In this interview, industrial expert Phillip Mitchell discusses the role of NFL-Biomarkers in discovering CNS medicines, research into neurodegenerative diseases, treatment monitoring, neurotoxicity detection and ai-driven biomarker selection.
Can you tell us about your background and the current role?
My name is Phillip Mitchell, I am currently a scientist director at Charles River Laboratories. I have a background in biochemistry and a Ph.D. In molecular biology. My career includes more than 30 years in discovering medicines, which include roles in the academic world, biotech, pharmaceutical environments and more recently, the contract research organizations sector.
What are some of the most important challenges and recent progress in biomarkers for discovering the central nervous system (CNS)?
CNS diseases represent a growing global health burden that is partly attributed to an aging population. Even with an improved understanding of disease mechanisms, however, a high failure percentage in discovering neuroscience, often because of the challenges of efficacy, remains. Moreover, many clinical investigations rely on subjective measures assessed by doctors as primary end points, which can be time -consuming and can be susceptible to variability.
In recent years, Neuroimaging Biomarkers, such as Posit RroneemissietoMography (PET) Liganden, have contributed considerably to the clinical stages of the development of the central nervous system by helping with the dose determination for research drugs that focus on new mechanisms. The discovery of less invasive, liquid -based biomarkers, especially in cerebrospinal liquid (CSF) and blood, has also been an important role in promoting CNS Biomarker Research, although there are remarkable challenges.
A prominent example is NeuroFilament Light (NFL), a structural protein that is found exclusively in neurons. NFL plays a crucial role in the stability of neuronal structures, in particular in large, gemelinated axons, which depend on NFL for radial growth. Low levels of NFL are continuously issued under normal circumstances, but a significant increase can occur in response to axonal damage caused by inflammatory, neurodegenerative, traumatic or vascular events. Given its stability and abundance, NFL is a valuable biomarker for assessing the health of CNS.
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How is NFL -Measurements applied in vitroPre -clinical and clinical stages of discovering and development of medicines?
NFL has extensive applications such as Biomarker in various stages of CNS research, from in vitro and pre -clinical studies for clinical examinations. In vitro Studies have used NFL to measure inflammatory toxicity by measuring microglia in response to Antisense Oligonucleotides, for example. Similarly, pre -clinical models have shown that plasma and CSF NFL levels can indicate axonal health and disease progression in models of neurodegenerative and neuro -inflammatory diseases.
NFL levels are a surrogate biomarker in clinical environments used to follow the health of the central nervous system, to follow the sensitivity of neurodegenerative diseases and evaluate the effectiveness of treatment. The consistent sensitivity of NFL in these stages makes it invalidable for monitoring axonal degeneration and assessing neurotoxicity risks, underline his crucial role in therapeutic development and patient safety.
How does Nfl function as a biomarker for neurodegeneration and CNS -in the event of?
High NFL levels in CSF indicate leakage from wounded or degenerating neurons and research has shown that increased CSF NFL is strongly correlated with CNS -lessel. For example, a 2006 study on amateur boxers found a significant increase in CSF NFL after attacks, with levels that fell after the break. In addition, higher basic line -NFL levels are associated within the severity of injuries and faster disease progression in disorders such as Amyotrophe Lateral Sclerosis (ALS).
Numerous studies have shown a strong correlation between plasma and CSF -NFL levels, which suggests that plasma measurements can effectively reflect the current CNS damage. However, because NFL levels in plasma are typically lower than in CSF, ultra-sensitive tests are essential for accurate quantification.
In the context of neurodegenerative diseases such as Huntington and Alzheimer’s disease (AD), increased NFL levels in patient plasma and CSF serve as valuable diagnostic and prognostic indicators, correlating disease progression and helping to distinguish between different levels of injury.
How is NFL used in advertising research and what insights do it offer for the risk of dementia?
Increased NFL levels are typically observed in AD patients, compared to patients with mild cognitive impairment or healthy checks. Plasma NFL levels, however, increase with age, even with healthy populations, so these measurements must carefully consider the age. When used in addition to other biomarkers, such as amyloid-beta 42, NFL shows promising when identifying people with a higher risk of developing dementia.
This combined biomarker approach can improve the selection of the patient in the clinical studies of Alzheimer’s. Recent studies have established reference levels of Plasma-NFL in different ages, which contributes to the integration of NFL measurements in diagnostic and disease routines for neuropsychiatric and neurodegenerative disorders.
How can NFL levels indicate the treatment reactions in neurodegenerative diseases such as spinal muscle atrophy?
NFL levels have proven valuable in following treatment reactions in spinal muscle atrophy, which causes Motor neuron degeneration. For babies and children who were treated with the Antisense Oligonucleotide -Nusinersen, for example, NFL levels in CSF were normalized after treatment, coinciding with remarkable engine function improvements. This rapid decrease in the NFL levels suggests that NFL could serve as an early response marking, which helps doctors to assess the effectiveness of treatment and leading therapeutic decisions.
Similarly, a recent study was presented with -patients treated with Tofersen significant reductions of the NFL levels of plasma, although the primary clinical endpoints of treatment were not. The FDA granted approval based on these changes in the biomarker and underlined the role of NFL as a response marker for neurodegenerative disease treatments.
What is the meaning of NFL as a safety biomarker for detecting neurotoxicity induced neurotoxicity?
NFL levels offer a non-invasive, sensitive approach to detecting neurotoxicity, which is crucial for evaluating the safety of certain treatments, such as chemotherapy, known for causing peripheral neuropathy. Research has shown that changes in Serum -NFL levels subsequently start and severity of peripheral neuropathy can predict, so that clinicians can balance treatment effectiveness with the safety of the patient.
The role of NFL as a neurotoxicity marking has also been translated into pre -clinical institutions. In a phase 2b study for Huntington’s disease with the drug branap lam, some patients, for example, developed peripheral neuropathy. Follow-up studies showed increased NFL levels in animals treated with branaplam, despite the absence of neurological symptoms, which strengthens the usefulness of NFL as a pre-clinical security biomarker.
How does artificial intelligence (AI) currently influence the selection strategies for biomarkers?
AI improves the discovery of biomarkers considerably by rapidly analyzing large databases, including Proteomica, Metabolomics and Transcriptomics. AI streamlines data mining and helps to identify new biomarkers and therapeutic goals by analyzing risk factors of diseases.
At Charles River Laboratories we recently collaborated with Aitia, a company that specializes in AI-led Biomarker prediction. This collaboration uses cancer patient-dedicated xenographt models to create “digital twins” that simulate the reactions of the patient and offer a precise, efficient approach to biomarker selection when discovering medicines.
About Phillip Mitchell
Phil Mitchell has been promoted in molecular cell biology (cancer) of the Institute of Cancer Research, and a BSC -Hons in Biochemistry of the University of Liverpool. He is currently the scientific director of integrated biology at Charles River Laboratories, where he has led pre -clinical drug discovery efforts for more than eight years, specialized in the development of assays and in vitro pharmacology.
About Charles River Laboratories
Bee Charles RiverWe are passionate about our role in improving the quality of people’s life. Our dedicated team of pre -clinical neuroscience CRO scientists want the same as you: finding a cure for the devastating diseases of the central nervous system. From basic research to approval of the regulations, we have the leading science, the reach of services and a cooperation approach that you need to discover and develop new therapies.
We understand the challenges and complexities in the search for possible therapies for neurological disorders. The combination of our extensive drug discharge services and expertise in the field of neuroscience supports the creation of adaptable, innovative and efficient solutions for your research. Our team of neuroscientists continues to establish the most relevant in vitro And In Vivo Models and tests of acute and chronic neurological diseases to help our partners identify and test new connections in this challenging area.