Nucleoside therapy for telomere diseases

Awardee: Agarwal Suneet

Institution: Boston Children's Hospital

Grant Amount: $63,000.00

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

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Summary:

Telomere biology disorders (TBDs) are a spectrum of diseases characterized by life-threatening complications including bone marrow failure, liver and lung disease. Tissue and organ transplantation remain the primary treatments, but cures that address the underlying problem and restore telomere length to improve symptoms throughout the body are lacking. We recently discovered that molecules called nucleosides can increase telomere length in human cells, including those from patients with TBDs. This is exciting because nucleosides have already been used in children with another rare disease, and appear to be safe and effective for that disease. In this proposal, we will now rigorously test whether these same nucleosides can effectively increase telomere length in human stem cells, both in the dish and in animal models. If successful, these experiments will provide critical results that will help take nucleosides into clinical trials for patients with TBDs.

Targeting the endocannabinoid system to treat epilepsy in Niemann Pick disease type C

Awardee: Lola Ledesma

Institution: Centro Biologia Molecular Severo Ochoa

Grant Amount: $40,140.00

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

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Summary:

Pharmacoresistent epilepsy is frequently found in NPC patients. This condition impact heavily in the quality of life of the patients and their families. Several studies have reported the ability of cannabinoids to reduce the frequency of seizures with a safe profile even in pediatric population. We have also shown the downregulation of the endocannabinoid system in the brain of an NPC mouse model and patient. We thus propose the enhancement of the endocannabinoid system as anti-epileptic treatment in the disease. We will assess the efficacy and safety of this strategy in a mouse model for NPC using oral administration of exogenous cannabinoids or of an inhibitor of the endocannabinoid degrading enzyme FAAH.

Antisense Oligonucleotide as Substrate Reduction Therapy for Mucopolysaccharidoses type III

Awardee: Manor Yehoshua

Institution: Sheba Medical Center

Grant Amount: $57,645.00

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

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Summary:

Our project aimed at finding a much-needed treatment for MPS type III, a condition that currently has limited treatment options. Leveraging the advanced capabilities of RNA-based therapy, specifically Antisense Oligonucleotides (ASOs), we are crafting a method to reduce the buildup of the harmful substance of heparan sulfate in the body and brain that is the hallmark of this illness. This technology has not only proven to be more effective but also more cost-efficient compared to other existing therapies. Moreover, it has demonstrated successful outcomes in both laboratory settings and preliminary human trials. By building on this innovative approach, we aspire to create a treatment that can significantly alleviate the CNS symptoms of all types of MPS III patients, potentially revolutionizing the management of this condition and offering hope for improved quality of life to those affected.

Social Outcomes in Adults with RASopathies: The SOAR Study

Awardee: Jonathan Payne

Institution: Murdoch Children's Research Institute

Grant Amount: $60,755.00

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

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Summary:

Psychosocial difficulties and increased mental ill-health have been described in some RASopathies, however the literature lacks a systemic account of these difficulties, especially in adulthood. Understanding the nature, severity and impact of mental health and psychosocial adversity in adults with a RASopathy will be critical to inform clinical practice and to guide intervention strategies. The overall goal of the SOAR study is to take a holistic approach to evaluating a broad road range of psychosocial outcomes in adults with a RASopathy, including mental health, social integration, quality of life and daily living skills. We will also examine how these outcomes relate to demographic and personal variables such as employment, housing arrangements, family composition, and health status. SOAR will be a survey-based study and include over 300 adults with a RASopathy across Australia and the UK. By comprehensively characterizing the psychosocial outcomes in adults with RASopathies, this project will help shape clinical services and management of individuals with RASopathies.

CLA Chatbot: Developing a Scalable Artificial Intelligence-Powered Communication Tool for Families Affected by Complex Lymphatic Anomalies

Awardee: Bryan Sisk

Institution: Washington University

Grant Amount: $60,679.00

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

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Summary:

Complex lymphatic anomalies (CLAs) affect the development, structure, and function of the lymphatic system causing variable and often severe clinical manifestations that are difficult to diagnose and treat. Accessing high-quality information is essential to receiving optimal care for patients with CLAs. In prior study of patients and caregivers with CLAs or other vascular anomalies, we found that having better quality of information exchange with clinicians was associated with better physical health, mental health, and ability to navigate the healthcare system. Parents also viewed accessing high-quality information as central to their role as advocates. Yet, most families with CLAs report poor communication with clinicians, limited access to reliable information, and reliance on social media and internet searches for information. To improve understanding and support the ability of patients and caregivers to manage CLAs, we will develop a novel and scalable communication tool that retrains ChatGPT large language model (LLM) to answer questions about complex lymphatic anomalies (CLAs). We hypothesize that CLA Chatbot will provide accurate, understandable, and comprehensive responses to questions generated by patients with CLAs and caregivers. CLA Chatbot will be scalable, easily translatable to other rare diseases, and will directly inform future federally funded efficacy trials.

Neuromuscular Activation of Muscle in Children with the ZC4H2 Mutation

Awardee: Richard Lieber

Institution: Shirley Ryan AbilityLab

Grant Amount: $61,815.00

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

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Summary:

Our research will determine whether the weakness experienced by children with the ZC4H2 mutation is due to their inability to voluntarily recruit muscle groups or weakness in the muscle itself. This will be accomplished by measuring both mechanical and electrical activity of the major flexors and extensors in the body. In this way, we can focus development on therapies related to the actual functional problem in these children.

The mitochondrial-related defects in WDR45-defective cells and how to reverse them

Awardee: Mario Mauthe

Institution: University Medical Center Groningen (UMCG)

Grant Amount: $60,000.00

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

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Summary:

The WDR45 gene, which when mutated causes BPAN, produces a protein called WDR45. WDR45 is involved in autophagy, a process that is responsible for removing damaged cellular components. Furthermore, we have observed that the mutated WDR45 protein also affects critical cellular structures called mitochondria, which play vital roles in energy production and metabolism regulation. Similar malfunctioning of mitochondria is also observed in several BPAN-related diseases (other NBIA subtypes) such as PKAN, CoPan, PLAN and MPAN. Within this project, our team will investigate how mutations in WDR45 affects the mitochondria and thereby contribute to the BPAN pathology. Our final goal is to reverse the changes in mitochondria, which are caused by the mutated WDR45 protein, using pharmaceutical compounds. We will start working in cellular model systems, and then move to validating our findings in BPAN patient-derived cells.

Advancing gene therapy for BPAN

Awardee: Manju Kurian

Institution: UCL

Grant Amount: $60,000.00

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

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Summary:

For those affected by progressive, life-limiting brain disorders associated with high brain iron, there are currently no effective treatments. We wish to address this important issue by developing a new therapy for children and young people with Beta Propeller Protein Associated Neurodegeneration (BPAN), a devastating condition caused by a genetic fault (or ‘spelling mistake’) in the gene, ‘WDR45’. In BPAN, the body cannot properly recycle waste products and as a result, toxic iron builds up in the brain. BPAN touches the lives of several hundred people worldwide. Affected children have developmental delay and seizures in childhood. During adolescence, there is a rapid decline in abilities, which is often so progressive that by early adulthood, many are wheelchair bound with severe dementia. BPAN is sadly associated with a high risk of premature death. There are currently no therapies that prevent the progression of BPAN. As such, we believe that developing a new treatment for BPAN is a research priority with potential to benefit hundreds of people globally. With this aim, we propose to develop gene therapy to deliver a healthy copy of the faulty gene directly into the brain. We will establish a state-of the-art laboratory model of disease (a ‘brain in a dish’) and use an excellent mouse model that shows key features of human disease, to test our gene therapy approach to see whether it rescues the problems caused by the faulty gene in BPAN. A successful gene therapy study in our laboratory will allow us to accelerate a clinical gene therapy trial for children with BPAN. Our hope is that gene therapy will halt disease progression, increase life expectancy, and provide a better quality of life for individuals and their families living with this condition.

Exploring CDKL5 Impact on Extracellular Vesicle-Mediated Cell-to-Cell Communication: Uncovering Hidden Pathways and Innovative Therapeutic Avenues

Awardee: Maurizio Giustetto

Institution: University of Torino

Grant Amount: $60,960.00

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

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Summary:

The main objective of this study is to explore the potential role of CDKL5 in extracellular vesicles (EVs)-mediated cell-to-cell communication and the consequences of CDKL5 mutation. Newly generated data obtained in our lab, thanks to previous financial support from MDBR, disclosed a restricted panel of EV-miRNAs with an altered expression both in CDD patients’ saliva and in murine CDKL5 mutant neurons cultures. Although these findings suggested that CDKL5 is involved in the composition of EVs cargo content, the consequences of these changes are still unknown.

Development of the novel treatment of idiopathic multicentric Castleman Disease using patientderived cell transplantation in an immunodeficient mouse

Awardee: Takuya Harada

Institution: National Hospital Organization Kyushu Medical Center

Grant Amount: $63,270.00

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

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Summary:

We have established a patient-derived xenograft (PDX) mouse model of idiopathic multicentric Castleman disease (iMCD). Through preliminary research on these mice, we have discovered the contribution of specific immune cells called peripheral helper T (Tph) cells to the pathophysiology of iMCD. By examining the dynamics of these cells in both patients and the mouse model, we are studying further research to understanding the pathophysiology of iMCD.

Immunotherapy and improved diagnosis and prognosis of the small vessel disease CADASIL

Awardee: Helena Karlström

Institution: Karolinska Institutet

Grant Amount: $109,856.00

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

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Summary:

Cerebral small vessel diseases (SVD) are medical conditions that cause great human suffering and costs for society. SVD cause approximately 20% of all strokes and more than 40% of dementia cases in elderly and are on the rise in an ageing population. SVD are difficult to diagnose, as current imaging modalities only recognize vessels, which are approximately ten times larger than those primarily affected by SVD. It is an emerging notion that the brain vasculature is affected in SVD which contributes to the neurodegenerative process. CADASIL is the most common hereditary form of SVD and to investigate this monogenic variant will be of importance for providing valuable insights into the molecular mechanisms underpinning idiopathic SVD and for development of therapeutic treatment. In this proposal we want to explore ways to restore the brain vascular system in a CADASIL mouse model which has an ongoing pathology (aggregated NOTCH3) by two immunization treatment strategies i.e an active and a passive vaccination approach against aggregated NOTCH3. We have recently shown promising in vivo results with an active immunization study in a CADASIL mouse model where we immunized aggregated NOTCH3 just before pathology onset for four months (preventive study). Our results are very encouraging since we observe that NOTCH3 accumulation around the small vessels in the brain is reduced, but without any Notch3 related side effects (coverage of the vascular tree in the retina, kidney morphology and inflammation status is unaffected). We also observed reduced levels of NOTCH3 ECD in the blood after immunization, which could be of great importance for diagnosis, monitor prognosis and therapeutic efficacy (Oliveira et al EMBO Mol Med, 2023). The results from these will be important novel step towards future therapy development for the disease.

Channel scaffolding and its contribution to SCN2A disorders

Awardee: Paul Jenkins

Institution: University of Michigan Medical School

Grant Amount: $61,280.00

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

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Summary:

Thanks to critical genomic data like the Simons Simplex Collection, the scientific community possesses dozens of highly reliable risk genes through the identification of rare de novo variants in patients with autism spectrum disorder (ASD). Loss-of-function in SCN2A, which encodes the neuronal sodium channel NaV1.2, has one of the strongest ASD associations . A large number of SCN2A variants have been shown to alter channel biophysical properties contributing to deficits in electrical signaling within the brain. Strikingly, a significant number of SCN2A variants have little to no detectable effect on channel functional properties, suggesting they are contributing to disease etiology through alternative mechanisms. In this proposal, we will test the hypothesis that these variants contribute to disease phenotypes by disrupting normal channel scaffolding causing channel mislocalization and neuronal dysfunction.

Systematic dissection of STXBP1 3’ UTR regulation to facilitate therapeutic development

Awardee: Xuebing Wu

Institution: Columbia University

Grant Amount: $75,460.00

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

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Summary:

Most STXBP1 mutations cause diseases by inactivating one copy of the gene. A potential therapy is to increase the expression of the remaining functional copy. By systematically mutating the noncoding regulatory sequences of STXBP1, we have identified promising targets of antisense oligos (ASOs) that can potently increase STXBP1 expression. We will test these ASOs in patient-derived neurons. If successful, these ASOs will be able to treat most STXBP1 patients, regardless the identity of the mutation.

Integrative omics: A novel approach to unravelling the complexity of STXBP1 encephalopathies

Awardee: Wendy Gold

Institution: The University of Sydney

Grant Amount: $75,460.00

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

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Summary:

The paucity of any disease modifying therapeutic entering the clinic for STXBP1 is largely due to an incomplete understanding of the complex underlying disease pathophysiology and function of STXBP1 and the lack of useful clinical biomarkers. Clinical biomarkers can predict disease state, disease severity, and treatment efficacy and have the potential to enable earlier diagnosis, support novel treatments, and serve as surrogate outcome measures of improvement in key characteristics of disease and associated comorbidities in clinical trials. Through a multi-disciplinary, integrative “omics” analysis of patient blood samples, we aim to identify clinical biomarkers, disease drivers, and therapeutic targets that will contribute to improved clinical monitoring, treatment options, and outcomes for STXBP1 encephalopathies.

Developing peptide-conjugated antisense oligonucleotide therapy for COL6-related congenital muscular dystrophy

Awardee: Haiyan Zhou

Institution: University College London

Grant Amount: $70,133.00

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

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Summary:

Collagen VI-related congenital muscular dystrophies (COL6-CMDs) are one of the most common types of CMDs. There is no curative treatment available. In the last few years, we have provided strong proof-of-concept evidence that experimental oligonucleotide therapy is a promising approach for the treatment of this fatal neuromuscular condition. My group has tested antisense oligonucleotide (ASO) therapeutic strategies in skin cells cultured from COL6-CMD patients and have already identified the lead ASO compounds able to correct the common disease mutations. However, for ASOs to work efficiently in humans, it is essential they target the skeletal muscle interstitial fibroblasts (MIFs), the major cell population producing collagen VI protein in muscle. So far, MIFs targeting has proved to be challenging to the field and has clearly obstructed the therapeutic development in COL6-CMDs. My group has recently identified a series of short protein fragments (peptides) that specifically bind to a cell surface receptor of MIFs, while also promoting the cellular internalization that will be needed when an oligonucleotide is attached to the peptide. Crucially, our data also demonstrated that some of these peptides efficiently target fibroblasts in a preferential manner, an important finding to avoid the accumulation of oligonucleotides in unwanted cell types. Here we propose a project aiming to further develop this exciting approach by using optimized MIF targeting peptides as a strategy to enhance the uptake of therapeutic ASOs to MIFs specifically, with an ultimate aim of developing a new therapy for COL6-CMD. The experiment plan includes: 1) To optimize the peptide sequences by testing alternative amino acids to improve the binding affinity, increase internalization and endosomal escape and reduce any potential cytotoxicity. 2) To validate the conjugates, for exon-skipping strategy in targeting MIFs, using cultured patients’ fibroblasts. 3) To generate a pilot in vivo biodistribution profile of pep-ASO conjugates, in wild-type mice. By the end of this project, we expect to identify the optimal peptide-ASO conjugates ready for further in vivo validation in the available humanized mouse model of COL6-CMD and to promote the future clinical translation of ASO therapy in COL6-CMD.

ADAR mediated RNA editing for treatment of collagen VI related muscular dystrophy

Awardee: Russell Butterfield

Institution: University of Utah

Grant Amount: $70,133.00

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

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Summary:

The collagen VI related muscular dystrophies (COL6-RD) are inherited disorders of muscle characterized by progressive weakness and a combination of distal joint laxity and proximal joint contractures. Missense mutations substitute the glycine residues in the conserved Gly-x-y repeat of the triple helical (TH) domain are the most common mutation in COL6-RD patients. This mutation allows incorporation of abnormal chains into secreted tetramers resulting in a dominant negative effect. Currently, there are no treatment for these disorders and the dominant negative mutations pose significant challenges for developing novel treatments since simple gene-replacement will not be effective to counter the dominant-negative mechanism. In this study, we propose to apply an in-situ RNA editing strategy by recruiting adenosine deaminase acting on RNA (ADAR) with guide RNA to simultaneously correct multiple G-to-A dominant negative mutations in COL6-RD patient-derived fibroblasts. We hypothesize this strategy will significantly decrease the mutant alleles’ presence at mRNA level and result in decreased intracellular retention and increased deposition of collagen VI matrix.

pH-dependent mechanisms of disease caused by TBC1D24 mutations

Awardee: Dennis Brown

Institution: Massachusetts General Hospital

Grant Amount: $60,000.00

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

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Summary:

There are several lines of evidence, both from genetics and protein-protein interaction studies that there is an important physiological link between Tbc1d24 and a molecular proton pump, called V-ATPase. The major function of the V-ATPase is to pump acid (in the form of protons) into small vesicles inside the cell, such as synaptic vesicles and lysosomes. A low, acidic pH within these vesicles is required for their normal function, in particular neurotransmitter loading of synaptic vesicle in neurons or degradation of various molecules in lysosomes. In addition, proper pH gradients are required for efficient intracellular vesicle trafficking and recycling of proteins, telling them where to go inside a cell, which is extremely important at neuronal synapses. V-ATPase is not a single protein, but a protein complex, consisting of 13 core proteins, or subunits. While severe mutations in V-ATPase subunit genes causing a loss of protein function are incompatible with life, some mutations result in various diseases and syndromes, including epilepsy, hearing loss and DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation and seizures). These diseases are remarkably similar to those caused by mutations in the TBC1D24 gene. We discovered recently that V-ATPase physically binds to Tbc1d24, as well as four other proteins that are structurally similar. They all contain a so-called TLDc conserved domain. We found that some mutations in the TLDc domain of one of these other proteins, called Ncoa7, disrupted its ability to bind to V-ATPase, which inhibited its acid-pumping capacity. Importantly, some of these “inhibitory” mutations correspond to the known pathogenic mutations within the Tbc1d24 protein in affected patients. Therefore, we hypothesize and aim to prove that some TBC1D24 pathogenic mutations destabilize the interaction of Tbc1d24 with V-ATPase, resulting in impaired acidification of vesicles within cells, including neuronal cells. We also plan to study where precisely the Tbc1d24/V-ATPase interaction takes place to better understand which intracellular vesicles are more severely affected by the mutations. This will facilitate the development of new treatment strategies and drugs specifically designed to target (stabilize) Tbc1d24-V-ATPase interactions. The hope is that if we can repair this interaction, it will restore the process (e. g., acidification) or pathways disrupted by at least some of pathogenic mutations in the TBC1D24 gene.

Linking SETBP1-HD EEG Biomarkers to Clinical Profiles

Awardee: Caitlin Hudac

Institution: University of South Carolina

Grant Amount: $88,740.00

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

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Summary:

A better understanding of how the brain works in SETBP1 haploinsufficiency disorder (SETBP1-HD) will be helpful to predict what treatments will be most successful. We will collect data and build biological markers (or “biomarkers”) that will capture how individuals with SETBP1-HD focus and learn about the world. Our biomarkers use electroencephalography (EEG) to record brain electricity across the head from over 100 recordings sites on a wet cap. We will collect data from an additional 25 participants with SETBP1-HD using mobile EEG data collection. Critically, this study will be the first to link these brain biomarkers to language, cognitive, and attention clinical profiles. This project will produce valid and reliable biomarkers that can be used as outcome measures to improve treatment and interventions and progress clinical trials.

Clinical trial readiness through longitudinal disease reconstruction in TBC1D24-related disorders

Awardee: Jillian McKee

Institution: University of Pennsylvania/ Children's Hospital of Philadelphia

Grant Amount: $26,962.00

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

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Summary:

The proposed research aims to understand the diverse clinical landscape and create a timeline of the likelihood of different clinical features in TBC1D24-related disorders across the lifespan. Data previously published in the literature and extracted from electronic medical records at our large academic medical center will be combined with medical records obtained from the TBC1D24 Family Foundation. Our goal is to understand the natural history and genetic basis of varying disease courses in TBC1D24-related disorders to improve clinical care. We hypothesize that we can identify previously unknown subgroups, disease trajectories, and medication responses that will allow us to predict patient outcomes more precisely, choose appropriate medical treatment strategies, and inform clinical trial design.

Congenital hyperinsulinism models for novel drug discovery

Awardee: Michael Kalwat

Institution: Indiana Biosciences Research Institute

Grant Amount: $70,200.00

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

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Summary:

Patients with congenital hyperinsulinism (HI) are in a continual battle to regulate their blood glucose levels. HI is caused by genetic mutations that lead to inappropriately high insulin levels in the blood. Insulin is normally released from beta cells within the pancreas only after meals when blood glucose is elevated. However, in HI these cells are dysfunctional and release too much insulin even when glucose levels are low. The only FDA-approved drug for HI, diazoxide, has side-effects and some patients are unresponsive. Therefore, new treatments need to be developed. To accomplish this requires the creation of new methods that allow us to test drugs on cells which mimic the human disease. In our project, we will create a human beta cell model that mimics HI and we will test new drugs to determine their ability to suppress insulin release and their mechanisms of action. Our project is broken into two Aims. In Aim 1, we will create a human β-cell line that expresses a mutant version of a gene found in HI. We will use this line alongside normal β-cells to test our new drug compounds. In Aim 2, we will collaborate with a medicinal chemist to improve the effectiveness of our top candidate compound and we will perform experiments to identify exactly which proteins are involved in our drug’s actions. We anticipate that the success of this project will propel our lab’s progress in HI research and enable us to develop improved model systems and make discoveries that will benefit HI patients.