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KCNQ2 research meets its cousins in Naples, Italy

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Did you ever wonder about Q2’s “cousins”?

You probably know by now that in the gene name KCNQ2, K is for potassium and CN is for channel. But what about Q2 (and 1, 3, 4, and 5)?  You might want to go to Italy to find out! The KCNQ family (aka Kv7) will have a sort of “reunion” this week at the International Kv7 Channel Symposium in NaplesResearchers from the across Europe, the United States (hello, Dr. Ed Cooper!), Australia, and China will gather to focus on their common ties and the ways they can help each other out for the benefit of many.

Download powerpoint slides for the meeting here!

 

Dr. Maurizio Taglialatela, MD, PhD, professor of pharmacology at the University of Naples Federico II and member of the medical advisory board for the Jack Pribaz Foundation, will host his colleagues in his hometown. “We hope to merge together in this meeting the best work done in the areas of neuroscience, cardiac, and muscle,” Taglialatela says, “so that cross-fertilization among disciplines might help in promoting better research and therapeutic opportunities for our patients.” 

Recently Gina Pribaz Vozenilek interviewed Dr. Maurizio Taglialatela by email about the goals of the conference and the importance of considering the Kv7 genes together. 

GPV: Can you explain the family of Kv7 genes and how they are related to one another?

MT: Among ~ 80 potassium channel genes found in humans, those belonging to the Kv7 family regulate the activity of cells in many organs including brain, heart and muscle. The five known Kv7 family members (Kv7.1-5 or KCNQ1-5) show distinct cellular and subcellular localization in each cell and often cooperate functionally with each other. For instance, KCNQ1 is mainly found in the heart whereas KCNQ2 and KCNQ3 are more abundant in the brain. Alteration of their function can cause diseases such as epilepsy, cardiac arrhythmias, or deafness, depending on their tissue- and time-specific expression pattern. KCNQs show a similar structure and function, and have peculiar regulatory properties, distinct from those of most other potassium channels.

GPV: What is the potential value of looking at all the Kv7 genes together synergistically in terms of helping understand KCNQ2 encephalopathy?

MT: At least in specific cell types and at distinct developmental stages, some members of the Kv7/KCNQ family, namely KCNQ3 and KCNQ5, are found in the brain, where they can work together with KCNQ2 and modulate its function. Mutations in KCNQ3 and, more recently, KCNQ5 have been shown to cause neurological diseases with features partially-overlapping KCNQ2 encephalopathy, although gene- and even mutation-dependent phenotypes are also emerging. Therefore, understanding structural and functional similarities and differences among KCNQ family members may potentially provide new strategies for the treatment of KCNQ2 encephalopathy; in fact, available Kv7-acting drugs all have serious limitations, including poor selectivity among Kv7 family members. For instance, information on specific pharmacological properties of cardiac Kv7.1 channels might facilitate the development of “brain” Kv7.2-specific drugs without the potential negative side effects that cause arrhythmias.

GPV: Conversely, how have advances in KCNQ2 research improved knowledge in the study of other KCNQ illnesses? 

MT: As said before, despite the previously-mentioned similarities in functional characteristics and structure among members of Kv7/KCNQ family, each of them plays a different functional role at distinct sites in the human body; thus, the knowledge generated from KCNQ2 studies could provide the opportunity to target diseases completely distinct from KCNQ2-related diseases, such as hypertension, urinary dysfunction, pain, arrhythmias, and GI disorders.

GPV: What are your hopes for this conference?

MT: The goal of this conference is to facilitate the sharing of knowledge and ideas among scientists working in different fields in which the Kv7 channels play a relevant functional role; we hope that such cross-fertilizing experience will deepen our understanding of KCNQ-related illnesses and reveal emerging and yet under-explored areas in which Kv7 channels are involved, such as (just to mention a few …) cancer, depression, anxiety, and autism-related disorders. The meeting will also strengthen existing collaborative research networks and create new ones, further enhancing the opportunity for young scientists to train in prestigious labs around the world.  Furthermore, given the participation of several pharmaceutical companies, the meeting will provide a unique opportunity to share results between academy and industry to speed the pace toward finding a cure for KCNQ-related illnesses.

 

Illinois recognizes KCNQ2 Awareness Week!

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Jack with State Senators Don Harmon and Kwame Raoul at the Ann and Robert H Lurie Children’s Hospital of Chicago on Friday to celebrate the new KCNQ2 Awareness week in Illinois.

Friday night, March 2, 2018, at the Ann and Robert H. Lurie Children’s Hospital of Chicago saw a memorable gathering of doctors, lawmakers, scientists, parents, siblings and children affected by KCNQ2-related epilepsy.

Spreading KCNQ2 awareness is important to me
                                       –Rick Terven

On that day, the State of Illinois gave the KCNQ2 community a sense of hope with the passing of a resolution that designates the first week of March as KCNQ2 Awareness Week. This recognition is the latest exciting step that adds to our efforts to bring attention and resources to the fight against KCNQ2-related epilepsy.
“Spreading KCNQ2 awareness is important to me, because there are ways to improve the outcomes for many children with neonatal onset epilepsy disorders,” says Rick Terven, dad of one-year-old Amelia who has KCNQ2-related epilepsy.
“We can help children in those critical first few months to get diagnosed and properly treated much quicker than is currently happening in many instances.” It was through the efforts of Rick and Michelle Terven that this resolution was passed. A huge thanks to them!
All had the chance to speak with the doctors and scientists who are constantly pushing forward in this field. The families visited with each other and the siblings played together. At the end of the day, we all had a little more hope than we did before.

 

Pediatric epileptologist Dr. John Millichap, who was in attendance at Friday’s festivities, says, “Public awareness of KCNQ2 encephalopathy is important for many reasons.  I would like to emphasize that physicians caring for young children with unexplained seizures should consider genetic testing early since a positive result can lead to specific options for treatment and prevention of sequelae.”

 

What a fantastic event for the families of these beautiful children. What started out as a few isolated cases has grown into a global crusade to help these kids win this war.

Click here to donate to KCNQ2 research

 

 

Announcing the Sophie Award for Young KCNQ2 Investigators

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This is a story about faith in the future.

Sophie was born in Arkansas to parents Sasha and Colten on January 4th, 2015. When Sophie was diagnosed with KCNQ2 at 4 weeks old, her parents did what most parents faced with this diagnosis do: whatever they can to help their children.

Sadly, little Sophie, who had further medical complications, died at just 13 months old. For Sasha and Colten, that desire to do whatever they could to help Sophie turned into a desire to help other KCNQ2 children. They made a tough decision and donated her brain to science. This donation will help in the study of epilepsy and KCNQ2.

So to honor Sophie and her parents’ tremendous gift, The Jack Pribaz Foundation is establishing a new award for KCNQ2 research. We are calling it the Sophie Award for Young KCNQ2 Investigators.

This is an award that looks bravely forward, like Sasha and Colten have. It is a grant in the amount of $15,000, designed to support and encourage research of KCNQ2-related epilepsy.

We are thrilled to announce the first Sophie Award winner today at the 70th Annual Meeting of the American Epilepsy Society in Houston, Texas.  The recipient is Dr. John Millichap, attending physician at the Neurology and Epilepsy Center at the Ann and Robert H. Lurie Children’s Hospital in Chicago and Assistant Professor of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine. We chose Dr. Millichap for his outstanding dedication to bridging bench science and clinical application and for his contributions to the medical literature. His work is advancing understanding of KCNQ2-related epilepsy into the next generation of scientists and clinicians.

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Dr. John Millichap

“I’m so proud to receive this award and to be a part of KCNQ2-related epilepsy research,” said Dr. Millichap. “The spirit of collaboration I’ve found on an international scale among both researchers and families is uncommon and powerful. Together we have come a long way in a relatively short time, but there is a lot of work ahead of us,” he said. “Receiving the Sophie Award is exciting but also humbling, because at the heart of our efforts are children and families who desperately need science to catch up with their conditions.”

We are very passionate about this prize because it is a special opportunity to support KCNQ2 research and also to recognize the important partnership that KCNQ2 families have with researchers. That’s what Sophie’s gift was all about.

Look into the future with us. Gifts made to the Sophie Award for Young KCNQ2 Investigators will go to sponsor scientists, grad students, doctoral candidates, and young professors of the future in Sophie’s memory.

Contribute to the Sophie Award for Young KCNQ2 Investigators here.

We sincerely thank Sasha and Colten for their dedication to the KCNQ2 cause. And we congratulate them, too– they had a new baby boy this summer! They give us so much hope!

 

Novel KCNQ2 activators as promising drugs for epilepsy treatment

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You have heard of Potiga, a drug used to treat KCNQ2-related epilepsy. But what about new drugs in development like SF0034 or RL648_81?  KCNQ2 Perspectives asked renowned pharmacologist and Jack Pribaz Foundation scientific adviser Dr. Maurizio Taglialatela to provide an overview of potassium channel openers. We are grateful for his help in understanding these drugs and offering a glimpse of what promising new treatments may lie on the horizon.

Precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle. For genetic diseases such as most epileptic encephalopathies (EE), precision medicine aims to provide individually tailored treatments based the underlying genetic cause.

For KCNQ2-EE, molecular diagnosis may influence the choice of antiepileptic drugs. In fact, most of the genetic variants identified in KCNQ2-EE, when studied in vitro by conventional electrophysiological methods, cause a decrease in KCNQ2 channel function (loss-of-function or LOF variants). An antiepileptic drug which enhances KCNQ2 channel function may represent a novel therapeutic approach in those patients carrying LOF KCNQ2 variants.

Retigabine

Among currently available antiepileptic drugs, retigabine or ezogabine (trade name Trobalt or Potiga) is the only one whose clinical efficacy is related to this specific mechanism of action. Unfortunately, although retigabine is approved for use in adults with epilepsy, its use in infants and children is very limited. Moreover, post-marketing studies revealed the occurrence of side effects with retigabine, including a blue discoloration of the skin and mucosae and pigment deposition in the retina. It is yet unknown whether this latter effect, which appears as a consequence of the drug’s photodegradation and oxidation upon exposure to UV radiations, affects vision in the long term. Another side effect occurring with retigabine is urinary retention, possibly a consequence of the poor selectivity of retigabine/ezogabine for KCNQ2 channels over channels of the same subfamily (particularly KCNQ4), which do not appear to play a significant role in epilepsy, but which are involved in the control of bladder smooth muscle contractility.

SF0034

To improve retigabine safety and selectivity, in the last few years, several research groups have synthesized and characterized the pharmacological properties of a large number of retigabine analogs (as well as other KCNQ2 activators structurally unrelated to retigabine). Among the novel molecules resulting from these efforts is SF0034, a compound which, when compared to retigabine, is more potent and KCNQ2-selective (Kalappa et al., 2015). Preclinical studies in animals also revealed that SF0034 exhibits a more potent anticonvulsant activity and less toxicity than retigabine. In addition, SF0034 was significantly less active on KCNQ4 channels, leading to the suggestion that, in comparison with retigabine, side effects associated with activation of this channel subtype may be less likely to occur with SF0034. SF0034 seems to be more chemically stable and does not produce blue metabolites, suggesting that it may be a useful clinical candidate for epilepsy and other diseases linked to KCNQ2 hypofunction (such as tinnitus).

RL648_81

Even more recently, another analogue of retigabine, named RL648_81, has been reported in the literature (Kumar et al., 2016); this compound is 3 times more potent than SF0034 and 15 times more potent than retigabine in activating KCNQ2 channels in in vitro electrophysiological studies. The same studies also revealed that RL648_81 is also more selective than retigabine for activation of KCNQ2 channel over channels formed by other KCNQ subtypes. However, no pharmacokinetic data on drug absorption, metabolism, distribution and elimination from the organism is yet available for RL648_81 (either in experimental animals or in humans), and no antiepileptic efficacy has been proven for this drug in preclinical or clinical studies. Nonetheless, it seems likely that this more potent, selective and chemically stable KCNQ2/3 activator may be yet another attractive candidate for treating or preventing hyperexcitability disorders, overcoming some of the undesirable side effects associated with retigabine.

Donate to The Jack Pribaz Foundation to help fund research on KCNQ2 treatments

In conclusion, based on the discovery that KCNQ2 channels play critical roles in epilepsy pathogenesis and treatment, both academic and industry efforts are being actively pursued to develop novel KCNQ2 activators. Whether these novel drugs will prove useful as targeted therapies to improve neonatal seizures and developmental outcome in neonates with KCNQ2-EE remains to be demonstrated in the years to come.

References

Screenshot 2016-05-07 10.52.10Born in Naples, Italy, Dr. Maurizio Taglialatela, MD, PhD, is a full professor of pharmacology at the University of Molise in Italy, where he was Dean of the Faculty of Health Science from 2005-2012. He earned both his Medical Degree and PhD in Cellular and Molecular Biology and Pathology from the University of Naples. At the University of Molise he serves as the scientific director of the Center for Pharmacovigilance of the Regione Molise, the chairman of the Center for Higher Education of Public and Private Management of the University of Molise, and the coordinator of the PhD Program in Translational and Clinical Medicine. Dr. Taglialatela has contributed to numerous international research committees for pharmaceutical drug development.  In the last fifteen years, he has dedicated most of his efforts to investigate the molecular pathogenetic mechanisms responsible for neuronal channelopathies, concentrating on developing experimental tools and drugs to investigate the structure-function analysis of disease-causing human mutations found in human KCNQ channel genes, in order to indentify in-vitro biomarkers useful for disease diagnosis, prognosis, and therapy.