The Musolino Laboratory at the Center for Genomic Medicine at Massachusetts General Hospital and Harvard Medical School is a translational neuroscience laboratory focusing on developing gene targeted therapies for inherited inborn errors of metabolism and cerebrovascular disorders that lead to stroke and leukodystrophy. Dr. Patricia Musolino leads a team of scientists working on therapeutic treatments for five different diseases at the bench and clinical coordinators supporting patients and families at the clinic. Our research team is a small but growing group of researchers eager to push forward the science necessary to treat patients who are affected by these rare neurological diseases.

1. Gene Therapy and Editing for Smooth Muscle Dysfunction Syndrome. Smooth Muscle Dysfunction Syndrome is a rare disease with less than 50 known cases worldwide. It is caused by a specific genetic mutation in the ACTA2 gene that affects smooth muscle cells. Smooth muscle cells are found in many different organs in the body. These include the large blood vessels that carry blood around the body (aorta), brain blood vessels, lungs, eye pupil muscles, gut, bladder and even the womb in women. Patients experience repeated strokes, aorta dissections, respiratory issues and progressive neurological disability. The Musolino lab and collaborators are currently working on a multi-faceted approach to provide patients with a functional copy of the ACTA2 gene. This work involves extensive characterization of disease models as well as optimizing gene targeted therapy administration.
2. Gene Therapy Development for Generalized Arterial Calcification of Infancy. Generalized arterial calcification of infancy (GACI) is characterized by widespread arterial calcification and/or stenoses of large and medium-sized vessels resulting in a range of clinical manifestations including myocardial infarction, respiratory distress, hypertension, cardiomegaly, and stroke. GACI is estimated to affect one in 200,000 pregnancies. Mortality is particularly high in early infancy; approximately 55% of patients die within the first 6 months of life despite intensive care and supportive measures. Currently, there are no approved therapies for these rare disorders of ectopic calcification, including GACI. The Musolino lab and collaborators are currently working on pre-clinical studies to optimize a gene targeted therapy to deliver a functional copy of the ENPP1 gene. This optimization includes novel targeting techniques including optimization of size and components such as promoters and signaling sequences.
3. Gene Therapy Development for Molybdenum Cofactor Deficiency and Sulfite Metabolism Disorders. Molybdenum Cofactor Deficiency (MoCD) is a genetic, neurodegenerative condition of the neonatal period characterized by encephalopathy, catastrophic brain atrophy, and severe neurological disability. Patients typically present in the first days of life with seizures, feeding difficulties, hyperekplexia, high pitched cries, and abnormal muscle tone. MoCD is estimated to affect one in 200,000 newborns globally. Mortality is particularly high in early childhood; approximately 55% of patients die within the first 3 years of life and the median survival rate is 3 years. This project offers a unique approach to targeted gene therapies as the mutated MOCS1 gene is a bicistronic gene that encodes two separate proteins that join to form a complex. This involves an understanding of the complex splicing and localization of each of the two MOCS1 proteins. Our work also brings extensive knowledge to the characterization of the mouse model and novel use of an optimized endogenous MOCS1 cDNA.
4. Developing a targeted approach to treating x-linked ALD. X-linked adrenoleukodystrophy (ALD) is a devastating neurologic disorder caused by mutations in the ATP binding cassette subfamily D member 1 (ABCD1) gene, a half transporter responsible for the import of very long chain fatty acids (VLCFA) into peroxisomes. Hemizygote males develop normally but up to 60% will develop an inflammatory demyelinating disorder called cerebral ALD (cALD) that leads to incapacitation or death within 2-3 years. To address this critical knowledge gap, the Musolino lab used a novel ex-vivo ALD BBB model system consisting of cultured human brain microvascular endothelial cells and showed that loss of ABCD1 expression alters tight junction permeability and facilitates leukocyte extravasation. We continue to use disease models to identify molecular pathways involved in tight-junction regulation and endothelial-leukocytes permeability. Overall, our goal is to produce a less toxic and more targeted approach which is urgently needed to treat children in the pre-symptomatic stage, especially now that newborn screening for ALD is being implemented across the US.