Targeting immunosuppression in LAM

Awardee: Yan Tang

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

Grant Amount: $71,051.00

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

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Summary:

Lymphangioleiomyomatosis (LAM), pulmonary manifestation of TSC, is a destructive and often fatal lung disease of women, which can lead to lung failure and the need for lung transplantation. LAM can occur as an isolated disorder (sporadic LAM) or in association with TSC. TSC-LAM patients often have angiomyolipoma (AML), the kidney manifestation of TSC. About 60% of sporadic LAM patients also have AML. It seems that LAM and AML share same genetic mutations. We performed single cell analysis on five LAM lungs and six AML specimens and found that subsets of candidate TSC-deficient cells exhibit elevated stemness and dormancy transcriptional programs in both LAM and AML. TSC diseases also exhibit an altered immune microenvironment. We have analyzed adjacent normal kidney tissues for four of the six AML specimens and found that AML tumors are enriched with dysfunctional T cells compared to paired normal kidney. In depth analysis further revealed that stemness-dominant samples are deprived of proliferating T cells, key component in immune system to control tumor growth. In this project, we will investigate how the stemness state of TSC-deficient cells affects immune microenvironment in LAM and assess whether targeting tumor stemness can rejuvenate T cells to better control LAM development.

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.

Deep Tissue and Cellular Phenotyping of APBD: A Bench to Bedside Approach

Awardee: Priya Kishnani

Institution: Duke University Medical Center

Grant Amount: $50,000.00

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

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Summary:

Adult Polyglucosan Body Disease (APBD) is an inherited metabolic disease that causes progressive neurodegeneration and reduced physical function and quality of life. There is currently no available treatment for APBD, but over the past decade, the APBD mouse model has been used to investigate potential therapeutics. However, without a full understanding of (1) the specific cells and tissues involved in APBD, and (2) how the disease pathology changes over the course of the disease, our ability to design effective treatments for APBD is limited. Utilizing a multidisciplinary approach with specialists in medical genetics and pathology, we will evaluate the extent of cellular involvement and degree of disease in human and mouse tissues. Ultimately, this work will provide precise therapeutic targets and measurable endpoints for both animal model experiments and progression to clinical trials.

Combinations of small molecule as potential therapeutic agents for APBD

Awardee: Or Kakhlon

Institution: Research Fund of the Hadassah Medical Organization

Grant Amount: $50,000.00

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

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Summary:

This proposal intends to significantly improve already very promising compounds for obtaining a cure for the adult neurodegenerative disorder Adult Polyglucosan Body Disease which inflicts paralysis, loss of sensation, and lack of urination control on its victims. These compounds will be applied in special formulations which can stabilize them and increase their tissue penetration. Using this methodology and also compound combinations we anticipate that a cure for this devastating disorder will be within reach as a syrup or a pill. APBD, or Adult Polyglucosan Body Disease, is a neurological disorder inflicting paralysis, loss of sensation, and lack of urination control on its victims. The purposes of this proposal are (1) to further improve already promising compounds for the treatment of APBD and (2) to establish new markers for the disease. The compounds will be improved by applying them in combinations and in special formulations which can stabilize them and increase their tissue penetration. The new blood markers will be: (a) neurofilaments, which are proteins derived from fragmented dead neurons and thus should decrease if treatment is successful; (b) a set of molecules in the blood, called metabolites, which can recognize the severity of the disease and how effectively it can be improved by interventions, such as the mentioned compounds.

Testing the specificity and efficacy of compounds that inhibit cAMP signaling, for the development of potential therapeutics for FD/MAS

Awardee: Fernando Fierro

Institution: University of California Davis

Grant Amount: $80,642.00

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

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Summary:

The Hoffman and Fierro laboratories would like to continue testing compounds to inhibit the excess cAMP production seen in FD/MAS. Proposed studies focus on testing the efficacy and specificity of small molecules, including some candidates identified in the laboratory of our collaborators at UCSF.

Spatial transcriptomics to elucidate the mechanism of anti-RANKL inhibition of fibrous dysplasia bone lesions

Awardee: Julia Charles

Institution: Brigham and Women's Hospital

Grant Amount: $40,321.00

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

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Summary:

Fibrous dysplasia causes fibrotic bone lesions, full of immature bone forming osteoblasts, that result in pain, deformity and fracture susceptibility. Antibody that blocks the cytokine RANKL inhibits formation of bone eroding osteoclast cells and also improves bone lesions in fibrous dysplasia, but how this works is not known. We propose to profile what both mutant and bystander wild-type cells are producing before and after RANKL is blocked to try to understand how this treatment works. This is important because blocking RANKL has side effects that limit use and understanding how it improves bone lesions could lead to developing alternative therapies.

Probing Central and Peripheral Mechanisms of Pain and Dysfunction in Fibrous Dysplasia/McCune-Albright

Awardee: Jaymin Upadhyay

Institution: Boston Children's Hospital

Grant Amount: $40,321.00

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

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Summary:

Pain remains a multifaceted and often poorly treated symptom in Fibrous Dysplasia/McCune-Albright (FD/MAS). In this project, we propose to identify and treat biopsychosocial or centralized aspects of pain in FD/MAS. We hope to expand upon what is currently understood about pain in FD/MAS and work towards providing improved treatment options to patients with FD/MAS.

Publications:

Identifying Pain Subtypes in Patients With Craniofacial Lesions of Fibrous Dysplasia/McCune-Albright Syndrome

Preclinical Validation of potential GLUT1 inducing agents for GLUT1 Deficiency Syndrome (GLUT1 DS).

Awardee: Alex MacKenzie

Institution: Children’s Hospital of Eastern Ontario, University of Ottawa

Grant Amount: $61,901.00

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

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Summary:

Glucose is an essential energy source for the growing brain; low glucose levels in the brain can result in severe delay and disruption in brain development. This is the situation in the rare genetic disorder glucose transporter 1 deficiency syndrome (GLUT1 DS). GLUT1 DS is caused by mutations in the SLC2A1 gene that makes the so called transporter protein GLUT1 which is responsible for transporting glucose from the blood into the brain. A child with GLUT1 DS has only about half the normal level of brain glucose resulting in microcephaly, the development of seizures, as well as movement, and speech disorders that get progressively worse as they age. Although in GLUT1 DS, one of the SLC2A1 genes is mutated, every person has two copies of each gene; the “turning up” of the remaining normal SLC2A1 gene to make more of the GLUT1 protein in infants and children with GLUT1 DS represents a possible treatment for this untreatable disorder. We have studied the impact of several hundred clinically approved drugs on human blood vessel cells to determine if any of them increase the expression of GLUT1; eight such drugs have been identified. The top GLUT1-inducing drugs as well as roughly an equal number of drugs with similar impact that other scientists have found and published on will be tested on a mice model that, like humans with GLUT1 DS have mutated GLUT1. We shall use a variety of approaches, including so-called PET scan, which gives read outs of actual brain glucose levels before and after drug treatment, to see which are successful in increasing glucose transport to the brain. Drugs with the capacity to increase GLUT1 levels could be used as a treatment for GLUT1 DS and will be the subject of a clinical trial.

Deep phenotyping of mouse models of UBE3A gain-of-function

Awardee: Jason Yi

Institution: Washington University School of Medicine

Grant Amount: $47,158.00

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

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Summary:

Dup15q syndrome is caused by a duplication or triplication of maternal chromosome 15q11-13 whereas individuals with paternal duplications are typically developing. There are more than 20 genes within chromosome 15q11-13, but among them, Ube3a is the only gene expressed exclusively from the maternal allele in neurons. These observations strongly suggest that excessive UBE3A protein activity is the major driver of disease phenotypes in Dup15q syndrome. This proposal will perform deep phenotypic analysis of an allelic series of mice that possess gain-of-function mutations in Ube3a of increasing severity. By doing so, our study will identify specific phenotypes in mice that are caused by excessive UBE3A protein activity. These studies will provide valuable models and information that can be leveraged to design therapeutic strategies for this disorder.

Development of a Novel Viral Vector Gene Therapy Approach to treat CACNA1A Cerebellar Disorders

Awardee: Samuel Young

Institution: University of Iowa

Grant Amount: $73,731.00

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

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Summary:

Currently, no clinically approved therapeutic strategy that treats the root cause of CACNA1A disorders exists. Due to the recent clinical successes of viral vector-mediated gene therapy, it is an attractive strategy to treat CACNA1A disorders. However, the CACNA1A cDNA sequence is 7.5 kilobases and 8.4 kilobases complete cDNA, which is too large to be used with Adeno-associated Virus (AAV), since AAV has a ~5 kb packaging capacity. Although AAV is the most widely-used gene therapy viral vector in the clinical setting, it is severely limited to treat CACNA1A disorders. Therefore, non-toxic viral vectors with large carrying capacities that are capable of long-term stable transgene expression in Purkinje cells and potentially other cerebellar cell types are needed. Development of a viral vector gene therapy approach to treat all forms of CACNA1A disorders is critical to mitigate the devastating impact on the quality of CACNA1A patient lives. This proposal represents the first steps towards establishing the feasibility of a novel gene therapy approach for CACNA1A cerebellar disorders. While our research is an early discovery stage project, the ability to generate a viable gene therapy approach will lead to a breakthrough in treating the root cause of all CACNA1A disorders.

Development of a validated and patient-specific GNAO1 model for screening and testing of therapeutics

Awardee: Harald Mikkers

Institution: Leiden University Medical Center, Netherlands

Grant Amount: $100,000

Funding Period: September 15, 2023 - September 14, 2024

Summary: This project will advance and improve a state-of-the-art personalized medicine tool for GNAO1. He will use funding from the Bow Foundation to create a validated stem cell GNAO1 model that opens the doors to various drug screening efforts. The work will investigate how GNAO1 impacts neurons and evaluate the suitability of the iPSC-based model for testing of therapeutics and drug responses

Establishing a Krabbe Disease Newborn Screening Biobank and Natural History Database Platform

Awardee: Laura Adang

Institution: Children's Hospital of Philadelphia

Grant Amount: $150,000

Funding Period: August 1, 2023 - July 31, 2024

Testing mechanisms and intervention strategies in GNAO1 dystonia

Awardee: Kirill Martemyanov

Institution: University of Florida Scripps Institute for Biomedical Innovation and Technology

Grant Amount: $100,000

Funding Period: August 1, 2023 - July 31, 2024

Summary: This project will help advance scientific understanding about the mechanisms of dystonia. Many GNAO1 patients suffer from dystonia, commonly known as involuntary muscle movements. Bow Foundation funding will allow Dr. Martemyanov to use a mouse model to shine light on the impact of GNAO1 on dystonia and brain signals while also testing possible treatment strategies.

Personalized Anti-Sense Oligonucleotide Therapy in a Patient with GNAO1 Mutation

Awardee: Jennifer Friedman

Institution: University of California San Diego and Rady Children’s Hospital

Grant Amount: $100,000

Funding Period: August 1, 2034 - July 31, 2024

Summary: Dr. Friedman partnered with the n-Lorem Foundation to support the administration of an experimental antisense oligonucleotide (ASO) medicine that targets the GNAO1 gene. Funding from the Bow Foundation will help Dr. Friedman collect and evaluate the clinical observations of this cutting-edge treatment, including changes in baseline over time and data from predetermined outcome measures. This preclinical work will allow the research team to determine if ASO treatments for other GNAO1 patients are a viable approach for other patients.

Assessment of the therapeutic potential of TATk-hCDKL5 isoform 1 and 2 produced in recombinant Antarctic Pseudoalteromonas haloplanktis TAC125

Awardee: Maria Luisa Tutino, PhD

Institution: University Federico II of Naples

Award Amount: $149,985.00

Funding Period: May 1, 2023 - April 31, 2024

Therapeutic potential of Ca2.3 inhibitors in CDD mouse and human models

Awardee: Marisol Sampedro Castanedo, PhD

Institution: Francis Crick Institute

Award Amount: $149,942.00

Funding Period: May 1, 2023 - April 31, 2024

Clinical trial for antisense oligonucleotide therapy in a patient with ADLD

Awardee: Margot Cousin

Institution: Mayo Clinic

Grant Amount: $50,000

Funding Period: May 1, 2023 - April 30, 2024

Summary: The long-term research goal is to advance disruptive innovation to transform care for individuals with ADLD through the development of a translational therapeutics program using team science. We hypothesize that a gapmer ASO to knockdown LMNB1 expression will be safe and well tolerated and that it will ultimately improve clinical outcomes in patients with ADLD. The objectives in this application are to develop and execute a first-in-human clinical trial to determine safety, tolerability, and potential clinical benefit of an LMNB1-targeted ASO therapy in a single patient with ADLD.

Development of 3D ADLD microfiber and organoid models for studying biomarkers and drug testing

Awardee: Stefano Ratti

Institution: University of Bologna

Grant Amount: $50,000

Funding Period: May 1, 2023 - April 30, 2024

Summary: The project aims at developing reliable ADLD microfiber and organoid models for investigating
biomarkers and for drug testing. The novel models to be developed with this substantial 1 -year funding include 3D microfiber co-cultures of astrocytes and oligodendrocyte precursors (OPCs) and brain organoids. These models will be created from the fibroblasts of patients with the LMNB1 gene duplication and deletion phenotypes and healthy donors.  

Analyzing CNS cell type specific transcriptomics in ADLD

Awardee: Quasar Padiath

Institution: University of Pittsburgh

Grant Amount: $50,000

Funding Period: May 1, 2023 - April 30, 2024

Summary: In this proposal, ADLD brain tissue samples will be utilized to carry out both bulk and
CNS cell type specific transcriptomics (RNA Seq analysis). Such an analysis will identify pathways there are perturbed as a result of lamin B1 overexpression and interrogate lamin B1 overexpression across different CNS cell types. These studies will help identify pathways contributing to the demyelination phenotype that may serve as potential therapeutic targets. In addition, cell type specific analysis can identify cells that are targeted for lamin B1 overexpression and cell type specific pathways that are perturbed providing critical insights into which cell types are responsible for the disease process.

New Drosophila models of CDD

Awardee: Maximo Ibo Galindo, PhD

Institution: Centro de Investigación Príncipe Felipe

Award Amount: $148,950.00

Funding Period: May 1, 2023 - April 31, 2024