Stephanie Telesca, Co-founder of The KCNC1 Foundation
Ethan M. Goldberg, M.D., Ph.D., Associate Professor in the Division of Neurology at The Children’s Hospital of Philadelphia and in the Departments of Neurology and Neuroscience at The University of Pennsylvania Perelman School of Medicine in Philadelphia, PA, USA
Gary Clark, Director Screening Technologies, Metrion Biosciences
Gary Clark: Metrion has a huge amount of experience in automated patch clamp for HTS and also fluorescence-based systems.
A fluorescence-based assay will give you a yes/no answer on hits. It's generally faster and more cost-effective to screen on a FLIPR or a fluorescence-based assay. However, it doesn't give you the same level of detail or information that you would get on an automated platform.
Ethan Goldberg: We're still analysing the data, and there are a range of compounds with different properties. Which compound or compounds might come to patients, and which patients might be eligible remains to be seen. There is data that these compounds are safe, and we're hopeful that a preclinical program will lead to something that can be available to patients at some point, but the analysis of the data still has to be completed. I should mention that the clinical trial was an industry sponsored trial that was run by a colleague of mine at Penn. I'm not a clinical trialist, so I wasn't directly involved in the in the clinical trial.
Ethan Goldberg: That’s a very complicated question. Yes, we have tried fluoxetine in one patient. There are millions of people who have taken fluoxetine and, if it acted as a Kv3 channel modulator, I wonder what its action might be on native Kv3 channels in the brain. More work needs to be done on that. We've had limited experience with it so far. But as Gary mentioned, there is a published case report1 with some data and heterologous systems and then some sort of correlative clinical data. This is always an issue with these case studies where you have a child with a neurodevelopmental disorder that has been ongoing for many years. They're already on many anti-seizure medications. They receive another trial medication for some period of time, and interpreting what the effects of that medication are and whether they can be attributed to that particular medication trial. It's very complicated.
Ethan Goldberg: We’re just finishing a trial with fluoxetine based on the case report. We will be starting a trial for Eliana, probably sometime soon with one of the hits from the drug study. So more to come.
Stephanie Telesca: I came across Perlara, a group of PhD scientists who are helping families or small foundations like the KCNC1 Foundation navigate the space of funding for a treatment for their child. They helped me identify Metrion, a leader in ion channel drug discovery. We looked at all the different CROs out there, and Metrion was the best fit.
Stephanie Telesca: Our next major step is to create a patient registry. A lot of the patients in our online community are really keen to participate and to share their information and their child's progress. So that will be my next big focus for the Foundation. In terms of steps for a treatment for other individuals, that is going to take a little bit more time and more fundraising. It's a big endeavour for a very small Foundation, but hopefully with collaboration and working with others, we will be able to expand into different variants, and even look at the other gain of function variants to see if any of the results from our current study, on Eliana’s variant are relevant for that group.
Ethan Goldberg: It's always difficult to predict the potential impact of technologies that are under development or haven't been developed yet. An important next advance is understanding how disease associated genetic variants interact with development. We know that, for example, KCNC1-related disorders are due to de novo, or in some cases, inherited variants that are present from conception. But just like the healthy human brain, the brain of a child with a neurodevelopmental disorder also continues to develop, maybe in a different way, and that may be partially compensatory or corrective. It may be part of the pathologic process, or it may be epiphenomenal, such that the actual status of a child at age 1, 2, 5, 10 involves the underlying genetic variant, plus all of these other processes such that the actual target might be changing and might not be directly informed by the biophysical effects of the variant on the channel as it appears in, for example, a heterologous system. So, I think maybe not a new technology itself, but a greater understanding of what these technologies are telling us and linking across them is important. Something that I do think would be very helpful, would be improved ways of understanding the sub-unit composition and subcellular expression of Kv3 channels throughout the brain. We still don't really know what the native state is of these channels. They heteromultiplyse, they're modulated by second messenger systems, etc, and have very complex patterns of expression in specific cell types in different sub cellular compartments. Understanding that is something that some of these single cell biology or high-resolution imaging technologies could tell us in the future.
Stephanie Telesca, Co-founder of The KCNC1 Foundation
Ethan M. Goldberg, M.D., Ph.D., Associate Professor in the Division of Neurology at The Children’s Hospital of Philadelphia and in the Departments of Neurology and Neuroscience at The University of Pennsylvania Perelman School of Medicine in Philadelphia, PA, USA
Gary Clark, Director Screening Technologies, Metrion Biosciences
Gary Clark: Metrion has a huge amount of experience in automated patch clamp for HTS and also fluorescence-based systems.
A fluorescence-based assay will give you a yes/no answer on hits. It's generally faster and more cost-effective to screen on a FLIPR or a fluorescence-based assay. However, it doesn't give you the same level of detail or information that you would get on an automated platform.
Ethan Goldberg: We're still analysing the data, and there are a range of compounds with different properties. Which compound or compounds might come to patients, and which patients might be eligible remains to be seen. There is data that these compounds are safe, and we're hopeful that a preclinical program will lead to something that can be available to patients at some point, but the analysis of the data still has to be completed. I should mention that the clinical trial was an industry sponsored trial that was run by a colleague of mine at Penn. I'm not a clinical trialist, so I wasn't directly involved in the in the clinical trial.
Ethan Goldberg: That’s a very complicated question. Yes, we have tried fluoxetine in one patient. There are millions of people who have taken fluoxetine and, if it acted as a Kv3 channel modulator, I wonder what its action might be on native Kv3 channels in the brain. More work needs to be done on that. We've had limited experience with it so far. But as Gary mentioned, there is a published case report1 with some data and heterologous systems and then some sort of correlative clinical data. This is always an issue with these case studies where you have a child with a neurodevelopmental disorder that has been ongoing for many years. They're already on many anti-seizure medications. They receive another trial medication for some period of time, and interpreting what the effects of that medication are and whether they can be attributed to that particular medication trial. It's very complicated.
Ethan Goldberg: We’re just finishing a trial with fluoxetine based on the case report. We will be starting a trial for Eliana, probably sometime soon with one of the hits from the drug study. So more to come.
Stephanie Telesca: I came across Perlara, a group of PhD scientists who are helping families or small foundations like the KCNC1 Foundation navigate the space of funding for a treatment for their child. They helped me identify Metrion, a leader in ion channel drug discovery. We looked at all the different CROs out there, and Metrion was the best fit.
Stephanie Telesca: Our next major step is to create a patient registry. A lot of the patients in our online community are really keen to participate and to share their information and their child's progress. So that will be my next big focus for the Foundation. In terms of steps for a treatment for other individuals, that is going to take a little bit more time and more fundraising. It's a big endeavour for a very small Foundation, but hopefully with collaboration and working with others, we will be able to expand into different variants, and even look at the other gain of function variants to see if any of the results from our current study, on Eliana’s variant are relevant for that group.
Ethan Goldberg: It's always difficult to predict the potential impact of technologies that are under development or haven't been developed yet. An important next advance is understanding how disease associated genetic variants interact with development. We know that, for example, KCNC1-related disorders are due to de novo, or in some cases, inherited variants that are present from conception. But just like the healthy human brain, the brain of a child with a neurodevelopmental disorder also continues to develop, maybe in a different way, and that may be partially compensatory or corrective. It may be part of the pathologic process, or it may be epiphenomenal, such that the actual status of a child at age 1, 2, 5, 10 involves the underlying genetic variant, plus all of these other processes such that the actual target might be changing and might not be directly informed by the biophysical effects of the variant on the channel as it appears in, for example, a heterologous system. So, I think maybe not a new technology itself, but a greater understanding of what these technologies are telling us and linking across them is important. Something that I do think would be very helpful, would be improved ways of understanding the sub-unit composition and subcellular expression of Kv3 channels throughout the brain. We still don't really know what the native state is of these channels. They heteromultiplyse, they're modulated by second messenger systems, etc, and have very complex patterns of expression in specific cell types in different sub cellular compartments. Understanding that is something that some of these single cell biology or high-resolution imaging technologies could tell us in the future.
Stephanie Telesca, Co-founder of The KCNC1 Foundation
Ethan M. Goldberg, M.D., Ph.D., Associate Professor in the Division of Neurology at The Children’s Hospital of Philadelphia and in the Departments of Neurology and Neuroscience at The University of Pennsylvania Perelman School of Medicine in Philadelphia, PA, USA
Gary Clark, Director Screening Technologies, Metrion Biosciences
Gary Clark: Metrion has a huge amount of experience in automated patch clamp for HTS and also fluorescence-based systems.
A fluorescence-based assay will give you a yes/no answer on hits. It's generally faster and more cost-effective to screen on a FLIPR or a fluorescence-based assay. However, it doesn't give you the same level of detail or information that you would get on an automated platform.
Ethan Goldberg: We're still analysing the data, and there are a range of compounds with different properties. Which compound or compounds might come to patients, and which patients might be eligible remains to be seen. There is data that these compounds are safe, and we're hopeful that a preclinical program will lead to something that can be available to patients at some point, but the analysis of the data still has to be completed. I should mention that the clinical trial was an industry sponsored trial that was run by a colleague of mine at Penn. I'm not a clinical trialist, so I wasn't directly involved in the in the clinical trial.
Ethan Goldberg: That’s a very complicated question. Yes, we have tried fluoxetine in one patient. There are millions of people who have taken fluoxetine and, if it acted as a Kv3 channel modulator, I wonder what its action might be on native Kv3 channels in the brain. More work needs to be done on that. We've had limited experience with it so far. But as Gary mentioned, there is a published case report1 with some data and heterologous systems and then some sort of correlative clinical data. This is always an issue with these case studies where you have a child with a neurodevelopmental disorder that has been ongoing for many years. They're already on many anti-seizure medications. They receive another trial medication for some period of time, and interpreting what the effects of that medication are and whether they can be attributed to that particular medication trial. It's very complicated.
Ethan Goldberg: We’re just finishing a trial with fluoxetine based on the case report. We will be starting a trial for Eliana, probably sometime soon with one of the hits from the drug study. So more to come.
Stephanie Telesca: I came across Perlara, a group of PhD scientists who are helping families or small foundations like the KCNC1 Foundation navigate the space of funding for a treatment for their child. They helped me identify Metrion, a leader in ion channel drug discovery. We looked at all the different CROs out there, and Metrion was the best fit.
Stephanie Telesca: Our next major step is to create a patient registry. A lot of the patients in our online community are really keen to participate and to share their information and their child's progress. So that will be my next big focus for the Foundation. In terms of steps for a treatment for other individuals, that is going to take a little bit more time and more fundraising. It's a big endeavour for a very small Foundation, but hopefully with collaboration and working with others, we will be able to expand into different variants, and even look at the other gain of function variants to see if any of the results from our current study, on Eliana’s variant are relevant for that group.
Ethan Goldberg: It's always difficult to predict the potential impact of technologies that are under development or haven't been developed yet. An important next advance is understanding how disease associated genetic variants interact with development. We know that, for example, KCNC1-related disorders are due to de novo, or in some cases, inherited variants that are present from conception. But just like the healthy human brain, the brain of a child with a neurodevelopmental disorder also continues to develop, maybe in a different way, and that may be partially compensatory or corrective. It may be part of the pathologic process, or it may be epiphenomenal, such that the actual status of a child at age 1, 2, 5, 10 involves the underlying genetic variant, plus all of these other processes such that the actual target might be changing and might not be directly informed by the biophysical effects of the variant on the channel as it appears in, for example, a heterologous system. So, I think maybe not a new technology itself, but a greater understanding of what these technologies are telling us and linking across them is important. Something that I do think would be very helpful, would be improved ways of understanding the sub-unit composition and subcellular expression of Kv3 channels throughout the brain. We still don't really know what the native state is of these channels. They heteromultiplyse, they're modulated by second messenger systems, etc, and have very complex patterns of expression in specific cell types in different sub cellular compartments. Understanding that is something that some of these single cell biology or high-resolution imaging technologies could tell us in the future.