Exploring neuroinflammatory biomarkers and predictors of the efficacy of botulinum toxin type A (BTA) in trigeminal Neuralgia

This is a new study by Lars Bendtsen from the Danish Headache Center of the University of Copenhagen. BTA has been used sparingly to treat TN over the last 5 years and there is no quality research to demonstrate the value of BTA, which could be underused and of great benefit to more TN patients worldwide. Additionally, there has been recent research that indicates that inflammation is playing a greater role in TN than was previously thought. BTA can affect the inflammatory process and therefore, can be used to help elucidate the underlying pathophysiology and identify the biomarkers that are affected by inflammation. This study will be a randomized, double blind, clinical trial of BTA in approximately 80 TN patients in Denmark. The study outcomes will be a measure of what proportion of TN patients respond to BTA, measures of the pain relief achieved, and identification of biomarkers affected by BTA. These biomarkers may prove to be a way to identify which patients will respond to BTA therapy and which patients will not, while also providing a better understanding of the role of inflammation in TN.

Primary Investigator:
Lars Bendtsen, MD, PhD, Dr.Med.Sci

In Search of a Cure: Finding the Genes that Predispose to Trigeminal Neuralgia

A compressed trigeminal nerve is sometimes the reason why a patient suffers. However, it’s a fact that many people, if imaged, would present a similar compression, but experience no pain. Why? That question inspired our scientists to hypothesize there is a genetic predisposition to TN. Their plan is to find these defective genes in TN sufferers, which could then provide targets for designing customized drugs or gene therapy. For their analysis, they collected DNA samples from nearly 1,000 patients at seven US locations, one in Canada, and one in the UK. Their findings from this analysis may unlock the mystery of why some people suffer, and so many others do not.

Current Status:

The collection, processing, and analysis work on this project has been completed. Because this is the first large scale genetic analysis ever done on TN, the team is taking extra time to verify the results by replicating the findings with genetic data from other databases. This replication work was not anticipated at the beginning of the study but will hopefully serve as further validation of the study’s results and make the findings more useful. The study findings are being prepared for publication and hopefully will be published this year. We expect significant findings from this study that will enhance future research for a cure to TN.

Investigators:
Scott Diehl, Ph.D.
Kim Burchiel, M.D.
Ze’ev Seltzer, BMS, DMD

Towards Gene Therapy for Trigeminal Neuralgia

The primary goal of this project, led by Dr. Todd Golde at the University of Florida, is to identify a novel gene therapy approach to treat and cure TN and related neuropathic pain. Gene therapies rely on a modified viral vector to enable delivery of the genetic “payload” to cells. In this case, the viral vector is, in essence, the “shuttle” that enables the payload to be delivered to the nerve. There are many potential genetic “payloads” that might be used to dampen or block pain signaling in the nerve. Our team’s research involves systematically evaluating various viral vector shuttles, and various delivery methods. In addition, they will generate payloads that suppress pain signaling by either knocking out (CRISPR mediated gene silencing), or reducing the level (miRNA based antisense approaches) of factors important in pain signaling.

Current Status:

This project was aimed at developing viral vectors (AV) that could transport chemical cargos to specific locations in the nervous system and knock out TN pain. The project began with a number of potential cargoes, and AV vectors that would be tested for efficacy. In the beginning it proved very difficult to build AV vectors that were compatible with the various cargoes that were identified. After much work, the AV vector problem was partially solved but the combination of vector and cargo did not reach the level of expression required in the nerve. The project has been put on hold and won’t be restarted unless some new techniques are developed to solve the issues.

Investigators:
Todd Golde, M.D., Ph.D.
Robert Caudle, Ph.D.
Yona Levites, Ph.D.
John Neubert, DDS, Ph.D.

Identifying Sensory Genes That Are Critical to Neuropathic Pain, Including Trigeminal Neuralgia

We believe we still don’t know all of the elements responsible for the initiation of Trigeminal Neuralgia pain. The question is which genes are critical and can these be selectively regulated to manage TN, but, to date, the focus of the field has been on a relatively small number of genes.  Dr. Allan Basbaum is examining a relatively large number, and wider variety of, genes using the “one gene at a time” approach. This study was prompted to a great extent by his team’s comprehensive analysis of a dorsal root ganglion (DRG) from intact and nerve-injured mice. This analysis identified almost 1200 genes that affected pain after the injury. To prioritize genes for future study as causing TN, they chose some that have been reported repeatedly in the scientific literature, genes that showed the greatest change in expression after injury, and the so-called dark genes which until recently have largely been ignored. The plan is to identify the genes that impact TN, and then create or find the therapies needed to “manage or fix” them to end the pain.

Current Status:

Dr Basbaum’ s project transitioned into a different study than initially envisioned, and his team has been looking at novel analgesic targets that have unique potential. They identified the alpha 2A adrenergic receptor(a2AAR) as a known pain receptor that is targeted by IV anesthetics (dexmedetomidine) that relieve pain and cause sedation.

Their hypotheses was that agonists of a2AAR that fit the receptor, but were chemically dissimilar to the anesthetics might have different effects and they might be able to separate the sedation from analgesia functions. To identify these agonists, they virtually reviewed each of the 301 million molecules in the ZINC15 library, to computationally determine which molecules would structurally fit with the similar a2bAR binding site, and dock with it. They prioritized results by those that physically fit the receptor and where chemically unrelated to known drugs and anesthetics.

They selected 48 potential compounds for further testing and several acted as partial or full agonists to the receptor. One of these compounds, 9087 not only worked well but also docked with fewer G protein subtypes than any known drugs, which is a positive sign that 9087 activates a more selective number of pathways than anesthetics.

Optimization work on the agonists identified a more potent analog compound called PS75. The physical features of these agonists allowed them to reach high brain concentrations after systemic dosing. In animal behavioral assays the agonists relieved pain behaviors of neuropathic, inflammatory and acute thermal pain. Most importantly none of the compounds caused sedation, even at high doses.

This work has shown that it is possible to separate the analgesic properties from the sedation effects of highly potent anesthetics with these new agonists. This makes them very high candidates for further drug development. These compounds are now being tested in a variety of pain conditions, including TN, to determine how broadly they work.

Investigator:
Dr. Allan Basbaum, Ph.D.

Mapping Towards a Cure: Finding the Brain Signature Centers that Cause Trigeminal Neuralgia

Led by Dr. John Neubert at the University of Florida, our team of researchers hypothesized that specific neural centers in the brain and spinal cord are active prior to, and during, a TN attack, essentially “lighting up” with activity. These neural centers hold the key to providing pain relief, as they give us a specific area to target for curative treatments- if we can block these centers, we can prevent the pain. Using highly advanced magnetic resonance imaging, our team has scanned over 60 TN patients, and located what we believe are the “pain centers” of TN patients.

Current Status:

This was a study aimed at identifying all the brain centers that are activated when a patient is experiencing TN Pain, so that we could track the pathway of the pain signal.

Other researchers have run similar studies in the past on other pain conditions, but they were not measuring actual patient pain levels at the same time that they measured brain activity as Dr. Ding has done. The test results and correlations are also difficult to interpret because all the studies produced different results which renders the other studies of limited use.

The team, led by Dr Mingzhou Ding, has just published the first of 3 papers on their research study into this issue which is entitled “Imaging the Neural Substrate of Trigeminal Neuralgia Pain Using Deep Learning”. The team measured real TN pain that occurred while the patients were being scanned in the fMRI, and then applied conventional correlation analysis and 2 different artificial intelligence (AI) inspired deep learning methods to the data. The two deep learning approaches used were convolution neural networks (CNN) and graph convolution neural networks (GCNN).

Overall these approaches found more new areas identified with TN pain and there is more consistency in the data. Six regions were identified in all 3 methods including the superior temporal, insula, fusiform, precentral gyrus, superior frontal gyrus and the supramarginal gyrus. This is important because as studies build convergence around the pain pathway, the more valuable the data becomes in identifying sites for clinical interventions to stop the pain. The data is also important as we begin to integrate the effect of genetic mutations on TN. Scientists can compare if certain mutations are related to significant signal areas in the pain processing pathway and better understand the mechanisms involved. These results utilizing a functional paradigm in which TN patients tracked their real pain level in real time shed new light on the pain pathway issue. In particular it was found that the neural activities in these 6 areas not only closely tracked the pain level fluctuations, but they also mediated network-level communications among different brain regions. Combining these AI inspired methods with conventional methods to seek converging evidence may become a promising method used in future neuroimaging studies. The next two papers from this study should be published by year end. We will then consider if any more research in this area should be conducted.

Investigators:
John Neubert, DDS, Ph.D.
Marcello Febo, Ph.D.
Mingzhou Ding, Ph.D.
Robert Caudle, Ph.D.

Evaluation of a Cellular Therapeutic for the Treatment of Trigeminal Pain

Neurona Therapeutics is a pre-clinical stage biotechnology company that was founded by four leading-edge neuroscientists and stem cell pioneers at The University of California, San Francisco. Led by Dr. Cory Nicholas, Ph.D., Neurona has formed a strategic research collaboration with the Facial Pain Research Foundation, to develop a human inhibitory interneuron therapeutic (neuro-stem cells) for the treatment of neuropathic pain conditions like TN.  As an example of the unique collaboration we foster between our scientists, our researchers at The University of Florida are providing the animal subjects to test whether Neurona’s neural stem-cells can stop neuropathic facial pain in animals. If successful, we will then move to human trials.

Current Status:

Neurona’s work on their inhibitory stem cell product has continued to progress. Unfortunately, Neurona is under the same financial market pressures as CODA was and they have had to refocus their immediate clinical work on the therapeutic indication that has the shortest time to market. Their product for refractory seizures is further developed than the TN product so they have to concentrate most of their effort on the seizure product right now. The preclinical work on seizures has gone well and serves as a proof of concept for their platform. In animal testing the product has been able to reduce hyperactivity in the nerve thus preventing seizures and has not shown any dose limiting toxicity. They have received an approval from the FDA to start phase 1 human clinical trials on this product which they are preparing for. We continue to engage with Neurona and are trying to determine when they will be able to focus more on their TN product.

Investigators:
Dr. Cory Nicholas, Ph.D.
Dr. John Neubert, Ph.D.
Dr. Allan Basbaum, Ph.D. 

Determining Efficacy of CODA ‘Switch’ Receptors in a Model of Neuropathic Pain

CODA Biotherapeutics, Inc., is a preclinical-stage biopharmaceutical company developing a gene therapy to stop TN. Led by Dr. Orion Keifer, CODA has formed a strategic research collaboration with the Facial Pain Research Foundation, with the goal of utilizing CODA’s chemogenetic gene therapy platform to identify and develop potential new therapies and cures for Trigeminal Neuralgia, and related neuropathic pain. Under the collaboration, CODA is working with the FPRF to establish a research continuum that is dedicated to identifying the mechanisms underlying neuropathic facial pain and to developing groundbreaking therapeutic strategies that aim to permanently stop the pain.

Current Status:

CODA’s is a biotechnology company developing a switch that could be inserted into a nerve using gene therapy. The switch would not respond to any natural chemicals or signals within the body. The switch would be controlled by taking a oral drug that could regulate the activity of the switch up or down by changing the dose of the oral drug. Placing this switch in a hyperactive nerve such as what occurs in TN could dial down the level of hyperactivity and hopefully return it to normal levels which would eliminate the pain. CODA’s work was significantly impacted by the Covid shut down, but when they could resume full operations they made good progress in screening multiple oral control drugs in combination with different switches. Unfortunately, the last 5 months has been very tumultuous in the biotech world with funding for biotech companies falling very dramatically. CODA ran out of money and could not raise new capital and they had to declare bankruptcy in February. There are still many scientists that believe in the CODA approach and maybe in the future someone will pick up their technology and bring it to completion. At this point the Foundation will have no further updates on this project.

Investigators:
Orion P. Keifer, Jr., M.D., Ph.D.

Cholesterol Homeostasis in Peripheral Nerve Myelin with a Focus on Statins

The aim of this research, led by Dr. Lucia Notterpek, Ph.D., was to prove that unhealthy and/or damaged myelin- the protective coating of nerves- is the reason why some patients have TN pain. We have confirmed this in animal subjects, and treatments to stop their pain by repairing this damaged myelin have been successful. We hope to achieve this in humans organically, through dietary supplements, rather than with medications, and believe this will be an effective therapy for those who’ve developed TN as a result of myelin-related causes.

Investigators:
Dr. Lucia Notterpek, Ph.D.
Dr. Susan Percival, Ph.D.
Dr. Wendy Dahl, Ph.D.

Exploring Neuropeptide Guided Botulinum Light Chain for Use in Blocking Pain Transmission

The overall long-term goal of this project is to begin a search for new, novel, pain control therapies to supplant highly addictive opioids.  Dr. Rob Caudle at the University of Florida has chosen botulinum toxins as his therapeutic agent, which have already proven very successful in treating migraine headaches.  However, he has modified these toxins with a unique research approach. The newly created substances are directed to the appropriate sensory neurons, which Dr. Caudle and his team have identified, where they are internalized, and disrupt neurotransmission- the result of which, is the inhibition of pain.

Current Status:

This project was funded by the foundation for several years and has achieved most of the project aims that were set out at the beginning of the study. The light chain version of Botulinum was found to be effect at stopping pain in animals and the therapy benefits persisted beyond the ability to measure them. The light chain version paralyzes only sensory nerves, there is no impact on motor nerve signals which makes it safer and easier to use. The study is now approaching the preclinical phase of work in preparation for clinical testing. The cost of this next phase of work is beyond what the foundation can fund, and when projects reach this level they need to attract government or industry funding to bring them to completion. Doctor Caudle is seeking a NIH grant.

Investigators:
Robert Caudle, Ph.D.

The Role of TMD in the Diagnosis of Trigeminal Neuralgia

There is considerable confusion regarding the diagnosis of TMD (Temporomandibular Disorder), and because of the lack of good diagnostic tools, many TMD patients end up being referred to neurologists and neurosurgeons as TN patients. Since there is significant symptom overlap between the two conditions, some of these TMD patients end up being mistakenly treated for TN.

The study will quantify how often TMD patients are mistakenly referred as TN patients. It will determine how many patients fit the diagnostic tools for both TN and TDM, and will define new diagnostic tools that will correctly predict a TMD patient. The result being a new protocol to screen oral facial pain patients for TMD suspects. The benefit of this work will be that TMD patients will be less likely to be treated for TN, and TN patients less likely to be treated for TMD because of an overlap in symptoms and the lack of good diagnostic tools.

Current Status:

This study is still collecting data so there is no update currently.

Investigator:
Kim Burchiel, M.D.

Click here to visit our library of published research articles on Trigeminal Neuralgia.