The aim of the research group working at the Istituto Superiore di Sanità in Rome is to understand the dysfunctional molecular mechanisms causing MLC disease. MLC is mainly due to mutations in MLC1, a protein highly expressed in the brain by a population of cells called astrocytes.
When MLC was discovered over 20 years ago, researchers, doctors and families knew very little about the disease. Since the disease wasn’t yet connected to genetics, diagnosis was only possible when experts recognized brain MRIs and the clinical symptoms. Since 1996, major advancements in MLC research have shown that MLC is caused by mutations in two different genes: MLC1 and GlialCAM, allowing for easier diagnosis. Multiple animal models have been developed and tested to improve our understanding of the disease. However, there is much to be done before treatments can be fully developed and brought to clinical trials.
Next steps include conducting long-term clinical studies on the disease progression, understanding the exact function of the MLC1 and GlialCAM proteins, uncovering how this disease alters normal brain function, and then using this knowledge to develop and test therapies. The good news is that there are many researchers working to solve these problems globally and real progress is being made. Alliance MLC is in communication with the researchers and ensures that they stay connected with each other, as well as with physicians and MLC families.
HISTORICAL RESEARCH OVERVIEW
AAV vector = AAV stands for adeno-associated virus. It is a virus commonly used in gene therapy to deliver the healthy gene to the correct tissue or cell type in the body.
Astrocytes = a type of brain cell that performs many important functions including providing energy and support to neurons, responding to injury and regulating the balance of ions and water
Astrocytic vascular contacts = the site where astrocytes connect to the blood vessels in the brain
Astrocytoma cell line = astrocytomas are a type of brain tumor that begin in cells called astrocytes. These cells can be removed from the tumor and cultured as an immortal human cell line. Since access to human brain cells is rare and unethical to procure, these are often used to study human astrocyte function and diseases affecting these cells, such as MLC.
Biomarkers = a measurable indicator found in the body that can be used to assess disease progression or how the body responds to a treatment
Cell membrane = also known as the plasma membrane, is a thin layer that surrounds the exterior of a cell, creating a barrier that controls what enters and exits the cell
Cellular morphology = the physical appearance and shape of cells
Cellular motility = the ability of cells to move or change positions
Gene expression = genes can be turned ‘on’ or ‘off’ in the body. It’s expression is a measurement of how much turned on or off it is.
Gene therapy = a medical approach that modifies an individual’s genes to treat or cure a disease
Cerebellum = a section of the brain located at the back of the head. Its main function is to maintain motor balance and coordination.
Glia cells = also known as glial cells or just glia, are a type of support cell in the nervous system. There are several types of glia cells including astrocytes, the cell type of interest in MLC1
Differentiation = the process of turning a stem cell into a different specialized cell type
Histopathological = studying diseased tissue using a microscope
In vivo = the Latin word for living. Refers to work done in a living organism.
Induced pluripotent stem cells = stem cells that can be differentiated into any cell type in order to study a disease in the most relevant cell. These are created by taking skin or blood samples from an individual and ‘reprogramming’ them back to a stem cell.
Intronic mutation = during the production of a protein, the body must first read the DNA of the gene and copy it into a form (mRNA) that can be translated into a protein. This gene includes sections called introns and exons. Exons are the parts of the genes that become proteins, while introns are ‘cut out’ of the gene before it is translated to the protein. Intronic mutations are mutations in the intron. Most mutations occur in exons since it is the part of the gene that is directly read by the body to become protein. However, in some cases introns can contain mutations that cause disease.
Knockout mice = mice that have been engineered to have little or no expression of a specific gene. This is done in order to study the effect of a particular gene on an organism or to approximate a human disease in a mouse model.
Murine models = rat and mouse models, used as an animal model to study the disease
Myelin vacuolation = a characteristic finding in MLC where the layers of the myelin sheath are separated from each other
Pathogenesis = the pathology or pathogenesis of a disease is the way that a disease develops, often referred to as the disease mechanisms.
Pharmacological treatments = the treatment of a disease using medication/drugs
Preclinical = research occurring before clinical testing in humans, investigations to determine if a therapy (e.g. drug, procedure, treatment) will be useful to treat the disease
Prenatal molecular diagnosis = diagnosis diseases and disorders in a fetus (unborn baby)
Reprogramming = the process of turning a specialized cell back into a stem cell
Splice site mutation = during the production of a protein, the body must first read the DNA of the gene and copy it into a form (mRNA) that can be translated into a protein. This gene includes sections called introns and exons. Exons are the parts of the genes that become proteins, while introns are ‘cut out’ of the gene before it is translated to the protein. The process of cutting out the introns and ‘pasting’ together the exons is called splicing. A splice site mutation is when the DNA has a mutation in the region where this ‘cutting and pasting’ occurs. This can affect the ability of the body to properly ‘paste’ the sequence of the protein together, thereby impacting the structure of the protein.
Transport membrane protein = a type of protein found at the membrane of the cell which is involved in moving molecules into and out of the cell
Vascular system = also called the circulatory system. This is the system of arteries and veins that carries blood through the body delivering oxygen and nutrients to different tissues.
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Meet the Researchers
Assumpció Bosch, full professor in Biochemistry and Molecular Biology, is working at the Institute of Neurosciences at the Universitat Autònoma de Barcelona (UAB), in Spain. She has more than 25 years of experience in the characterization of murine models of disease and in preclinical gene therapy studies for rare disorders involving the nervous system.
Binbin Cao is a pediatric neurologist at Xi’an Jiaotong University. In 2005, her team was the first to begin studying Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC) in China. Their focus included researching clinical and genetic features and the pathogenic mechanism of the disease.
The laboratory of Dr. Cohen-Salmon is located in the Centre interdisciplinaire de Recherche en Biologie (CIRB) Collège de France in Paris. They are a fundamental neurobiology laboratory focusing on the role of specific cells of the brain: the astrocytes. These cells have the unique property to contact and regulate the vascular system in the brain and she studies these specific regulations.
Raúl Estévez, full professor in Physiology, is working at the Faculty of Medicine and Health Sciences in the University of Barcelona (UB)/Institute of Neuroscience and IDIBELL, belonging also to CIBERER, a network of Spanish groups working in rare diseases. He started to work in Megalencephalic Leukoencephalopathy with subcortical cysts (MLC) 20 years ago.
Studying MLC has been a focus of researchers at the Amsterdam Leukodystrophy Center (ALC) for the past 30 years. The ALC is headed by Prof. Marjo van der Knaap, child neurologist and world leading expert on leukodystrophies. She saw her first MLC patient in 1991 and has studied the disease since then.
Hyun-Ho Lim, Ph.D. is a Principal Investigator of the Korea Brain Research Institute (KBRI). Dr. Lim received his Ph.D. in Molecular Neurobiology in 2005 from Gwangju Institute of Science and Technology.
Rogier is a cell biologist trained in electrophysiology and advanced live cell imaging. By combining studies on cell physiology with insights from the clinic, the ALC team aims to better understand disease mechanisms and identify therapeutic opportunities. Ultimately, the aim of these laboratory studies is to help develop the urgently needed MLC therapy and bring it to the clinic.
Kenji Tanaka, full professor in Neurochemistry, is working at Institute for Advanced Medical Research, Keio University School of Medicine in Japan. He has been conducting glial cell research for more than 20 years and has been working on several leukodystrophy mouse models since 2003.
Dr. Wang is a Professor of Pediatrics at Peking University First Hospital. In 2005, Dr. Dr. Wang along with Dr. Binbin Cao and her team were the first to begin studying Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC) in China. Their focus included researching clinical and genetic features and the pathogenic mechanism of the disease.
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