Research

The research projects of Together for PCDH19 Research non-profit organisation (Insieme per la ricerca PCDH19 Onlus)

Since 2013, Together for PCDH19 Research non-profit organization is active in the collection of funds entirely devolved to research projects that can find a cure for those affected by mutation of the PCDH19 gene but also in order to finance methodologies and tools that support physicians throughout the world in diagnosing it, or excluding it, as soon as possible.

Below is a brief summary of the main research projects that have already led researchers to a series of important results.

 

May 30, 2018

 

Together for PCDH19 Research awarded € 61,500 to two-year research “Genetic silencing of PCDH19 as treatment for Early Infantile Epileptic Encephalopaty“, which will be conducted by Maria Passafaro (CNR Neuroscience Institute of Milan) and Alfredo Brusco (Unit of Medical Genetics of the University of Turin).

 

The research aims to use the siRNA technique (silencing of the mutated gene) on in vivo mouse models of PCDH19 (conditional mice) and to use these data for future translational approaches for patients.

 

September 25, 2017

 

With great joy and satisfaction, we announce that Silvia Bassani (from the research team of Maria Passafaro of the CNR Institute of Neuroscience of Milan has been awarded a 3-year Grant Telethon for the research “Solving the puzzle of protocadherin-19 mosaicism to understand the pathophysiology of PCDH19 Female Epilepsy (PCDH19-FE)“.

 

Telethon only finances projects based on solid preliminary data. Silvia Bassani has collected such preliminary data also thanks to the funding that Together for PCDH19 Research has ensured for its research team.

 

Thanks to this funding, the CNR will thus be able to continue studies to identify pathogenic mechanisms and new pharmacological therapies that can contribute to the treatment of the disease caused by mutation of PCDH19 and of neuro-development such as autism, intellectual disability and epilepsy.

 

February 28, 2017

 

Together for PCDH19 Research has allocated € 9,000 for a research conducted by prof. Roberto Cosimo Melcangi, of the Institute of Neuroendocrinology of the University of Milan, “Assessment of neuroactive steroid levels in plasma of female patients affected by PCDH-19 mutations“.

 

The study examines the possible involvement of neurosteroid hormones in the pathology caused by mutations in the PCDH19 gene. The levels of these hormones were measured in the blood samples of girls affected by the mutation and of healthy girls of the same age (control samples). The results were also made available to the Neuroscience Department of the Bambin Gesù Hospital in Rome, which is also studying the possible implication of these hormones in the disease.

 

December 20, 2016

 

Conclusion of Maria Passafaro‘s project, “Unravelling the molecular mechanism of mutated PCDH19 function in Female Limited Epilepsy“, financed with € 100,000, from Together for PCDH19 Research and The Cute Syndrome Foundation.

 

Research has shown that PCDH19 is expressed primarily at the hippocampus level and preferentially in immature neurons.

 

Furthermore, preliminary results indicate that this protein also undergoes a proteolytic cut by intracellular enzymes, able to release the cytoplasmic tail which is localized in the nucleus. This result is extremely important, as it shows a new role of the protein in the nucleus that must be studied in order to have a complete picture of its function and to develop possible drugs.

 

October 27, 2016

Together for PCDH19 Research has allocated an additional € 15,000 for the research “Modeling Pcdh19-Associated Epilepsy With Patient-Derived Neurons” conducted by Professor Jack Parent of the University of Michigan.

January 7, 2015

Together for PCDH19 Research, with the collaboration of the BNL Foundation, has financed for about € 20,000 the research “PCDH19 and the establishment of planar cell polarity in ‘iPS-derived developing neurons’ in a X-linked model of Epilepsy” led by Dr. Alessandra Terracciano (Department of Neuroscience of the Bambin Gesù Hospital of Rome). The research has allowed to characterize the expression and localization of PCDH19 in human neuronal development. The study focused in particular on the first phase of cell polarity, when the iPSC system reproduces the neural tube organization in embryonic phase. This in vitro system has allowed us to study the involvement of PCDH19 in the development of the human brain, defining expression times and protein localization. The data obtained from inferior animal models (zebrafish and chicken) were thus replicated, confirming the involvement of PCDH19 in the regulation of cell adhesion and in the geometry of neuronal proliferation. The study shows that the expression of PCDH19 seems to provide the cell with position information with respect to other cells, essential for the proper development of the brain. These results partly elucidate the mechanism of action of the PCDH19 protein, and may help to identify a time window useful for an eventual early therapeutic target.

 

April 17th 2015

Together for PCDH19 Research and The Cute Syndrome Foundation have allocated $ 20,000 for a study concerning “ Modeling Pcdh19-Associated Epilepsy With Patient-Derived Neurons” and conducted by Professor Jack Parent of the University of Michigan. According to the words of Jack Parent: “The goals of our research are to understand the role of protocadherin-19 (PCDH19) in brain development and how PCDH19 mutations lead to epilepsy. To accomplish these goals, we are modeling PCDH19 Epilepsy using two cutting edge scientific approaches. First, we generate (excitatory and inhibitory) brain cells from patient skin biopsies using the induced pluripotent stem (iPS) cell method. With patient-derived brain cells in a dish, we can investigate the mechanisms by which altered nerve cell development and excitability cause seizures. We are also generating a rat model by disrupting the PCDH19 gene in a subset of cells in the embryonic rat brain. To do this we use a technique called in utero electroporation combined with sophisticated gene editing methods. We will examine how brain cells that lose PCDH19 affect development of the cerebral cortex and nerve cell excitability. Both patient-derived cell and rat models will also provide platforms to screen for new therapies to treat PCDH19 Epilepsy”.

June 24, 2014

Together for PCDH19 Research continues also this year to finance the research of Professor Jozef Gecz (University of Adelaide-Australia) for a total of € 35,000, Understanding the action of DNA mutations in PCDH19-­Female Epilepsy (PCDH19-­FE). According to the words of Professor Gecz: “Since we identified the PCDH19 gene in female limited epilepsy in 2008 we have identified that neurosteroid levels are altered in PCDH19-­FE girls. This exciting discovery provided a plausible mechanism for PCDH19-­FE through the action of neuronal steroids, which are well known to play important role not only in epilepsy, but also autism and learning and memory. As a result, we expect to demonstrate the role of steroid hormone signaling in PCDH19-­FE, which will pave the way for a full-­scale case-controlled clinical trial of ganaxolone or allopregnanolone in PCDH19-­FE and ultimately a targeted treatment of this disorder”.

 

March 15, 2014

Together for PCDH19 Research financed the research conducted by Nicola Specchio and Marina Trivisano (Neurology Unit – Neuroscience Department – Bambino Gesù Pediatric Hospital of Rome) for € 8,000, entitled Definition of cognitive-behavioral aspects of epilepsy associated with mutation of Protocadherin 19 (PCDH19) (Definizione degli aspetti cognitivo-comportamentali dell’epilessia associata a mutazione di Protocaderina 19 (PCDH19)).

The aim of the study is to define the cognitive and affective-behavioral aspects of epilepsy associated with PCDH19 gene mutation and to evaluate its progression over time. A second objective of the research consists in the correlation of neuropsychological aspects with the critical / epileptic phenotype. In particular, we want to verify the influence of clinical variables such as the duration of the disease, the frequency of seizures and clusters, the type and duration of antiepileptic therapy, on neuropsychological aspects and highlight what are the variables that most affect the cognitive functions. In this way, it could be assessed whether the neuropsychological outcome is influenced by the presence of persistent electroencephalographic abnormalities, as in the case of epileptic encephalopathies, or on the contrary, if the clinical aspects and EEG depend, independently, exclusively on genetic factors.

February 2013

Conclusion of Professor Jozef Gecz’s research: Understanding the molecular pathology of PCDH19 disorders. The research was funded by 7 families belonging to the association Together for PCDH19 Research for a total of € 115,000.

The study confirmed the initial hypothesis of a possible involvement of the neurosteroid hormone allopregnanolone in the pathology caused by mutation of PCDH19.