Date: September 1, 2016
Two recent major initiatives, the European Commission's Human Brain Project and the NIH's Brain Research through Advanced Innovative Neurotechnologies (BRAIN) have put a renewed focus on the development and application of innovative technologies for neuroscience. Our Fall event will highlight the use of neuroscience technologies especially with respect to applications within Drug Discovery and Cognitive Health.
We're excited to announce that the Society for Laboratory Automation and Screening will be giving away a full registration (a $1,075 value) to SLAS2017. One name will be drawn at random from entries received during the event at the end of the technical program. Don't miss this opportunity to join LRIG members February 4-8, 2017, in Washington, DC! More details on SLAS2017 are available at slas2017.org.
Using In Vivo Optogenetics to Identify Novel Druggable Targets in Specific Neuronal Circuits
Circuit Therapeutics is the industry leader in optogenetics, pioneering new treatments using this groundbreaking tool. Optogenetics utilizes light to excite or inhibit nerve cells with precision and biologically-relevant timing. This transformational technology is enabling researchers to modulate neurons and neural circuits in vitro and in vivo to gain insight into the circuits function in health and disease, to simulate disease state, or for development of new therapeutic interventions. Optogenetics has gained rapid acceptance globally and is being used in research laboratories worldwide.
Optogenetics requires two key components: A light-sensitive protein, or opsin, and light. Depending on the opsin, light can either activate neurons with excitatory opsins (Channelrhodopsin), inhibit neurons with inhibitory opsins (NpHR, eArch), or initiate cellular signaling cascades (OptoXR). By activating or inhibiting individual circuits in the central and peripheral nervous systems, we can modulate the animal's behavior, explore the fundamental function of a given circuit, or modulate the specific symptom of a disease. The understanding of the consequences of activating or inhibiting individual circuits on symptoms and behaviors leads to novel treatments and therapeutics.
Using Optogenetics we map brain circuits that are responsible for specific neuropsychiatric disease symptoms, and gain insights into the etiology of the disease. By characterizing the underlying neuronal sub-populations we are able to discover novel drug targets that modulate these circuits. We can then use circuit-based rodent models to test drugs, and use our understanding of circuitry to perform more effective clinical trials, delivering the right drug to the right patient. Optogenetics facilitates new ways to approach drug development in the nervous system with the potential to treat any neurological disease with higher precision and less side effects.
Novel Blood Brain Barrier Target Validation with Gyros ELISA Platform and Phenix High Content Imaging System
The blood-brain barrier (BBB) poses a major challenge for developing effective antibody therapies for neurological diseases. Using proteomic analysis of isolated mouse BECs, we identified multiple highly expressed proteins, including basigin, Glut1, and CD98hc. To measure if these targets can be utilized to bring therapeutic antibodies into the brain, Bispecific antibodies were generated, pairing with an anti BACE arm to reduce AΒ in the brain in order to further demonstrate that the antibodies are delivered into the brain parenchyma as measured by pharmacodynamic response. When assaying antibody concentration in the serum and brain, we encountered strong matrix interference. To overcome this issue the human IgG assay was generated in the Gyros platform which was able to tolerate up to 10% brain matrix. Using the Gyros human IgG assay we were able to show that antibodies against CD98hc showed robust accumulation in brain after systemic dosing, and a significant pharmacodynamic response as measured by brain AΒ reduction. To further investigate safety profile of targeting CD98hc, we generated a cell based amino acid uptake assay and also investigated the trafficking of internalized antibody and CD98hc using Phoenix high content imaging system. We were able to demonstrate that antiCD98hc antibodies did not block amino acid uptake in cell based assays and did not induce CD98hc trafficking to the lysosome. The discovery of CD98hc as a robust receptor-mediated transcytosis pathway for antibody delivery to the brain expands the current approaches available for enhancing brain uptake of therapeutic antibodies.
Leveraging Mobile Technology to Enhance Cognitive Health
Cognitive control is defined by a set of neural processes that allow us to interact with our complex environment in a goal-directed manner. Humans regularly challenge these control processes when attempting to simultaneously accomplish multiple goals (multitasking), generating interference as the result of fundamental information processing limitations. Furthermore, these same cognitive control abilities show distinct impairments not only when one ages, but also when faced with a number of clinical impairments. Here I will describe our novel approach to characterizing and remediating deficiencies observed in these cognitive control abilities using video game like technology in healthy young and older adults, as well as clinical populations involving ADHD, autism, and depressed individuals amongst others. The research associated with these efforts will describe one particular cognitive training approach for older adults using a custom video game called NeuroRacer: critically, this training resulted in performance benefits that extended to untrained cognitive control abilities (enhanced sustained attention and working memory), with an increase in neural activity associated with cognitive control predicting the training-induced boost in sustained attention and preservation of multitasking improvement 6 months later. These efforts now extend to using these tools in different populations and technologies: Dr. Anguera will take conference attendees further into the realm of mHealth technology and applications as he shares the results of the BRIGHTEN study on how incorporating mHealth technology can improve recruitment and retention for clinical trials. His session also will address the value of mHealth technology in working with mental health issues, and how leveraging approaches and innovations typically seen in the video games can positively disrupt the way cognitive control abilities are assessed and remediated today.
High-Throughput Screening of State Dependent Nav 1.7 Sodium Channel Modulators in Automated Electrophysiology Assay
Ion channels regulate cell membrane electrical signal excitability, signal propagation, fluid homeostasis, hormone and transmitter secretion, thus are important drug targets for many pathological conditions. Emerging evidence implicates that voltage gated sodium channel Nav1. 7 is the threshold channel mediating pain sensitization in humans by amplifying small subthreshold depolarization in peripheral nerve fibers and dorsal root ganglia. Multiple technology platforms have been established for voltage gated sodium channel drug screening, however electrophysiological patch clamp remains the gold standard method by offering the most direct and information-rich assay, but is limited by throughput. Here we report the recent breakthrough of utilizing automated patch clamp (APC) technology to screen for Nav1.7 modulators from a ~10,000 compound library. The APC screening was optimized by balancing cell patching success rate, signal window, signal stability, and reference inhibitor sensitivity. The overall whole cell APC success rate was achieved at 81%, with average Z Prime 0.72, and correlation coefficients R > 0.9 with conventional manual patch clamp. A GeneData high-throughput data analysis method was also developed to achieve fast data analysis. Follow-up hit confirmation, subtype selectivity and mechanism of action studies were also performed. In summary, the results demonstrate that our newly developed APC and HTS data analysis platform provides a robust and reliable electrophysiological functional assay for Nav1.7 modulator screening and lead profiling.
For general or vendor inquiries regarding LRIG Bay Area, contact Mike Biros.
Thanks to our sponsors: