DYSTRO-SMARTY: A novel nanotechnology platform for delivery of nucleic acids to treat Collagen VI-related Congenital Muscular Dystrophy

Awardee: Cecilia Jimenez-Mallebrera

Institution: Hospital Sant Joan de Deu

Grant Amount: $48,876

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

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Summary:

Nucleic-Acid based therapies are being developed at a fast pace with 11 currently approved products and many more in the pipeline. However, delivering therapeutic amounts of these nucleic acids to the target tissue remains the major hurdle, particularly for muscle diseases. Here we propose to apply a validated nanotechnology platform, SMARTY, based on non-liposomal lipid-based nanovesicles, called Quatsomes, to deliver nucleic acids to treat COL6-related Congenital Muscular Dystrophy (COL6-CMD). These nucleic acids are antisense oligonucleotides (ASO) that we have designed and tested to correct a common mutation in collagen VI genes. ASO will be conjugated to the Quatsomes and their physico-chemical properties, distribution and integrity inside the cell as well as their specificity and efficacy to correct collagen VI mutations will be systematically investigated in cells from COL6-CMD patients. The Quatsomes platform (patent WO/2020/229469), developed by our collaborators (at VHIR and ICMAB-CSIC), has already been exploited for other applications for effective intracellular delivery of nucleic acids. Moreover, Quatsomes will be produced by a GMP compliant manufacturing process. This will facilitate the future translation and approval of this potential therapy by regulatory agencies bringing COL6-RD closer to Clinical Trial Readiness.

Studying in-situ, in-vivo, and in-silico the pleiotropic action of collagen-VI to identify potential late-onset risks in COL6-CMD patients

Awardee: Jeanette Erdmann

Institution: Universität zu Lübeck

Grant Amount: $48,876

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

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Summary:

Due to better healthcare, COL6-CMD patients have a significantly longer life expectancy today than a few decades ago. For future health management of these patients early recognition of potential late-onset disease risks such as aneurysms, cardiovascular, and intestinal diseases can be vital. We will make use of col6a2 KO zebrafish (by morpholino antisense oligonucleotides) to comprehensively study the pleiotropic action of collagen-VI. Moreover, we will leverage human genetic data from UK biobank to identify by phenome-wide association study associations between genetic variants in COL6A2 gene and potential disease risks. Both strategies may help us to identify potential late-onset risks in COL6-CMD patients.

Rescuing oligodendrogenesis and myelination as possible treatment for Pitt-Hopkins patients

Awardee: Simone Mesman

Institution: Swammerdam Institute of Life Sciences, University of Amsterdam

Grant Amount: $78,530

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

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Summary:

In the brain of Pitt-Hopkins patients myelination, fatty sheets surrounding axons of neurons, is affected. The correct construction of these myelin sheets is crucial for proper brain functioning and neuronal communication. Incorrect myelination generally results in affected brain functioning and could be an underlying cause for defects in brain functioning as detected in PTHS. We propose to study myelination under inflence of PTHS-related Tcf4 mutations, by investigating myelination profiles in PTHS patients and by studying the effects of these mutations on oligodendrogenesis, the generation of oligodendrocytes the cell-type that produces myelin.

Multiplex analysis of variant effects for SLC2A1 gene

Awardee: Christina Gurnett

Institution: Washington University, St Louis

Grant Amount: $64,465

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

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Summary:

The goal of this research is to quantitatively determine the functional impact of all possible genetic variants in SLC2A1 and construct algorithms to accurately predict disease onset and severity correlating through calibration with known pathogenic and benign variants. Toward this goal, we propose to employ a high-throughput framework to assess the functional impact of genetic variants in the SLC2A1. We will introduce hundreds of SLC2A1 variants individually into the haploid cell line (HAP1) via multiplex homology-directed-repair (HDR) using CRISPR and a donor library, so that each cell obtains a single variant knocked into the endogenous SLC2A1 gene. Damaging variants that completely disrupt SLC2A1 function (and glucose uptake) will result in impaired cell growth and will drop out of a population of cells sequenced at different time points. We have preliminary data demonstrating the utility of this approach to quantify the functional effects of 15 SLC2A1 variants. We now propose to scale this assay to generate comprehensive, quantitative functional data for the entire SLC2A1 coding region.

Discovery of glycogen synthase inhibitors for validation as a novel therapeutic target for adult polyglucosan body disease (APBD)

Awardee: Wyatt Yue

Institution: Newcastle University, UK

Grant Amount: $99,025

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

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Summary:

Adult polyglucosan body disease is caused by a defective gene encoding glycogen branching enzyme GBE1, resulting in its low activity. The GBE1 enzyme is essential for making glycogen very compact inside the cell, otherwise the glycogen that is being synthesised by another enzyme glycogen synthase GYS1 will form clogging clumps. Drug development programmes for APBD and related diseases have largely sought to deliver an artificial version of the GBE1 gene, or turn down the native GYS1 gene, both emerging gene therapy approaches that remain experimental and costly for the long run. Our vision is to develop a daily pill for APBD patients as a transformative oral therapy. In the first step towards this goal, we aim to develop small molecules that act on the GYS1 enzyme as a drug starting point. To achieve this, we will take advantage of our unique knowledge about the shape of GYS1 enzyme, as well as cutting-edge computational and screening methods to find small molecules.

Discovery of new therapies for hypertrophic cardiomyopathy in RASopathies using an innovative hiPSC-based high-throughput drug screening platform

Awardee: Fabrice Jaffré

Institution: Weill Cornell Medical College

Grant Amount: $75,431

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

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Summary:

Children with RASopathies often present with severe cardiomyopathies and have a 22% mortality rate by the end of the first year of life. Currently, no specific treatment exists for RASopathy children with hypertrophic cardiomyopathy, therefore there is an urgent need to identify novel therapeutic strategies. The overall goal of this proposal is to uncover innovative therapeutic approaches using human induced pluripotent stem cell-derived cardiomyocytes as a RASopathy disease model and as innovative human 2D and 3D high-throughput drug screening platforms. Completion of this proposal will identify therapeutic molecules for RASopathy children with hypertrophic cardiomyopathy at an unparalleled speed.

EXPLOITING NEURONS- AND BRAIN-DERIVED EXOSOMES AS BIOMARKER FOR CDKL5 DEFICIENCY DISORDER

Awardee: Maurizio Giustetto

Institution: Univ. of Torino - Dept. of Neuroscience

Grant Amount: $75,000

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

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Summary:

The identification of objectively measurable parameters is urgently needed to speed up the diagnosis of CDKL5 deficiency disorder (CDD) and to evaluate the outcomes of both pre-clinical and clinical trials. Although exosomes, nanovescicles seceted by all cell types, can be exploited as unbiased, quantitative and non-invasive biomarker for clinical diagnosis, so far, no information is available on the molecular profile of exosomes in CDD. The goal of our proposal is to fill this gap and by establishing and validating a novel molecular, reliable biomarker for CDD patients.