Exploring the effectiveness of novel treatment targeting myelination deficits on Williams Syndrome clinical symptoms

Outline

Williams syndrome (WS) is a neurodevelopmental disorder caused by a heterozygous microdeletion in chromosome 7q11.23. WS is characterized by hypersociability1, increased rates of anxiety disorders and attention-deficit hyperactivity disorder (ADHD), neurocognitive deficits, fine and gross motor abnormalities, and other medical comorbidities including cardiovascular anomalies and neonatal hypocalcemia1-4.

Unmet Need

Unfortunately, currently there is no specific pharmacological treatment for individuals with WS. Therefore, treatments in WS are symptomatic3 as there are no treatments that target the pathophysiological pathways.

Our Solution 

We recently discovered a novel pathophysiological mechanism involved in multi-faceted myelination deficits in brain tissue from WS patients and mouse model for WS5. These deficits include reduced expression of myelin-related transcripts, myelinating oligodendrocyte cell numbers, myelin thickness and axonal conductivity5. Of special interest and therapeutic relevance, restoring myelination properties in mouse model for WS with the FDA-approved drug clemastine (clinically used to treat multiple sclerosis, which is another myelin deficiency-related neurological condition) rescued the cellular, structural and behavioral deficits5. Overall, our findings demonstrate that restoring myelin properties in mouse model for WS is sufficient to ameliorate key deficits associated with WS5, suggesting an exciting and novel drug treatment for WS patients worldwide.

Differentiation

The current "Gold Standard" treatment for WS include only symptomatic treatment, without treating the basic pathophysiological pathways underlying WS phenotypes. Clemastine is an FDA-approved drug, clinically used to treat multiple sclerosis, that enhances oligodendrocytes precursor cells (OPCs) maturation5,6, therefore dealing with the primary cause of the neuropathology and improving myelination properties. By treating the cause of the myelin deficits that we characterized in individuals with WS and mouse models5, which is lack of OPC maturation into myelinating oligodendrocytes in WS, we hope we can suggest a new pharmacological treatment for individuals with WS, a treatment that is focused on improved myelination.

In addition, other patients suffering from neurological conditions which are characterized by myelination deficits can also gain from our proposed project, by adding knowledge to the understanding of myelination deficits mechanisms and treatment. The synergistic cooperation with Prof. Doron Gothelf from Sheba Medical Center, the director of the clinic that coordinates research and treatment of individuals with WS from all over Israel, put us in an advantageous position to successfully implement this translational clinical study.

To our knowledge, we are pioneers in the field of myelination deficits understanding in WS5, suggesting a solution to the primary cause of the neuropathology by enhancing OPCs maturation. Our approach, aimed to reduce physical, behavioral and cognitive deficits of individuals with WS by improving myelination properties, is a unique approach which was never tested before with this population.

Intellectual Property

Boaz Barak is the first researcher on a list of researchers that applied a patent application, currently under process in the United States for more than a year already.

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