Award Amount: $69,885

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

---

Summary:

The RASopathies are a set of syndromes that include cardiofaciocutaneous (CFC) Syndrome, Noonan Syndrome, Noonan Syndrome with lentigines, and Costello Syndrome.  The syndromes are characterised by overlapping disease phenotype and there is a need to distinguish the different RASopathies in order to facilitate accurate patient diagnosis and identify better treatments. In this study we compare changes in patient DNA (genetic variants) that are causative of CFC and Noonan Syndrome. Further, we investigate a potential disease causing patient genetic variant to determine if they have CFC or Noonan Syndrome. The study harnesses gene editing technology to introduce genetic variants into stem cells, which are then matured into nerve cells. The nerve cell maturation process is monitored to identify syndrome-specific changes to inform syndrome classification in the patient, and to provide a better understanding of both CFC and Noonan Syndrome.

Targeting muscle stem cells for the treatment of Collagen VI muscular dystrophies

Awardee: Nicholas Dumont

Institution: CHU Sainte-Justine research center (University of Montreal)

Award Amount: $42,406

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

---

Summary:

Mutations in one of the genes encoding for Collagen VI cause Ullrich muscular dystrophy (severe form) or Bethlem myopathy (milder form). These rare genetic diseases are characterized by progressive muscle weakness and degeneration, which can lead to functional incapacities such as impaired or delayed walking. The effect of collagen VI deficiency on muscle degeneration has been characterized; however, its impact on muscle stem cells, the engine of muscle repair, is unknown. Therefore, the overall goal of this project is to investigate if the myogenesis capacity (formation of new muscle tissue) of muscle stem cells is affected by the lack of collagen VI. We will collect samples from patients affected by collagen-VI muscular dystrophies to study muscle stem cell defects in vitro. Moreover, we will use a 3D muscle-in-a-dish system to screen for therapeutic drugs that enhance the myogenesis capacity of muscle stem cells. Overall, this project will provide a better comprehension of this rare muscular disease, and it will open the way to new therapeutic avenues.

Novel tools for drug repurposing in COL6 myopathies: accelerating the route towards therapy.

Awardee: Paolo Bonaldo

Institution: University of Padova, Department of Molecular Medicine

Award Amount: $42,406

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

Global Registry for Inherited Neuropathies (GRIN) - Natural History Study Data Assessment of Charcot-Marie-Tooth (CMT) Patients (age 3-25) to Support Virtual Clinical Studies

Awardee: Florian Thomas

Institution: Hackensack University Medical Center

Award Amount: $55,090

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

Role of CTHRC1 in the Pathogenesis and Therapy of LAM

Awardee: Elizabeth Henske

Institution: BWH

Award Amount: $70,769

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

---

Summary:

This project is focused on a protein, CTHRC1 (collagen triple-helix repeat containing 1), that has never before been studied in LAM.  CTHRC1 is a protein that is usually secreted by cells and can be detected in the blood.  In other diseases, CTHRC1 is linked to the rate of cellular growth, and in several types of cancer, a high level of CTHRC1 in the blood is associated with a poor clinical prognosis.  

 In a new line of investigation in our lab, Dr. Nico Alesi has discovered that levels of CTHRC1 are elevated in cellular models of LAM.  CTHRC1 is also increased in human angiomyolipomas and in LAM cells.   Interestingly, levels of CTHRC1 are not suppressed by Rapamycin.  In TSC2-deficient cells, inhibition of CTHRC1 decreases cell growth. 

 These data suggest that CTHRC1 is a newly recognized driver of LAM cell growth.  Because levels of CTHRC1 are not affected by the mTOR inhibitor Rapamycin, CTHRC1 could help to explain why LAM cells are not eliminated during therapy with mTOR inhibitors.  Identifying therapeutic strategies to eliminate LAM cells is a key goal of this work. 

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

Determination of the retinal functions of VPS13B using a murine model and assessment of exon-skipping as a therapeutic strategy for Cohen Syndrome in patient-derived cells

Awardee: Laurence Faivre

Institution: CHU Dijon Bourgogne

Award Amount: $66,560

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

The “molecular tweezer” CLR01 as a new potent drug candidate to slow CNS pathology progression in MPS-I

Awardee: Alessandro Fraldi

Institution: University of Naples "Federico", Dept of Translational Medicine

Award Amount: $65,040

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

---

Summary:

Progressive neurological deterioration characterizes both severe (Hurler) and intermediate (Hurler-Scheie) forms of MPS-I. Unfortunately, to date, there is no treatment for the CNS pathology in MPS-I patients.

Under different stress conditions, certain aggregation-prone proteins misfold and self-assemble into neurotoxic insoluble deposits called amyloids. Aggregation and deposition of amyloid proteins in the brain is a hallmark of many neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. By studying mouse models of Sanfilippo syndrome we have recently shown that deposition of amyloid proteins also occurs in the brain of these mice and is a key event contributing to the neurodegenerative processes. Furthermore, extending previous observations, we have shown that similarly to the Sanfilippo syndrome, amyloid deposition also occurs in the brain of other mouse models of MPS and, in particular, is associated to neurodegenerative processes in the brain of post-mortem patients with MPS-I.
To counteract these amyloid-mediated pathological processes, we made use of a potent and specific inhibitor of amyloid protein aggregation known as CLR01. CLR01 is a lead compound of the “molecular tweezers” class of small molecules that act by a unique mechanism to efficiently inhibit abnormal self-assembly of multiple amyloidogenic proteins. CLR01 has been shown to be effective in protecting against neurodegeneration in mouse models of Alzheimer’s and Parkinson’s diseases. Moreover, previous studies also have shown that CLR01 has a wide safety margin in mice and crosses the blood-brain barrier when administered systemically. We have shown that subcutaneous injection of CLR01 in the mouse model of MPS-IIIA, the most and severe form of Sanfilippo syndrome resulted in a striking reduction of amyloid protein deposition in the brain and correction of neuropathological phenotype, including cognitive function.

Here we want to extend the proof of efficacy of CLR01 beyond MPS-IIIA and test the hypothesis that inhibiting amyloid deposition by CLR01 is an effective therapeutic option to slow CNS manifestations in MPS-I forms with CNS involvement. Overall our results may open the possibility to develop effective CNS therapies for MPS-I based on parenteral administration of CLR01, a drug with a unique mechanism of action and with a high translational potential.