Genetics Study 

Finds Genes That Cause Trigeminal Neuralgia

 Introduction by Michael Pasternak

In 2012 The Facial Pain Research Foundation approved a research study to find the genes responsible for trigeminal neuralgia. 

While each of our Foundation’s scientific projects are valuable, the one that has been the most awesome and challenging for me has been the Genetics/DNA project. Dr. Doug Anderson (FPRF Director of Research) and I have had to communicate with scientists from four different countries (including Joanna Zakrzewska in London) and Collection Centers in 9 different cities in three countries! Doug has spent months on this project “everyday”! He has also had to communicate with additional scientists interested in our efforts and has done this while still overseeing the creation and development and evaluation of all of our Foundation’s other projects! How did we and he get so lucky? 

While Doug has overseen and worked through the science some of our other Volunteers have been involved in working with the DNA Collection Centers, working through intellectual property problems, legal questions, raising the funds to pay for all of this, communicating to patients to give their DNA, creating PR pieces for the public to participate, keeping track of collection numbers, certifying completion of collections and data sent to OHSU and Rutgers, and making payments to the Collection Centers for their efforts. This project has been an enormous accomplishment. No Volunteer Foundation or organization has ever done this before! All completed while we grew our outstanding scientific project numbers to six and linked with two venture capital funded research projects. 

The FPRF has spent over $650,000 of funds raised by our Volunteers and donors on this project. The FPRF Trustees have committed another $325,000 to complete the project in the next year. 

So, now we have a team of scientists who have worked hard using their unique skills and understandings and have presented a report to our Trustees and asked to go forward to replicate the study during the next year to prove that what they have found are really the genes that will lead us to finding the cures. The Cilker Genetics/DNA Research Report has arrived. It is remarkable. We are extremely thankful to Drs. Devor, Burchiel, Seltzer, Diehl and Anderson for all of their voluntary efforts to create these findings. We are also truly thankful for Our Trustees and all of our Volunteers who helped raise the necessary funds to complete the tasks. This is an exciting time for all of us committed to ending the pain for all TN and related neuropathic sufferers. 

The Following is a Non-Technical Summary Report…The detailed full Scientific Report has been presented to the Foundation Trustees and contains confidential information. It will be confidential until the replication of findings has been completed. Following the report is an article by Dr. Scott Diehl for general distribution.

Genome-Wide Association Study

Of Trigeminal Neuralgia Type 1 (TN1) 

The William A. and Leila A. Cilker

Research Project

 A Report Prepared for the Board of Trustees of the Facial Pain Research Foundation by Kim J Burchiel, MD (Oregon Health and Science University), Marshall Devor, PhD (Hebrew University of Jerusalem), Scott R Diehl, PhD (Rutgers Biomedical Health Sciences), and Ze’ev Seltzer, DMD (University of Toronto)

Findings and Future Plans – Non-Technical Summary

The main goal of our study is to find genes that cause “Classical” Trigeminal Neuralgia Type 1 (TN1). This information will help clinician-scientists find cures that relieve patients’ severe chronic pain or prevent it from developing. Thus far, we’ve searched the genetic material (DNA) of TN1 patients at over a million places where people are known to differ from one another in their DNA letters (A, T, G or C). On average, any two people have about five million DNA differences between them. Most differences have no effect on health, but some cause or predispose to disease. Our challenge is to find the “needles in a haystack” that cause TN1, hidden among the millions of differences with no relation to TN1. We do this by comparing DNA of TN1 patients (cases) with that of people who do not have TN1 (controls).

 Our initial search focused on 348 Caucasian TN1 patients, a modest sample size for human genetic studies today. Nevertheless, we are delighted to report discovery of several regions in the human genome with promising evidence they may harbor genes causing TN1. Some regions include only one gene, but there are 17 genes in the genome location with the strongest statistical support, including 3 with biological functions involving nerve degeneration, excitability of neurons or responses to nerve injury. These genes are strong suspects, but to determine which genes actually cause TN1we need a combination of: a) more genetic data of the kind we have already been gathering, and b) information from a complementary approach that uses high speed DNA sequencing. This further research is absolutely necessary before our initial discoveries are ready for testing in animals or translation to the clinic. 

First, we must be absolutely certain our TN1 patients and controls do not happen to be very different by chance alone, but that the DNA differences occur because mutations hidden in the regions actually cause TN1. To do this, we will repeat our experiment a second time and see if we get the same results. We will analyze variation across the human genome for a new set of TN1 patients and controls using the most advanced genomic assays now available, more than doubling our sample size. If the same genome regions are again different in TN1 patients compared to controls (like lightning striking in the same place twice), this replication will confirm that TN1 disease-causing genes are indeed located there. Some regions have initial statistical support stronger than others, so these are more likely to be confirmed, but only by doing the assays and carefully evaluating what the data tell us will we know for sure which regions are confirmed. We do not expect all of our initially positive regions to be confirmed, but even if only one region is strongly confirmed this will be an extremely important advance, not only for TN1 but for the entire biomedical field of neuropathic pain in general. 2 Submitted January 3, 2018

Moreover, it is not enough to just find regions of the genome that harbor genes that cause TN1 – we also have to identify the specific genes and mutations in these genes that cause them to biologically malfunction, as this information is essential for translation to new therapies. It is possible that some of the mutations that cause TN1 are extremely rare, found only in TN1 patients and their close relatives. To discover additional TN1 genes and TN1-causing mutations, including those that are very rare, we will use the latest technologies for “reading” the DNA sequence of the entire human genome in a select subset of our TN1 patients. This method is called Next Generation Sequencing (NGS), and we propose to perform this assay for 100 TN1 patients.

Combining our previously-studied as well as our new TN1 cases gives us a sample of approximately 900 TN1 cases, of mostly Caucasian racial origin but with some non-Caucasians included too. Combining these with a similar number of controls will provide us with substantially increased statistical power to ask several very important questions such as the following: Do different genes cause TN1in young patients versus those who experience their first symptoms when older? (We already started to ask this first question in a limited way in the first phase of our research and with a larger sample can address this more rigorously.) Are there different genetic effects in males versus females, as found in many other genetic diseases? Are there different genes causing TN1 in the (typically younger) patients without vascular compression of their trigeminal nerve compared to patients whose trigeminal nerve has been damaged by years of vascular compression?

Our research may lead to a more complex picture of TN1 as being caused by not just mutations of just one gene, but in fact mutations found in several different genes may be associated with various subtypes of TN1. Genetics may reveal TN1 clinical subtypes that we currently do not even recognize exist, as has been found in numerous other neurological conditions including the epilepsies and the many forms of ataxia caused by different genes. While our primary goal remains identifying gene mutations that cause TN1, the research described here for the next phase of our study may also identify genetically distinct subgroups of TN1 patients as a very important secondary benefit of our genetic approach. Progress towards a cure (or, more likely, “cures”) will be more rapid and have greater chance of success if it is built on a foundation of knowledge about what is really going on biologically in different TN1 patients rather than if forced into a “one size fits all” therapeutic approach.

Project Timeframe: With adequate funding all research can be completed within one year. 3 Submitted January 3, 2018

Genetics Study

Brings Precision Medicine 

To Trigeminal Neuralgia

 By Scott Diehl

 The Genetics Study team supported by the Foundation has completed a search of over one million locations in the DNA of 348 Trigeminal Neuralgia (TN) patients. This “Big Data” effort has pointed to genes affecting excitability of neurons, nerve degeneration and responses to nerve injury. These genes are very strong suspects, and the team will now gather additional information from more patients and from a complementary approach that uses high speed DNA sequencing.

In the team's next effort, these genes will be tested in a new set of TN patients. 

If the same results are found again, this replication will be like lightning striking in the same place twice and confirm that mutations in these genes cause TN in some patients. These next steps are essential to confirm the initial findings and they may also reveal additional genes not detected with a strong enough signal in the initial search. Once confirmed, these discoveries will then be ready for testing in animals and translation to patients in the clinic. 

The genetics data gathered thus far are painting a complex picture of TN as being caused by not just mutations in any one gene. It appears more likely that several different genes are involved in different patients, a phenomenon known as “genetic heterogeneity.” For example, one of the most strongly supported genes is important only for TN patients whose symptoms first appeared after age 55. A different gene with different biological functions is implicated in patients who developed TN at a younger age. Genetic heterogeneity has been found in other neurological conditions including the epilepsies and the many forms of ataxia caused by different genes. This strategy, known as Precision Medicine, is a major US and International effort getting underway focusing on nearly all human health problems today (https://allofus.nih.gov/). 

While the primary goal of the genetics study is to identify gene mutations that cause TN, this research may also identify genetically distinct subgroups of TN patients as a very important secondary benefit. Progress towards a cure (or, more likely, “cures”) will be more rapid and have greater chance of success if built on a foundation of knowledge about what is really going on biologically in different TN patients rather than if forced into a “one size fits all” therapeutic approach. 

The Genetics Study Team supported by the Foundation is an international collaboration of leaders in the fields of neurosurgery, pain biology and human genetics at Oregon Health and Science University (Dr Kim Burchiel), The Hebrew University of Jerusalem (Dr Marshall Devor), the University of Toronto (Dr Ze’ev Seltzer) and Rutgers School of Dental Medicine (Dr Scott Diehl). Numerous additional locations have provided valuable assistance with recruiting patients.

The Long Pain Road

For Chris Nolze

By

Kathleen Sweeney

Chris Nolze was diagnosed with brain cancer in 2007 at the young age of twelve. It was his initial diagnosis and the first of his major medical health issues.  

He received radiation treatment after they did a biopsy on the tumor and placed a shunt in his head. It seems that where the tumor was located there was a lot of spinal fluid built up in his skull that was not draining. It was only the beginning of a number of challenges to follow. 

During and after the radiation treatment he wasn’t “presenting” as well as other patients. They were not sure what was going on. There were signs of other medical issues that kept coming up and they are finally now discovering that the medical issues he has been dealing with since that time “are related either directly or correlated, to the radiation treatment”. 

“Ever since my cancer I’ve had over 20 surgeries; … the majority of them were considered to be brain surgeries. Between the trauma from the tumor and then the trauma from all of the surgeries and then the trauma of radiation treatment my nerves were put at high risk … My cranial nerve and my trigeminal nerve just happened to be in that mix. “ 

When Chris had his wisdom teeth removed in 2012 he had complications that resulted in dry sockets. He was in pain but both he and his doctor thought it was due to the surgery. But it didn’t go away. Finally his dental surgeon suggested that they look into trigeminal neuralgia.  It was a stretch since he did not fit the “norm” being a young boy with pain on both sides that was constant. 

Neither Chris nor his parents had ever heard of trigeminal neuralgia. But since they had tried every possible medication at least twice and then in combinations and none of them gave him any relief they sought out his neurologist. 

His neurologist and oncologist both thought it was highly “unlikely” that he had TN since he wasn’t showing the “proper” symptoms. Besides, it “just wasn’t possible”! For the next six months his parents took him all over this country looking for a doctor who would have another diagnosis. 

Eventually they found Dr. Ben Carson in Maryland who tested the nerve on the right side of his face with a Rhizotomy treatment, which is the numbing or affecting of the nerve directly to see if it is the cause. “It helped the pain completely! … It was definitely a breath of fresh air.” It was the first relief he had had in six long months. “But I still did have constant pain on my left side.“ 

Shortly thereafter Dr. Carson scheduled Chris for an MVD (micro vascular decompression) on the other side, the left side. As he was recovering from that surgery the Rhizotomy “gave out” on the right side so they scheduled him for another MVD on the right side this time. 

The pain was relieved but the incision would not close. They discovered that the skull bone itself was infected. They brought in a plastic surgeon to remove a piece of the skull about the size of a quarter. He placed a mesh plate over the opening created and then pulled the muscle up and over it (some of which had also been removed.) Eventually the incision closed properly. 

Chris was pain free for about a year. 

Then both sides came back and at about the same time. And around this same time he also contracted a rare case of intractable singultus (out of control hiccups). His is only the third case in medical history with this particular form.  “They were speeding up on a daily basis and it got to the point where I would be doing over 200 hiccups in a minute! And it just kept getting faster and faster.” 

It was a chiropractor, thinking outside the box, who put pads near his mesh plate and connected a tens unit to it. When it was turned on the hiccups stopped “instantaneously!” 

So began another search for another doctor, this time with a tens unit connected to his head! Chris and his parents traveled the entire country again, finally finding Dr. Mark Linskey in California. He was actually Chris’ last and final hope of not having to live the rest of his life with a tens unit taped to his head. 

“In every sense of the word, Dr. Linskey saved my life” says Chris. An MRI showed compressions on both his brain stem and on his facial nerves. Dr. Linskey thought the compressions on Chris’ brain stem might be the cause of the hiccups. While performing a repeat MVD on the right side of his face he tried lifting two major arteries off the brain stem. The hiccups stopped. 

Out of curiosity and for research sake, Dr. Linskey released them and allowed them to go back where they were and the hiccups started back up again. When he lifted the arteries, they stopped. This confirmed that the cause of the hiccups was finally found! Since that surgery his right side has been not only TN pain free but he hasn’t had an abnormal case of hiccups since. 

Once Chris recovered from that surgery they did a repeat MVD for trigeminal neuralgia on the left side. That was in 2014 and he is still pain free to this day!! 

Although he cannot do any activities that might cause trauma to his head and has to avoid all sports, Chris is able to work part time. He is also studying online for his college degree, which he plans to receive this year. 

In that same year of 2014, he joined the Young Patients Committee of the Facial Pain Association. It is a small group of less than 10 people who are supportive of anyone with facial pain under the age of 40. They promote awareness and help research for the really young suffering from all types of facial pain (not just trigeminal neuralgia.) 

Chris also started his own foundation after his bout with cancer. He wants to give back to the community who “gave to my family and myself as we were going through everything. … I also wanted to raise funds for medical research for a lot of these radical conditions out there, especially trigeminal neuralgia. 

“I focus on raising funds for research … and I have actually raised and donated $692 from my foundation to the Facial Pain Research Foundation” by selling teal colored t-shirts with his foundation logo on the front.  A school friend of his hand knits teal scarves and he sells them also. All proceeds are donated to FPRF. 

Chris does all he can to get the word out and to bring awareness. He has been recognized by the mayor of his town in Tom’s River, New Jersey, a couple of times already, with township proclamations that show that his foundation’s efforts are being recognized. He received one in 2016 from Governor Christy proclaiming October 7th Trigeminal Neuralgia Awareness Day! Since then, Chris has also received multiple proclamations from the town council recognizing every time the foundation helps out or works to spread awareness. 

Chris volunteered that he wouldn’t change a thing if he could. “It helped sculpt me into the man I always wanted to be, that I was meant to be, and even if I had the opportunity to somehow stop everything from happening and go back in time and just live it out as ‘normal’ I wouldn’t change anything.” He is very insightful for his age. And very brave I might add. 

When asked for what advice he would give to anyone new to the pain of trigeminal neuralgia he replied “The number one piece of advice I would give is to not give up and to not lose hope because even though you may be faced with a hundred people saying ‘No. It’s not possible.’ that doesn’t mean that there is absolutely no help out there for you.” And “Let your heart kick in and just say ‘no I’m not going to give in until I get the answers - until I get the proper treatment. I know something wrong is going on right now.’” 

He added “It made me grow up much faster than I anticipated but in a way it also helped me.” I can vouch for that. Chris certainly seems a whole lot older and wiser than any 22 year-old I’ve ever known!

CODA Joins Facial Pain Research Foundation

International Scientific Consortium 

By Michael Pasternak

I am excited to say on New Years Day 2018, The Facial Pain Research Foundation (FPRF)  has six Foundation and two corporate funded scientific research projects actively working to find the cure for trigeminal neuralgia and related neuropathic pain.  The scientists working on these projects are members of our International Scientific Research Consortium.  In the past this World Famous WebNewspaper has printed numerous stories about the Foundation funded projects (see Dr. Douglas Andersons 2017 Report).  In October, 2017 the FPRF announced that Neurona Inc. (a corporate funded research project joined the FPRF Scientific Consortium. Neurona is focused on the discovery and development of cell-based therapies to treat intractable neurological diseases including TN and related neuropathic pain.  Today the Foundation is pleased to announce that CODA, another corporate funded scientific project, is joining the FPRF International Research Consortium. 

CODA Biotherapeutics is a San Francisco based pre-clinical stage biotechnology company developing a novel therapeutic platform for the treatment of chronic pain and other severe neurological disorders. CODA’s innovative platform relies upon a gene therapy approach to modulating aberrant neural activity, which CODA’s co-founders -- a team of forward-thinking biotechnology entrepreneurs, scientists, and clinicians -- believe will provide relief to patients suffering from intractable neuropathic pain such as that associated with trigeminal neuralgia and establish a new treatment paradigm for severe neurological disorders.  The entire CODA team enthusiastically welcomes the opportunity to join the Facial Pain Research Foundation’s Scientific Consortium in developing new treatment options for patients with trigeminal neuralgia.

Building upon the groundbreaking work of the company’s founders and Scientific Advisory Board members, several of whom have been associated with FPRF, CODA is using advanced synthetic biology approaches to engineer novel neurotransmitter receptors that respond selectively to non-addictive and non-opioid-based small molecules. These engineered neurotransmitter receptors are delivered to pain-signaling neurons using viral vectors by standard of care neurosurgical procedures. Hyperactive target neurons that express the receptor, including those in the trigeminal ganglia, can then be controllably silenced by oral administration of the safe small molecule. Because the treatment molecule exclusively activates the receptor, it is possible to achieve highly selective blockade of the critical pain signals from reaching the brain.  This effectively opens the “therapeutic window”, reducing the potential for adverse side effects. Preclinical studies in multiple neuropathic pain models have demonstrated that this technology provides robust, durable, tunable, and reversible pain control, without the side effects experienced with existing small molecule therapies (e.g. opioids, anticonvulsants, tricyclic antidepressants) or neurosurgical procedures (e.g. ablation, neurostimulation implants). CODA anticipates that this technology will be used to manage intractable chronic pain across a multitude of conditions, including trigeminal neuralgia, and it will be applied broadly to other peripheral and central nervous system disorders in the future.