Understanding the role of the lipid transport protein VPS13B in Cohen syndrome pathogenesis

Awardee: Berrak Ugur

Institution: Yale University

Grant Amount: $98,828

Funding Period: February 1, 2025 - January 31, 2026

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Summary:

Mutations in the VPS13B gene cause Cohen syndrome, a rare neurodevelopmental disorder characterized by developmental delays, muscle weakness, smaller head size, and progressive vision loss. VPS13B belongs to a family of proteins involved in lipid transfer between cellular membranes, a process essential for maintaining healthy cell function, particularly in the nervous system. Although VPS13B is present throughout the body and is known to be associated with the Golgi complex (a structure involved in protein and lipid transport within cells), its exact function has remained unclear. My research has shown that VPS13B primarily localizes to a specific area of the Golgi complex and plays a role in its recovery after disruption. This suggests that VPS13B’s function in lipid transfer may help maintain the structure and function of the Golgi complex. However, more research is needed to understand how these processes affect neurodevelopment and contribute to the symptoms of Cohen syndrome. The goal of the proposed research is to further investigate how VPS13B dysfunction leads to Cohen syndrome by identifying proteins that interact with VPS13B in neurons and determining key genes that work alongside VPS13B during development, potentially revealing new therapeutic targets for Cohen syndrome.

Rescue of defective lipid handling in Cohen syndrome

Awardee: Jens Luders

Institution: Institute for Research in Biomedicine (IRB Barcelona), Spain

Grant Amount: $83,282.00

Funding Period: February 1, 2024 - January 31, 2025

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Summary:

The molecular function of VPS13B, the gene that is mutated in Cohen syndrome, is still poorly understood. Our previous work suggested that mutation of VPS13B reduces the amount of certain types of fat molecules in patient cells. Since these fat molecules are essential for the structure and function of cells and for the formation of tissues and organs during development, a reduced amount of these fat molecules may cause the clinical features observed in Cohen syndrome patients. In this project we will test which aspect of the handling of these fat molecules – uptake, transport, or storage – is defective in cells of Cohen syndrome patients. We will then try to repair the defect by introducing variants of intact VPS13B into these cells. Since VPS13B is very large, we will also test smaller versions, which are easier to work with. We will then also try to repair the loss of VPS13B in two additional models, retinal tissue grown in a culture dish that is derived from patient cells, and zebrafish embryos that lack VPS13B, which recapitulate several Cohen syndrome features including brain and eye defects. The project aims to identify VPS13B variants that can be used to provide the crucial functions of VPS13B in cells that lack VSP13B. The results may be useful for developing gene therapy in the future.

Preclinical assessment of potential drug candidates in Vps13b knockout mice for the treatment of Cohen syndrome

Awardee: Muhammad Ansar

Institution: University of Lausanne

Grant Amount: $100,474.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

Cohen Syndrome is a rare genetic disorder caused by mutations in VPS13B gene. Patients suffer from developmental, intellectual, motor, metabolic, immunologic disorders, and visual impairments. Considering the current stage of research on Cohen syndrome and VPS13B, one of the most direct way of looking for treatment possibilities is to attempt drug repurposing of FDA-approved small pharmaceutical compounds. We recently performed a high-throughput microscopy screening assay based on the ability to revert the impaired cellular phenotype (Golgi morphology) of human VPS13B-deficient cells as well as in patients’ fibroblasts. We screened a library of 1280 FDA-approved pharmaceutical compounds, and the top 30 positive hits were further subjected to determine the dose-response. Out of the 30 positive candidates, we selected the four most effective compounds, previously used successfully in mice for the treatment of other pathologies, for which the toxicity is known, the effective dose is low, and there are little to no side effects in both mice and humans. The aim of the proposed project is to assess the treatment potential of the selected four drug candidates in the Cohen syndrome mouse model. In this project, the four selected candidate drugs will be fed to four groups of pregnant mice since the beginning of pregnancy. Drugs will be orally administered by mixing in food pellets. Pups born from these pregnancies will continue receiving the drugs and will be analysed until the age of three months. The treatment efficacy of the potential drug candidates in Vps13b knockout mice will be assessed by observing the most cardinal features of Cohen syndrome in mouse models.

Membrane homeostasis as potential therapeutic angle in Cohen Syndrome

Awardee: Jens Luders

Institution: Institute for Research in Biomedicine, Barcelona, Spain

Grant Amount: $47,161.00

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

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Summary:

Cohen Syndrome is a rare disease caused by mutations in the VPS13B gene. Patients affected by this disease are born with several disabilities and health problems. For example, children with Cohen Syndrome may develop slowly, have a small head size, intellectual disability, and an overall weak muscle tone. They frequently suffer from a reduction in the number of certain blood cells, which increases the risk of infections, and loss of vision, which becomes worse with age and can lead to blindness. Unfortunately, there is no treatment available for these patients. Since the molecular and cellular functions of the VPS13B gene are still poorly understood, it is unclear how its mutation leads to Cohen Syndrome. This makes it impossible to develop a treatment or therapy. We have recently obtained preliminary data suggesting that Cohen Syndrome may involve defects in primary cilia, hair-like structures on the surface of cells that function as a cell's antenna. They allow cells to receive and respond to signals from their environment and are very important for various developmental processes including formation of the brain and the retina. In this project we will uncover how defects in VPS13B may affect cilium formation and function in three different model systems: cultured cells including cells obtained from Cohen Syndrome patients, retinal tissue grown in a culture dish from patient cells, and zebrafish embryos, which recapitulate many developmental processes that also occur in humans including brain and eye development. Using the same model systems, we will then test if culture supplements or pharmacological treatments may be used to repair ciliary defects. If so, these treatments may be further developed into therapies in the future.

Determination of pathomechanisms and assessment of therapeutic strategies for Cohen Syndrome in patient derived cells and a murine model

Awardee: Muhammad Ansar

Institution: Jules-Gonin Eye Hospital, Ophthalmology Department of the University of Lausanne, Lausanne, Switzerland

Grant Amount: $$115,000

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

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Summary:

Cohen Syndrome (CS) is a rare genetic disease caused by the loss of function of the gene called VPS13B. Individuals with CS suffer from developmental, intellectual, motor, metabolic, immunologic and progressive vision loss problems. In this project we proposed to study and understand how the VPS13B gene functions and how the loss of this gene causes the disease symptoms. At the same time we’ll try to explore and test various treatment options by using cellular and mouse models, with the aim to ultimately find the cure for the CS disease or to at least stop the progressive loss of vision in these patients. Treatment strategies include the use of chemical drugs as well as gene therapy.

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