The BSF research grant program seeks to provide seed funding to young and established investigators in order to generate the preliminary data required for successful follow-on funding available from larger institutions.
2023 GRANT AWARDS
Vetted by BSF’s Scientific and Medical Advisory Board (SMAB), the 2023 grantees demonstrate BSF's unrelenting commitment to identifying potential treatments and better understanding the challenges experienced by our community of affected individuals.
Riekelt Houtkooper, PhD, Amsterdam University Medical Center
Idea Award, $50,000, over one year
Barth Syndrome (BTHS) is a rare, genetic disorder of lipid metabolism that affects mitochondria; the subcellular compartments in which most cellular energy is produced. It is caused by mutations in the Tafazzin gene, which leads to faulty production of an enzyme required to produce cardiolipin, an essential lipid of the mitochondrial membrane. In consequence, most people with BTHS suffer from reduced muscle function, heart disease, repeated infections, delayed growth and varying degrees of physical disability, severely compromising their quality of life.
As there is no specific treatment for this disease, current therapies for BTHS are focused on reducing and preventing complications. These include physical therapy to improve muscle tone, antibiotics to prevent or treat bacterial infections, and administration of medication to prevent heart failure. Exploring new and better therapeutic avenues to effectively treat BTHS is of outstanding relevance.
Nicotinamide adenine dinucleotide (NAD+) is an essential molecule for energy production in mitochondria, and crucially required for proper cell functioning. We have demonstrated that a molecule called nicotinamide riboside (NR), a vitamin B3 homolog that can make NAD+, is able to rescue exercise tolerance and mitochondrial function in fruit flies with BTHS. Building on these results, we aim to validate this potential therapy in mice with BTHS. To do so, we will feed BTHS mice with an NR-enriched diet for two months, during which their exercise capacity and heart function will be monitored. We will also run biochemical and molecular analyses to understand how NR acts at a molecular level.
With this project we aim to shed light on whether NR supplementation is a valid potential therapy for BTHS
lnduced Pluripotent Stem CelIs to Study Neutrophil Development in Barth Syndrome
Taco Kuijpers, MD, PhD, Amsterdam University Medical Center
Idea Award, $49,854, over a year and half
Awarded to Dr. Taco Kuijpers, this project is dedicated to investigating primary white blood cells, specifically neutrophils and their progenitors from Barth syndrome (BTHS) patients using a new approach. Instead of culturing these white blood cells from bone marrow stem cells, this project will generate induced pluripotent stem cells (iPSC lines) derived from skin cells. This approach allows studies of neutrophil development without repeated bone marrow samples or blood samples to better understand neutrophil dysregulation in BTHS. These cell cultures will be subjected to in-depth phenotyping and functional studies to pinpoint the exact reason for the low output of mature neutrophils and previously established alterations in surface markers. In addition, the group will test whether a compound that appears able to improve the developmental state in a BTHS fruitfly model can impact or reverse this low output and shortage of neutrophils in BTHS patient-derived iPSCs.
Elucidating Cardiolipin Immune Dysfunction in Barth Syndrome
Kate Schroder, PhD, The University of Queensland
Idea Award, $50,000, over one year
Barth Syndrome (BTHS) is a genetic disease that can cause life-threatening infections or heart failure. While mechanisms of heart failure in BTHS are well studied, how BTHS causes immune dysfunction to cause susceptibility to infection is poorly understood. We discovered that a key lipid that is dysregulated in BTHS is an important immune regulator. This project will investigate whether dysregulation of this immune regulator in BTHS is linked to immune dysfunction in these patients. This project will form a strong foundation for future mechanistic studies of immune dysfunction in BTHS, and provide new drug targets to prevent BTHS susceptibility to infection and immune dysregulation, thereby improving patient health and extending lifespan.
This co-funded project was made possible by a generous contribution from our affiliate Barth Syndrome Foundation of Canada
Optimizing Cardiac Energetics in Barth Syndrome
John Ussher, PhD, University of Alberta
Development Award, $100,000 over two years
The goal of our research is to determine whether improving the heart’s ability to produce energy in a child with Barth syndrome may be an exciting method to reduce the risk for heart disease and heart failure in these children. To be specific, we hypothesize that an energy source made by the liver, the ketone body, may be a better energy source for the heart to metabolize for energy in a child with Barth syndrome. Therefore, increasing ketone body metabolism in the heart may be a beneficial strategy to reduce the risk for heart failure in Barth syndrome children. Recently, a unique genetically modified mouse has been produced for scientific research that lacks the gene/protein (TAFAZZIN/Tafazzin) that malfunctions or is missing in people with Barth syndrome, and these mice also develop heart failure. We will breed these genetically modified mice in our lab, and provide them with a dietary supplement (ketone ester drink), or treat them with a drug (empagliflozin), both of which increase ketone body levels in the blood, which will increase ketone body metabolism in the hearts of these mice. We will test whether the ketone ester drink or drug treatment improve heart function in these mice and prevent heart failure. If our hypothesis is correct, our research will suggest that boosting ketone body metabolism in the heart might be an effective way to prevent heart failure in Barth syndrome children and improve their chances of surviving into adulthood, while also improving their quality of life.
AMERICAN HEART ASSOCIATION & BSF RESEARCH COLLABORATION
AHA/BSF Research Partnership is a funding program for investigator-initiated career development and knowledge discovery projects that directly involve Barth syndrome or cardiolipin research. Administered and peer-reviewed by AHA's annual pre-doctoral and post-doctoral fellowship program. Applications open up in September and procedures can be found on the AHA website.
Function of tafazzin in antibacterial immunity
Mack Reynolds, PhD Student, Johns Hopkins University
AHA/BSF Predoctoral Fellowship
The 2023 American Heart Association/Barth Syndrome Foundation predoctoral fellowship has been awarded to Mack Reynolds, an Immunology PhD student in Dr. Mary O’Riordan’s lab at the University of Michigan (Ann Arbor, MI). Mack’s project entitled, “Function of tafazzin in antibacterial immunity,” will examine how specialized immune cells called macrophages behave during bacterial infections when there is not enough tafazzin, like in patients with Barth syndrome (BTHS). Many individuals with BTHS are impacted by severe infections like skin infections or ulcers. Many studies have evaluated how neutrophils impact infections in BTHS but further knowledge of how macrophages behave during infections is needed and may uncover new avenues for potential therapies. Mack will first look at how proteins and fats involved in macrophage metabolism (i.e. how cells make energy) differ between macrophages with normal or low tafazzin levels after the cells have been infected with methicillin-resistant Staphylococcus aureus (MRSA) bacteria, a common cause of skin infections. He hypothesizes that when tafazzin is low and cardiolipin cannot be remodeled properly in macrophages, changes in the cell’s metabolism impact inflammation and clearance of infection. This research will help us learn more about how macrophages contribute to inflammation and infection in BTHS.
Role of cardiolipin in cardiac ADP/ATP translocator activity
Nanami Senoo, PhD, Postdoctoral Fellow, Johns Hopkins University
AHA/BSF Postdoctoral Fellowship
In conjunction with the American Heart Association (AHA), this two-year postdoctoral fellowship has been awarded to Dr. Nanami Senoo in Dr. Steve Claypool’s lab. Dr. Senoo will explore the structural and mechanistic relationship between cardiolipin (CL) and the nucleotide transporter ANT1. Building on recent yeast findings that CL facilitates in nucleotide transport across the mitochondrial inner membrane, Dr. Senoo will ask if a similar process is occurring in human cells via ANT1. She will further assess whether heart-specific CL abnormalities found in BTHS affected individuals impact ANT1 structure and function. Dr. Senoo’s proposed work has the potential increase our understanding of how CL functions in heart cells and answer whether ANT1 plays a role in BTHS disease biology.
ONGOING GRANT PROJECTS
Investigating the basis of neutropenia in Barth syndrome
Borko Amulic, PhD, University of Bristol
2022 Idea Award, $49,999, over one year
Awarded to Dr. Borko Amulic and Dr. Colin Steward, this project takes advantage of proximity to the National Health Service (NHS) Barth Syndrome Service at Bristol Royal Hospital for Children to investigate primary neutrophils and their progenitors from BTHS patients. With a dual approach to investigating neutrophil dysregulation in BTHS, it will first utilize a newly established system to investigate development and differentiation of BTHS neutrophils from circulating progenitor stem cells under conditions of inflammatory and metabolic stress. Secondly, it will build on previously obtained data to examine how hyperdegranulation affects the interaction of BTHS neutrophils with the endothelium both ex vivo and in a mouse model of Barth syndrome.
This project’s funding was made possible by generous contributions from our affiliates Barth Syndrome Foundation of Canada and the Barth Syndrome UK.
Feeding the starving heart in Barth Syndrome
Adam J. Chicco, PhD, Colorado State University
2022 Development Award, $82,400 over two years
Awarded to Dr. Adam J. Chicco, this project will test the hypothesis that providing alternative fatty acid fuels that bypass the long chain fatty acid (LCFA) oxidation system will improve exercise tolerance and cardiac functional capacity in Barth syndrome (BTHS) patients. Using the two tafazzin-deficient mouse models of BTHS currently available, this effort will determine if therapeutic doses of a synthetic shorter-chain fatty acid supplement recently FDA-approved for treatment of LCFA oxidation disorders (triheptanoin; a 7-carbon medium-chain triglyceride) improves exercise capacity, cardiac function, and mitochondrial metabolism. If results of these pre-clinical studies are positive, they will provide the basis for exploring a clinically feasible and inexpensive treatment for improving functional capacity and quality of life in BTHS patients.
This project’s funding was made possible by the generous support of the Will McCurdy Fund for Advancement in Therapies for Barth Syndrome.
ALCAT1 as a novel target for the treatment of cardiomyopathy in Barth syndrome
Jun Zhang, PhD, University of Texas Health Science Center at San Antonio
2022 Development Award, $100,000 over two years
Awarded to Dr. Jun Zhang, the proposed studies will determine the role and underlying mechanisms of ALCAT1 as a key regulator of mitochondrial dysfunction in Barth syndrome, further building on past BSF support for this hypothesis. This project will also validate inhibition of ALCAT1 by a small molecule inhibitor as a novel and potential treatment for cardiomyopathy in Barth syndrome.
This project’s funding was made possible by the generous support of the Will McCurdy Fund for Advancement in Therapies for Barth Syndrome.
Reina Tan, MD; Colin K. Phoon, MPhil, MD
Hassenfeld Children’s Hospital at NYU Langone, New York, NY
BSF Strategic Initiative Award, $350,000
Barth syndrome (MIM 302060) is a rare X-linked mitochondrial disease, characterized by cardiomyopathy, skeletal myopathy, neutropenia, and growth delay. It is caused by mutated tafazzin (TAFAZZIN), which results in severe deficiency and altered biochemistry of the phospholipid cardiolipin. The Barth cardiomyopathy (including the dilated, hypertrophic, and noncompaction forms) causes significant morbidity and mortality. Sudden death is hypothesized to be due to heart failure and ventricular arrhythmias. However, our understanding of the burden and progression of cardiac disease in Barth syndrome remains scant. This project is comprised of a collaborative clinical registry and retrospective/prospective observational study to determine the burden and progression of cardiac disease in a large cohort of patients with Barth syndrome, while developing prognostic markers and strategies for risk stratification. This proposal will be embedded within a large, long-term natural history study.
This co-funded project was made possible by generous contributions from our affiliate Association Syndrome de Barth France.
Optimization of Barth syndrome gene therapy
William T. Pu, MD, Professor
Boston Children’s Hospital, Boston, MA
BSF Strategic Initiative Award, Y1 $68,750; Y2 $69,300
Adeno-associated viral (AAV) vector-mediated expression of tafazzin is a promising potential therapy for patients with Barth syndrome. In mouse models of Barth syndrome, AAV-TAFAZZIN prevents and even reverses cardiac and skeletal muscle weakness. However, translation to clinical application requires optimization of the vector to maximize durability and efficacy and to minimize potential adverse reactions. In the first year, the Pu lab identified novel capsid (MyoAAV) and promoter AAV candidates with increased TAFAZZIN expression in target tissues (i.e. heart, skeletal muscle) and lower expression in off-target tissues (e.g. liver, kidney).
In the second year of funding, and in collaboration with BSF staff and consultants, the Boston Children’s Hospital team intends to select a lead vector candidate and manufacture the first research grade batch of the gene therapy material. Plans include testing the material in a mouse model lacking tafazzin specifically in the heart and skeletal muscle (learn more about conditional knockout mice here) to identify the dose level and assess the impacts on heart and skeletal muscle function (i.e. efficacy).
The first year of funding was kindly supported in part by Barth Italia through a donation from Eurizon Capital.
Activating Pyruvate Dehydrogenase Complex to Improve Barth Syndrome Cardiac Function
Charles E. McCall, PhD, Professor, Wake Forest University Health Sciences
Development Award, $100,000 over two years
Awarded in 2021 to the multi-disciplinary team of Professors Charles McCall, Miriam Greenberg, Peter Stacpoole, and Boone Prentice, this Development Award will investigate the drug dichloroacetate‘s (DCA) impact on the heart-specific TAFAZZIN knockout mouse. Involving animal research at Wake Forest University (McCall), cellular and cardiolipin expertise from Wayne State University (Greenberg), and clinical experience and research tools via the University of Florida (Stacpoole & Prentice), this mouse project asks whether DCA can be repurposed as an investigational drug and potential therapy for Barth syndrome.
This project’s funding was made possible by the generous support of the Will McCurdy Fund for Advancement in Therapies for Barth Syndrome.
Mauro Corrado, PhD, University of Cologne
Idea Award, $50,000 over two years
Awarded to Dr. Mauro Corrado in 2021, this Idea Award builds upon novel findings that cardiolipin plays a key role in the development and function of T cells - immune cells that play a role in adaptive immunity. Utilizing mouse models, Dr. Corrado is focusing on the implications of impaired immune function and its impact on the health and function of mouse muscle cells. Given the immune issues faced by affected individuals, this effort has the potential to provide a more holistic view of immune dysfunction in Barth syndrome.
This project’s funding was made possible by the generous support of the Paula and Woody Varner Fund.
Surveying TAZ genetic interactions and mutational landscape in human cells
Jason Moffat, PhD, Professor, University of Toronto
Idea Award, $50,000 over one year
Awarded in 2021 to Prof. Jason Moffat and Prof. Charles Boone of the University of Toronto, this Idea Award enables us to better understand the TAFAZZIN gene, in and out. Inwardly, Dr. Moffat proposes to connect changes in gene sequences to their functional consequences on protein function. Known as deep mutational scanning, this effort has the potential to expand our understanding about gene variants in our community. Outwardly, via a CRISPR-mediated genome-wide screen, Dr. Moffat proposes to identify genes that interact with TAFAZZIN and recorded gene variants. By increasing our understanding of TAFAZZIN interactions as well as gene variants and mutations’ impact on tafazzin protein function, the research team seeks to identify insights into the variable manifestations, or phenotype, of Barth syndrome.
This project’s funding was made possible by generous contributions from our affiliates Barth Syndrome Foundation of Canada and the Barth Syndrome UK.
Stacey E. Reynolds, PhD, Assistant Professor, Virginia Commonwealth University
Idea Award, $50,000 over one year
Awarded to Associate Prof. Stacey Reynolds in 2021 and in collaboration with Assistant Prof. Virginia W. Chu of Virginia Commonwealth University, this Idea Award aims to capture the fatigue experienced and voiced by our affected individuals. Dr. Reynolds’s team will first conduct interviews with affected individuals, siblings, and parents to capture the impact of fatigue on daily living. Dr. Chu will then capture individuals’ self-assessment of fatigue in real-time using a novel phone application and map those ratings onto activity data collected by wrist-worn watches worn by affected individuals. This mixed-methods approach aims to qualify and quantify fatigue in our community and is in direct response to the narratives shared during BSF’s 2018 Patient Focused Drug Development meeting with the U.S. FDA.
This project’s funding was made possible by the generous support of the Will McCurdy Fund for Advancement in Therapies for Barth Syndrome.
Development of mitochondria-targeted peptide compounds as Barth syndrome therapeutics
Nathan Alder, PhD, Associate Professor, University of Connecticut, Storrs, CT
Award - $50,000 over 1-year period
Awarded to Associate Professor Nathan Alder of University of Connecticut, this project will first ask how Szeto-Schiller compounds impact mitochondrial function – of which elamipretide is a member. These findings will then allow Dr. Alder and his team to focus on developing Szeto-Schiller compounds tailored to treat Barth syndrome. The potential impact of this project stems from Dr. Alder’s ideal expertise in cell-free model systems, alongside our increasing knowledge of the safety and efficacy (or positive impact) of elamipretide in our affected individuals. This project’s funding was made possible by the generous support of the Will McCurdy Fund for Advancement in Therapies for Barth Syndrome.
Deuterated polyunsaturated fatty acids as protective therapy in the treatment of Barth syndrome
Catherine F. Clarke, PhD, Professor and Chair, University of California at Los Angeles, Los Angeles, CA (UCLA)
Award—US $100,000 over 2-year period
Barth syndrome is uniquely associated with a deficiency and alterations in cardiolipin, a phospholipid that is an important component of the inner mitochondrial membrane. This deficiency and alterations in cardiolipin result in damage to the cell. Providing a “disease-resistant” cardiolipin to increase and replace the usual molecules may be therapeutic for individuals with Barth syndrome.
To test this hypothesis, Dr. Catherine Clarke of UCLA will apply this unique therapeutic idea by using chemically modified lipids to reduce the amount of cellular damage produced by deficient and altered cardiolipin.
If this novel specific lipid-replacement therapy preserves mitochondrial function, it could protect cells against the oxidative stress conditions known to exist in people with Barth syndrome.
This grant is made possible by support from the Will McCurdy Fund for Advancement in Therapies for Barth Syndrome
Investigation of a new nutraceutical for treatment of Barth Syndrome
Robin E. Duncan, PhD, Associate Professor, University of Waterloo, Waterloo, ON, Canada
2020 Award - $41,580 over 2-year period
Awarded to Associate Professor Robin Duncan of University of Waterloo, this project will assess the therapeutic potential and activity of a nutraceutical (a possible supplement therapy that is available without prescription) in preserving the viability of Barth syndrome cells. Following up on early results that this nutraceutical has the ability to help Barth syndrome cells survive at the same levels as normal cells, Dr. Duncan and her team will try to understand what is the process that helps preserve these cells, and further expand her research into the Taz knockout (TAZKO) mouse model. As an early stage research effort (aka preclinical study), this research aims to provide the foundational understanding of this nutraceutical and its impact on Barth syndrome. This project’s funding was made possible by generous contributions from our affiliates Barth Syndrome Foundation of Canada and the Barth Syndrome UK.
Structural and Biophysical Studies of Tafazzin
Steven Glynn, Associate Professor, Stony Brook University, Stony Brook, NY
2020 Award - $50,000 over 2-year period
Awarded to Associate Professor Steven Glynn of Stony Brook University, whom is a trained crystallographer (someone who purifies and generates protein crystals for structural studies). Dr. Glynn will apply his experience towards purifying normal and variant versions of Taz from yeast. If successful, he will determine what normal Taz looks like and how variant versions look and function differently. This important discovery science project will shed light on how some of the TAZ variants we know of and track impact Taz activity. As every biochemistry student learns early on – protein structure dictates function. This project’s funding was made possible by a generous contribution from our affiliate Association Syndrome de Barth France.
Cardiolipin Requirement for Mitochondrial Calcium Import
Vishal Gohil, PhD, Associate Professor, Texas A&M University, College Station, TX
Award - $50,000 over 1-year period
Awarded to Associate Professor Vishal Gohil of Texas A&M University, this discovery science project aims to understand how levels of calcium, mature cardiolipin (CL), and energy generation play a role in Barth syndrome. By using the highly modifiable yeast system, Dr. Gohil will probe what happens with reduced levels of mature CL (which is what happens in Barth syndrome) and its subsequent impact on the amount of calcium inside and outside of the mitochondria. Studying this relationship may further shed light on why Barth syndrome mitochondria produce lower levels of energy.
Resolution of the underlying basis for the impaired oxidation of fatty acids in Barth syndrome
Riekelt Houtkooper, PhD, Professor, Amsterdam Medical Center, Amsterdam, The Netherlands
Award—US $50,000 over 1-year period
Barth syndrome is a unique mitochondrial disease. Another type of mitochondrial disease that has common attributes with Barth syndrome is fatty acid oxidation (FAO) disorders. This is a group of diseases that affect approximately 1 in 10,000 births making it 30 times more numerous than Barth syndrome.
Dr. Riekelt Houtkooper of Amsterdam Medical Center will investigate how closely Barth syndrome resembles fatty acid oxidation disorders. Dr. Jan Dudek of University Medical Center Würzburg will collaborate with Dr. Houtkooper’s group to study the relationship of fatty acid oxidation and heart failure as it relates to Barth syndrome.
These projects aim to explain why underlying defective mechanisms in Barth syndrome impair the body’s ability to use fatty acids properly. Similarly, researchers aim to resolve the cause for the diminished oxidation of fatty acids in Barth syndrome with the ultimate goal of informing novel therapeutic strategies.
This grant is made possible in part by support from Association Syndrome de Barth France
Prenatal cardiac phenotype as a platform for testing Barth syndrome therapies
Colin Phoon, MPhil, MD, Associate Professor, New York University School of Medicine, New York, NY
Award: US $70,000 over 2-year period
Partial funding for this award was provided by the Paula and Woody Varner Fund
Essential activities of Tafazzin that are independent of cardiolipin remodeling
William T. Pu, MD, Professor, Boston Children's Hospital, Boston, MA
Award - $50,000 over 1-year period
Awarded to Professor William Pu of Boston Children’s Hospital and a member of the BSF SMAB, this project aims to understand the functions of mouse tafazzin (Taz) beyond generating mature cardiolipin (CL). By utilizing the Taz knockout (TAZKO) mouse model, Dr. Pu and his team found that replacing the Taz gene with different versions (variants of Taz), resulted in different levels of rescue for the TAZKO mice. Using these variant Taz versions as bait for proteins that interact with Taz, Dr. Pu and his research team hope to identify what are the other proteins that work with Taz independent of its CL-modifying function.
