CNS drug discovery isn't for the faint of heart. We can't be deterred by clinical failures, but it's clear that some approaches aren't working. It's time to start over, building upon the foundations of our current research. It's time to explore new tools and techniques, gathering the data that drives confident decisions in the earliest stages of development. It's time to break through with discovery of new, long-awaited therapies. Collaboration is key, as we pool knowledge and share experience that will allow us all to reach our goals.
The Disruptors: Conversations in Science
To pay homage to the most disruptive and visionary scientists leading the effort on the frontlines, Charles River is sharing stories about the state and direction of scientific research, discovery, and therapeutic development.
Meet the Disruptors
Preclinical Neuroscience Research Services
Antibody Discovery and Optimization
Antibody engineering advances have allowed for the fastest, most diverse, and optimized lead discovery in neuroscience disease areas. Shortening timelines and improving translational outcomes is possible, as illustrated in this GPCR case study of how a panel of novel inhibitors to CXCR5 were generated using the antibody library for antibody discovery and the Tumbler antibody optimization platform.
Antisense Oligonucleotide (ASO) Screening
ASO screens can be designed to evaluate a variety of proven mechanism of action approaches for antisense oligonucleotide therapy. To date, we’ve developed ASO screening assays primarily for rare neurodegenerative disorders.
CRISPR Cas9 gene editing has transformed drug discovery and development. It has been used successfully for editing the Huntington CAG repeat in human iPSCs and for high-content screening of disease-relevant in vitro assays for ALS.
In CNS research, we use high content imaging to characterize stem cell-derived neuronal lineages and a host of validated assays like apoptosis, autophagy, protein aggregation, cell or mitochondrial motility and migration, epigenetic modifications, maker expression, protein acetylation and phosphorylation, receptor internalization and degradation, sub-cellular localization and translocation of transcription factors.
Utilizing vast compound libraries, chemists use high-throughput screening to rapidly identify promising compounds for neuroscience target validation and identification.
Generating induced pluripotent stem cells (IPSCs) for neurological disease-relevant assays, coupled with specific differentiation protocols for production of neurons and/or astrocytes, improves translation to in vivo models.
Our ion channel assays guide your early screening investigations and selectivity profiling with 120 targets organized in functionally-validated disease areas. CNS-focused Channel Panels™ include pain, psychiatric disorders, neurodegeneration, and seizure disorders.
Modern medicinal chemistry is highly multidisciplinary, driving CNS drug discovery innovation from novel synthesis and delivery to screening. Small molecule and large molecule CNS targets range from GPCRs to kinase inhibitors and have proven useful for studying diseases of neurodegeneration such as Parkinson’s disease and Huntington’s disease.
Neurological disease research and drug discovery uses proteomics to search for disease or pharmacological signatures. This allows us to understand biological mechanisms and identify specific proteins and their modifications, e.g., ubiquitination or phosphorylation in Parkinson’s disease and Huntington’s disease models.
The Charles River Accelerator and Development Lab (CRADL™) offers turnkey vivarium rental space for both emerging and well-established biotech companies. Two locations, CRADL™ East in Cambridge, MA and CRADL™ West in South San Francisco, CA, serve researchers on both coasts of the United States.
Using CRISPR/Cas9 genome editing to create unique rat and mouse models of neurological disease offers the advantages of time savings, reduction in animal use, and improved overall cost-effectiveness.
Microbiome & Next Generation Sequencing
In recent years, the connection between the gut microbiome on host physiology and the onset of neurological disease has become recognized as an important area of interest. Next generation sequencing can assess the biodiversity of your animal colony and research experiments.
Neurological Surgical Procedures
Our skilled veterinary surgeons and technicians perform a comprehensive selection of procedures for rats, mice, guinea pigs, and large animals, including bilateral brain cannulation, microdialysis probe implantation, spinal nerve ligation, 6-OHDA Parkinson’s disease lesion models, and more.
You can reduce attrition rates with animal models that closely mimic neurological diseases. We can support your neuroscience research with a range of standard and custom in vivo pharmacology models for Alzheimer’s, Parkinson’s, psychiatric disorders, pain, brain injuries, and more.
Where small molecule drug therapy has failed, RNA interference has emerged to silence specific genes such as those identified for genetic neurodegenerative disorders like spinocerebellar ataxia and Huntington’s disease.
From CNS early discovery through clinical sample analysis, we continually develop and validate comprehensive bioanalysis (via mass spectrometry, immunohistochemistry, cell-based assays, flow cytometry, molecular biology, PK/PD, and biomarker) assays to meet the ever-changing demand of innovative drugs through the pipeline.
Predictive biomarkers are critical tools in CNS drug discovery and development, as they assess activity of candidate therapeutics and validate targets to provide mechanism of action, therapeutic efficacy, and toxicity.
Measuring behavioral changes is widely used for neurological diseases associated with cognition, psychiatric disorders, and neurodegeneration. This method is especially powerful when performed together with in vivo assays that assess neurochemical changes in the same animal.
Assessing the functional activity of your neuronal cell cultures, brain slices, or tissue can be cumbersome. Whatever your therapeutic area – neuromuscular, schizophrenia, neuropathic pain, or epilepsy – we have the equipment and expertise to conduct automated patch-clamp electrophysiology and multi-electrode array studies.
Impairment of motor skills is used as an early diagnosis marker in neuromuscular and neurodegenerative diseases. To test therapeutic compounds in animal models, characterizing fine motor impairment can reveal early changes in disease models and provide an opportunity to pharmacologically manipulate.
Microdialysisis a noninvasive method for collecting CSF and other fluid samples from the brain or tissues of awake animals. Samples are typically analyzed using LC-MS to assess neurochemical metabolites, therapeutic efficacy windows, or fluid biomarkers.
We can study neurotransmitters and metabolites from many different types of biological matrices using a variety of bioanalytical tools such as LC-MS, electrochemical detection, or fluorescence detection.
Neurological small animal imaging methodologies have the potential to dramatically increase the efficiency of lead candidate selection by providing earlier and more highly predictive data. See what state-of-the-art noninvasive preclinical imaging like pharmacological MRI, nuclear, and functional ultrasound imaging can add to your program.
Cognitive changes are challenging to measure in animal models. Touchscreen testing measures mouse behavior by recording a mouse’s actions and screen touch responses to images and locations on a computer screen.
Abuse and Dependence Liability Testing
Any new chemical entity that penetrates or targets sites in the central nervous system requires an assessment for abuse and liability. Our specialized neurobehavioral testing strategies can help you assess CNS-mediated effects in compliance with both international health and drug control guidelines.
Our comprehensive suite of in vitro assays and in-life capabilities enable the design of compounds that penetrate the tight junctions of the blood-brain barrier whilst avoiding efflux by transporters such as p-gp. This is imperative to achieve sufficient free-drug exposure in the brain to exhibit a pharmacological effect.
Services in neuropathology range from whole-body perfusions to specialized staining capabilities. Our skilled team of pathologists regularly assists with study design, development strategies, and regulatory submissions for a wide variety of compounds affecting the nervous system.
Testing your therapy for adverse effects on the chemistry, structure, or function of the nervous system is critical. Our neurotoxicology program is dedicated to a broad range of products from biologics to small and large molecules in both rodent and nonrodent species.
We incorporate both in vitro and in vivo models and assays into our toxicology and safety pharmacology studies. These range from in vitro electrophysiology assays that assess potential risks for specific neurodegenerative and neuroinflammatory diseases such as Huntington’s disease or neuropathic pain, to the design of FOB/Irwin screening in animal models.
From early discovery to animal model development to safety assessment, quantification of neuronal subpopulations and other central nervous system components can be a vital endpoint. Because the brain is such a unique and heterogeneous tissue, unbiased stereology is the only way to accurately quantify its structures.