The PCDH19 Alliance is a registered non-profit by the Internal Revenue Service under Section 501 (c)(3). We are 100% volunteer run. All the funds we raise go directly to funding research, supporting families, raising awareness, and finding a cure.

Copyright 2019 PCDH19 Alliance

926 A #212 Diablo Ave, Novato, CA 94947

EIN: 45-4020102

July 15, 2019

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Alliance-Funded Research

Thanks to your generous donations we are proud to invest in the most promising PCDH19 Research around the world. These research teams are currently focused on understanding why mutations in the PCDH19 gene can cause epilepsy, autism and other co-morbidities of PCDH19 Epilepsy.
Exploring proof of concept for genetic therapy in PCHD19        preclinical models
Paul Thomas, PhD and Stefka M Tasheva, PhD - 2019
“Changes in a brain gene called PCDH19 are a relatively common cause of epilepsy with and without intellectual disability. There is no current cure for the disorder and approximately half of the patients do not respond to  anti-epileptic drugs. The aim of this project is to investigate the possibilities for using gene therapy to treat the disease. To this end, we have developed a unique Pcdh19 mouse model that mimics the genetic changes that cause epilepsy. Using this pre-clinical model we will identify when pathological changes first occur in the brain of the affected females. Importantly, we will also determine whether the   pathological lesion is reversible and, if so, the latest developmental time point by which genetic intervention must occur. These experiments will provide unique insight into PCDH19 pathology and demonstrate for the first time whether it might be possible to cure PCDH19-GCE using genetic intervention.”
Modeling PCDH19-Related Epilepsy in human iPSC derived neurons and cerebral organoids
Jack Parent, MD and Wei Niu, PhD - 2018
“PCDH19-Related Epilepsy (PRE) is caused by mutations in the PCDH19 gene located on the X-chromosome. How PCDH19 mutations result in epilepsy is poorly understood, as is the function of PCDH19 during human brain development. We use human pluripotent stem cells obtained by reprogramming patient skin cells or by CRISPR gene editing to generate brain cells that model PRE in cell culture. The studies described in this grant will take advantage of state-of-the-art stem cell approaches, including growing 3D “mini-brains” (cerebral organoids) in a dish, to determine the function of PCDH19 and how its mutations lead to seizure-like activity. Progress in our studies will help to identify PRE-related abnormalities in brain development and seizure mechanisms that should lead to novel therapies.”
PCDH19: Proteolytic processing and gene regulatory function
Isabel Martinez Garay, PhD - 2017
“Girls with changes in PCDH19 develop epilepsy and, in many cases, cognitive impairment. We still do not know much about the roles of PCDH19 in the brain, possibly because this protein might have more than one function. As an adhesion protein, PCDH19 expressed at the cell surface helps cells to recognize and establish contacts with other cells. But PCDH19 can also influence gene expression. Because these functions take place in two different locations within the cell (membrane and nucleus), it is important to understand how PCDH19 fulfills these two roles and how they are regulated. In this project, we will use mouse embryonic stem cells to investigate if different cellular “scissors” cut PCDH19 at the cell membrane. This could release a fragment that is then shipped to the nucleus to regulate gene expression. We will also determine the genes that are turned on or off by PCDH19 in neuronal progenitors and neurons. These experiments will increase our knowledge about the basic biology of PCDH19, an essential step to understand why lack of PCDH19 in a subset of cells has such detrimental effects.”
Identifying the pathological mechanism of PCDH19 Epilepsy
Paul Thomas PhD - 2016
“Changes in the PCDH19 gene cause epilepsy and, in some cases, intellectual disability. An unusual and poorly understood feature of PCDH19-associated epilepsy is that it only affects girls. To investigate the underlying cause of PCDH19 associated epilepsy, we have developed Pcdh19 mouse models that mimic the genetic changes that cause epilepsy in girls and allow us to identify neurons in which the PCDH19 gene is active. We have recently found that PCDH19 is active in a subset of neurons that are responsible for “dampening down” electrical activity in the brain. We have also shown that changes in the Pcdh19 gene in female mice affect neuron connections. The aim of this project is to further investigate these preliminary results through detailed analysis of brain development and function in our mouse models. We will also begin to translate our research findings into a clinical context by looking for subtle changes in brain structure in affected girls. These experiments will lead to greater understanding of how changes in PCDH19 cause epilepsy in girls and facilitate the development of new treatments.”
Using IPS cells to understand PCDH19-related encephalopathy
Dr  Sergiu Pasca - 2016
 
“PCDH19 is a severe disease characterized by onset of epileptic seizures in infancy, intellectual disability and autism. The condition is caused by mutations in the PCDH19 gene present on X chromosome. PCDH19 codes for the protein protocadherin-19. Protocadherins are cell adhesion molecules involved in establishing connections between neurons. Our preliminary findings suggest that protocadherin-19 regulates the trafficking of GABA(A)Rs to synapses. GABA(A)Rs mediate fast inhibitory transmission in the brain. If GABA(A)R presence at synapses is affected, the correct balance between inhibition and stimulation of neurons is upset, possibly giving rise to epilepsy and disorders of neurodevelopment. However details of PCDH19’s function in brain are largely unknown. We propose to investigate the role of PCDH19 in mammalian neurons and neuronal circuits, by working both with cultured neurons and with animal models in which PCDH19 has been mutated in a subset of brain cells. Our study will help us better understanding how the mutation gives rise to dysfunction at the synapse, in the neuron, and in neuronal circuits, in order to guide the future development of treatments for the disease.”
In Vivo Investigation of the Cellular Interference Model Using Unique PCDH19 Mouse Model and Brain Tissue from a PCDH19 Affected Female
Jozef Gecz PhD and Paul Thomas PhD - 2015
 
“Changes in the PCDH19 gene cause epilepsy and, in some cases, intellectual disability. An unusual and poorly understood feature of PCDH19-associated epilepsy is that it only affects girls. To investigate the underlying cause of PCDH19-associated epilepsy, we have developed Pcdh19 mouse models that mimic the genetic changes that cause epilepsy in girls and allow us to identify neurons in which the PCDH19 gene is active. We have recently found that PCDH19 is active in a subset of neurons that are responsible for “dampening down” electrical activity in the brain. We have also shown that changes in the Pcdh19 gene in female mice affect neuron connections. The aim of this project is to further investigate these preliminary results through detailed analysis of brain development and function in our mouse models. We will also begin to translate our research findings into a clinical context through analysis of a brain sample from an affected female. These experiments will lead to greater understanding of how changes in PCDH19 cause epilepsy in girls and facilitate the development of new treatments.”
Unraveling the Molecular Mechanisms of PCDH19 in Cultured Neurons and in PCDH19 KO Mouse Model
Maria Passafaro PhD - 2015
 
“PCDH19 is a severe disease characterized by onset of epileptic seizures in infancy, intellectual disability and autism. The condition is caused by mutations in the PCDH19 gene present on X chromosome. PCDH19 codes for the protein protocadherin-19. Protocadherins are cell adhesion molecules involved in establishing connections between neurons. Our preliminary findings suggest that protocadherin-19 regulates the trafficking of GABA(A)Rs to synapses. GABA(A)Rs mediate fast inhibitory transmission in the brain. If GABA(A)R presence at synapses is affected, the correct balance between inhibition and stimulation of neurons is upset, possibly giving rise to epilepsy and disorders of neurodevelopment. However details of PCDH19’s function in brain are largely unknown. We propose to investigate the role of PCDH19 in mammalian neurons and neuronal circuits, by working both with cultured neurons and with animal models in which PCDH19 has been mutated in a subset of brain cells. Our study will help us better understanding how the mutation gives rise to dysfunction at the synapse, in the neuron, and in neuronal circuits, in order to guide the future development of treatments for the disease.”
The PCDH19 Registry 2014-2015
Researchers at Boston Children’s Hospital are currently putting together a registry for individuals with PCDH19-Related Epilepsy. The registry is an important tool to help researchers gain a better understanding of PCDH19-Related Epilepsy and ultimately develop more effective treatment options. If you or your child has been diagnosed with PCDH19-Related Epilepsy, your participation could help advance the knowledge of PCDH19-Related Epilepsy! 
 
In creating and maintaining a meaningful registry of patients with PCDH19-related epilepsy, our shared goals are to better understand the full range of clinical features that are associated with PCDH19 (including epilepsy and behavioral aspects) and to provide a resource of natural history data. As the promise of gene-specific medication is now on the horizon for epilepsy, it is critical that the PCDH19 phenotype be well defined so that there can be clear goals and outcomes to measure in any future clinical trial.
Click here to learn more and enroll.
Looking for more information on research? PubMed has it all. Click on the button below to go to a list of almost every published scientific article on PCDH19. When you get to the list, it is arranged by date published, with the newest date first, so be sure to scroll through the multiple pages, to get to older articles.