ALD Connect

Emerging Investigators

Our Emerging Investigator program is dedicated to engaging the next generation of researchers in the field of ALD. Applicants present their research proposals to a panel of our ALD experts, ensuring that only the most promising projects are selected. Emerging Investigators present updates on their research at our Annual Meeting and Patient Learning Academy. By providing funding and opportunities for continued learning, mentorship, and hands-on experience, the program aims to inspire and equip young scientists with the tools and knowledge needed to advance ALD research. This initiative is crucial for accelerating progress in understanding and treating ALD, as it nurtures fresh perspectives and innovative approaches.

2024 Emerging Investigators

Project: Investigating the Effect of ALD Microglia on Neural Network Maintenance and Function Using Multi-Electrode Arrays (PI: Kemp)

The brain has its own immune cells called microglia. These cells are thought to play a critical role in the development and progression of ALD. They are also important for the success of stem cell transplants. In addition to protecting the brain, microglia are important for keeping the brain’s communication networks healthy. The focus of this project will be to investigate how microglia affected by ALD affect these communication networks over time. This will be done by using a new laboratory technique to grow both microglia and brain cells from induced pluripotent stem cells derived from skin cells of ALD patients. We’ll then measure different aspects of how the brain networks are maintained and function. This project aims to provide important insights into the role of microglia in ALD and to improve the understanding of ALD pathology.

Nicki Covena

Nicki F. Coveña obtained a Bachelor of Science in Psychobiology, with a specialization in the molecular basis of neurodegenerative diseases. He then obtained a Master of Science in Molecular Neuroscience, where he gained extensive experience with a variety of cell culture models and molecular techniques. He is currently a PhD candidate at the Amsterdam UMC, where his research uses human induced pluripotent stem cell-derived models to investigate the complex role of microglia in ALD. Through his work, Nicki aims to advance and contribute to the molecular understanding of ALD pathology.

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2024 Emerging Investigators

Project: Studying Microvascular Dysfunction in Plasma and MRI as Biomarkers early Cerebral Adrenoleukodystrophy and Response to Treatments (PI: Musolino) 

Despite gene therapy(GT) and hematopoietic stem-cell transplantation(HSCT), the current approved treatments for cerebral adrenoleukodystrophy(cALD), delays in diagnosis result in fewer than 20% of affected boys being eligible for treatment. Current diagnosis relies on early lesion detection through MRI, which is performed every six months. However, this approach not only exposes children to frequent anesthesia, but also places them at risk of missing the optimal therapeutic window. Previous works have indicated that microvascular dysfunction on perfusion MRI precedes blood-brain-barrier(BBB) disruption, which has been identified as key in cALD pathogenesis. Plasma markers of vascular dysfunction could, therefore, identify early BBB dysfunction, predict cALD lesion onset and become biomarkers to track response to treatments. In this project, we will correlate cALD lesion progression and microvascular MR perfusion parameters with a set of angiogenesis and neurodegeneration plasma biomarkers in the world’s largest cohort of pediatric ALD patients, composed of patients with ALD-without cALD, untreated cALD and cALD treated with HSCT and GT. By identifying early cALD biomarker candidates, we will be able to stratify risk for cALD in a non-invasive and more accessible manner in asymptomatic patients, particularly newborns who are now nationally tested for cALD at birth. This will pave the way towards early identification of cALD, timely access to HSCT or GT, and potential discovery of new therapeutic targets.

Maria L.G.A. Seixas

Maria L.G.A. Seixas is a medical student and research intern at the Center for Genomic Medicine – Massachusetts General Hospital, Harvard Medical School. Born in Brazil, she was among the top 0.05% of 45,000 applicants selected for the prestigious Líderes – Fundação Estudar scholarship, part of the largest leadership program in the country, that brought her to Dr. Patricia Musolino’s lab, where she now conducts research on the investigation of plasma biomarkers and brain imaging for early cerebral adrenoleukodystrophy detection. At her university in Brazil, she established the first business-academic partnership in medical research and now dreams of transforming the lives of patients with (c)ALD through translational medicine.

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2024 Emerging Investigators

Project: Generating Isogenic ABCD1-edited Induced Pluripotent Stem Cells to Model Neuroinflammation in X-ALD (PI: Weinhofer)

A primary limitation in understanding the mechanisms acting in X-ALD is the lack of easily accessible and reproducible pre-clinical models involving human brain cells. Human stem cells can generate different brain cell types, offering a new possibility to study disease mechanisms and responses to treatment. This project focuses on generating human stem cells with identical genetic background but lacking or having a functional ABCD1 protein. This enables us to study how ABCD1 dysfunction impacts different brain cell types, their interaction, and their response to inflammatory triggers. In the future, identifying the most affected brain cell type and their altered responses in X-ALD could benefit the development of novel targeted treatment strategies.

 

Andrea Villoria-Gonzalez

Andrea Villoria-González graduated in Biochemistry from the Autonomous University of Barcelona in Spain and continued her master’s studies in Drug Discovery and Development at the University of Vienna in Austria. Her interest in metabolic rare disorders and the discovery of novel treatment strategies led her to join the research on X-ALD in the laboratory of Prof. Dr Isabelle Weinhofer at the Medical University of Vienna during her master’s thesis. She continues her research as part of her PhD studies, driving projects targeting the role of lipid metabolism in neuroinflammatory conditions such as cerebral ALD, where she uses human induced pluripotent stem cells to generate in vitro brain cell models.

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2024 Emerging Investigators

Project: Myelin Catabolism in Adrenoleuko­dystrophy (PI: Fatemi) 

One major unanswered question in the field is why the mouse model of ALD does not develop the classic symptoms of human childhood cerebral ALD including leukodystrophy or demyelination of the brain. Similarly, it is unclear how myelin lipids drive neuroinflammation in macrophages that lack the peroxisomal protein ALDP. This study aims to address these questions by studying the lipid composition of purified myelin from the mouse model of ALD and human patients with childhood cerebral ALD. This myelin will then be “fed” to macrophages, to study the ability of these cells to degrade the myelin lipids and explore how inflammation happens. We believe these studies will help us better understand ALD, and will allow us to develop better models and therapies for ALD in the future.

 

Nadav Weinstock, MD, PhD

Dr. Nadav Weinstock is a 4th year combined pediatrics and medical genetics resident at Johns Hopkins School of Medicine, planning to pursue a medical biochemical genetics fellowship next year. He is interested in neurometabolic disorders, with specific interests in leukodystrophies and lysosomal storage disorders. He completed his combined MD and PhD degrees at the Jacobs School of Medicine and Biomedical Sciences (University at Buffalo). His PhD thesis work was in neuroscience under Dr. Laura Feltri, where he studied the pathogenesis of Globoid Cell Leukodystrophy (Krabbe disease) using mouse models. He is currently supported as a T32 postdoctoral research fellow in the laboratory of Dr. Ali Fatemi (Kennedy Krieger Institute), where he studies adrenoleukodystrophy.

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2023 Emerging Investigators

  • Manouchehr Amanat, MD, MPH: Antisense Oligonucleotide Therapy in X-linked Adrenoleukodystrophy
  • Yorrick R.J. Jaspers: Lipidomic Fingerprinting of X-linked Adrenoleukodystrophy Bloodspots
  • Courtney Demmitt-Rice: Transcriptomic and Lipidomic Signatures in ALD

Manouchehr Amanat, MD, MPH

Bio

Dr. Manouchehr Amanat is currently working as post-doctoral research fellow at Kennedy Krieger Institute and Johns Hopkins Medical Institute. He achieved his Medical Doctorate degree from Tehran University of Medical Sciences in Tehran, Iran. He is developing novel RNA therapeutic agents such as antisense oligonucleotides in neurodevelopmental disorders. He is skilled at cell culture and growing induced pluripotent stem cells, advanced statistical methods and machine learning models using Python, and designing clinical trials.

Project: Antisense Oligonucleotide Therapy in X-linked Adrenoleukodystrophy

This project focuses on the application of antisense oligonucleotide therapy in the context of X-linked adrenoleukodystrophy (X-ALD). The primary objective of this research is to elevate the expression of the ABCD2-related protein as a compensatory mechanism for the deficiency of functional ABCD1-related protein in X-ALD patients. To achieve this, we have designed specific ASOs at Kennedy Krieger Institute to directly target ABCD2 mRNA to enhance protein expression. The experimental approach involves culturing fibroblasts derived from X-ALD patients, introducing ASOs, and subsequently quantifying the levels of ABCD2 mRNA and very long-chain fatty acids. A similar methodology will be applied to microglia cells derived from induced pluripotent stem cells. Ultimately, this project represents a significant step towards addressing the challenges posed by X-ALD.

Yorrick R.J. Jaspers

Bio

Yorrick R.J. Jaspers earned his Bachelor of Science in Chemistry from Leiden University and a Master of Science in Analytical Chemistry from the University of Amsterdam. Currently, Yorrick is in the final stages of completing his PhD at the Amsterdam University Medical Centra, where his research primarily revolves around advancing the field of lipidomics. His work focuses on developing and applying innovative lipidomics techniques to better understand and characterize metabolic disorders.

Project: Lipidomic Fingerprinting of X-linked Adrenoleukodystrophy Bloodspots

Newborn screening has significantly improved ALD diagnosis, but it has also led to the identification of genetic variants of unknown significance (VUS), which pose diagnostic challenges as we don’t know if they cause the disease. Our project seeks to address this issue by using a specialized technique called lipidomics to create unique biochemical profiles (fingerprints) of ALD in bloodspot samples. Using bloodspot samples offers several advantages, including non-invasive collection through a simple finger prick, making it suitable for newborns and infants. It can also be done at home or at local healthcare facilities and is easily transportable via regular mail, thereby mitigating logistical hurdles and reducing associated costs compared to other sample types. We will analyze bloodspot samples from ALD patients and healthy individuals, using a state-of-the-art mass spectrometer. This instrument allows us to rapidly analyze a wide range of lipids in the bloodspot samples. By comparing the lipid profiles of known ALD cases with those of VUS, we hope to gain insights into the potential disease-causing effects of specific genetic variants.

Courtney Demmitt-Rice

Bio

Courtney graduated with a BS in Biotechnology and did environmental toxicology research with honeybees prior to joining Dr. Josh Bonkowsky’s lab as a Neurobiology PhD student. Courtney enjoys being outdoors with her family, arranging flowers, gardening, and carpentry. Her youngest child has a rare leukodystrophy – this has fueled Courtney’s interest in clinical translational research and she looks forward to contributing to the rare disease community as both a caregiver and researcher.

Project: Transcriptomic and Lipidomic Signatures in ALD

Our project studies how ABCD1 mutations affect gene expression (transcriptomics) and metabolism of lipids and fats (lipidomics). We have two goals: first, to understand how these changes cause ALD disease pathology, especially of cerebral ALD, where the molecular change is poorly understood. Second, with the information from the “omics”, we will test a potential new therapy identified from a large zebrafish drug screen.

2022 Emerging Investigators

  • Chenxu Li: Nervonic Acid-A Potential Therapeutic Targeting Mitochondrial Dysfunction and Cellular Oxidative Stress
  • April Rickle: Testing the impact of the drug leriglitazone in a fruit fly model of ALD
  • Hemmo Yska: Attitudes of patients towards sex-specific ALD newborn screening

Chenxu Li

Bio

Chenxu Li is currently a PhD student from the Department of Experimental and Clinical Pharmacology at the University of Minnesota Twin Cities. Chenxu earned her BS degree in Pharmaceutical Analysis from Shenyang Pharmaceutical University in 2019. Upon graduation, she continued research as a graduate student and earned her MS degree in Pharmaceutics from the University of Minnesota in 2021. Soon after, she began investigating novel therapies for adrenoleukodystrophy as a PhD student under the supervision of Dr. Reena Kartha.

Project: Nervonic Acid-A Potential Therapeutic Targeting Mitochondrial Dysfunction and Cellular Oxidative Stress

Mutations in the adrenoleukodystrophy (ALD) protein result in the accumulation of very long chain fatty acids (VLCFAs), which in turn causes the elevation of harmful substances including reactive oxygen species. This can also further damage other cellular components such as the mitochondria, the energy source of the cells. Chenxu’s research mainly focuses on developing novel therapies for ALD, specifically targeting the effect of these toxic chemicals on mitochondria. She will investigate the mechanism of Nervonic Acid (NA), a dietary fatty acid, that can arrest or delay disease progression in ALD. By treating cells derived from patients with ALD using NA, this study will investigate how NA can mitigate the toxic chemicals and positively affect energy production in cells. Her hope is to develop NA as a safe and effective dietary intervention that can benefit all individuals with ALD.

April Rickle

Bio

April Rickle was born and raised in New Jersey. She attended Rutgers University- New Brunswick for her undergraduate studies where she worked in the Vershon lab studying Sir2 protein cofactor interactions in baker’s yeast. April graduated in 2019 with a BA in Molecular Biology and Biochemistry and joined Van Andel Institute Graduate School for her doctoral studies. There, she joined the Lempradl lab and began her work studying ALD via a fruit fly model of the disease. She hopes to continue researching rare diseases throughout her career. In her spare time, April enjoys spending time with her cats, crafting, and baking.

Project: Testing the impact of the drug leriglitazone in a fruit fly model of ALD

Leriglitazone (MIN-102) is the lead candidate in Minoryx’s pipeline. It is a promising new compound for the treatment of ALD. Previous research has been done in cell culture, mice, and in a clinical trial, but we do not fully understand how it affects the brain. We will treat a fruit fly model of ALD with leriglitazone and test how it affects movement and behavior; brain tissue degeneration; metabolism; and gene expression. By testing the effects of leriglitazone on our ALD model flies and comparing to our healthy flies, we can determine which aspects of disease leriglitazone treats and how it affects them. In addition, examining these factors in healthy and untreated ALD model flies will give us insight to the molecular mechanisms behind ALD overall. Doing this research will give us a better understanding of how leriglitazone treats ALD, as well as how ALD works in a broader sense.

Hemmo Yska

Bio

Hemmo Yska is a PhD candidate at the Amsterdam University Medical Centers in the Netherlands. After becoming a medical doctor, he worked as a resident in pediatrics. Due to his interest in scientific research and (pediatric) neurology, he decided to pursue a PhD where he (mainly) focuses on clinical research in the field of ALD and other leukodystrophies. Currently, together with the other members of the Dutch ALD group, he is involved in a number of projects that, for example, focus on the addition of ALD to the newborn screening and the identification of surrogate outcomes for spinal cord disease.

Project: Attitudes of patients towards sex-specific ALD newborn screening

Males with X-linked adrenoleukodystrophy (ALD) are at risk for developing adrenal insufficiency and/or progressive leukodystrophy (cerebral ALD) at an early age. Newborn screening (NBS) for ALD enables pre-symptomatic monitoring and therapeutic intervention, thereby preventing irreversible damage and saving lives. ALD has been included in NBS programs in more than 25 US states and several European countries are considering its addition. As girls are not at risk for developing the childhood cerebral form of ALD, some countries are reluctant to screen them for ALD. Sex-specific screening has not yet been implemented in newborn screening and there is limited scientific data regarding the attitude of patients to screening males only. In order to make a well-informed decision it is important to understand the attitudes of all groups and stakeholders that are involved in the disease. Therefore, a group that cannot be overlooked is the ALD patients themselves. Patients and their direct relatives can provide valuable insights on matters such as sex-specific screening and the potential burden of knowledge of a late-onset disease. With our study, we would like to learn whether ALD patients feel that boys only, both boys and girls or neither should be screened for the disease. In order to investigate this, we will send out a questionnaire to members of “the Dutch ALD cohort” and their relatives. The results will be of importance to all countries that are considering the addition of ALD to their NBS.

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