Targeting protein misfolding for drug discovery

We provide critical support to our Clients' target and lead discovery programs by offering access to a broad range of in vitro models and assays reflecting various aspects of proteopathies in neurodegeneration. With our ND service module, we can identify, prioritize, and validate both novel targets and lead compounds to progress our Clients' drug discovery programs.

Protein misfolding is closely linked to neurodegeneration

Progressive neuronal cell loss in the human brain is the pathological hallmark of several neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and Amyotrophic Lateral Sclerosis (ALS). Insights into the early processes triggering the neurodegenerative disease cascade is fundamental to the development of highly differentiated therapeutics for these diseases.

The pathophysiological hypothesis of several neurodegenerative diseases relies on the fact that certain proteins undergo changes in conformation, resulting in initially small oligomeric structures which over time progresses into large amyloid aggregates. By gain of function or loss of physiological function this results in neurotoxicity and neurodegeneration.

Neurodegenerative diseases associated with protein misfolding and aggregation are also called proteopathies. Multimodal animal and cellular modelling studies support that misfolded protein aggregation plays a crucial role in the neuronal vulnerability linked to neurodegeneration. Misfolded and aggregated proteins, such as α-synuclein in Parkinson’s disease and amyloid-β in Alzheimer’s disease, can affect many different intracellular mechanisms such as degradation pathways, mitochondrial function, membrane function and axonal transport.

Advanced in vitro model systems comprised of key neuronal cell types are necessary to accurately model aspects of neurodegeneration, and to increase our understanding on how different cell types, genes and cellular mechanisms are involved in protein production, misfolding, aggregation and clearance. Increased knowledge of these processes will ultimately lead to discovery and validation of new targets, and result in development of novel therapeutics.

Linnea Strid Orrhult
external collaborations manager

We have extensive expertise in creating novel assays for neurodegenerative disease research

“By combining our expertise in proteopathy disease modelling with advanced technologies, such as high content imaging and optical electrophysiology, we create high quality assays for target and lead discovery. Don’t hesitate to contact us if you would like to learn more.”
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Groundbreaking assay platform for proteopathy research

By using our advanced primary and stem cell cultures, target modulation and expression technologies, as well as proprietary readouts, we create highly innovative in vitro disease models for proteopathy-focused target and lead discovery.

Our ND service module is based on complex CNS in vitro disease models where aspects of neurodegeneration, such as protein aggregation and cellular toxicity, are replicated by addition of protein oligomers and fibrils¹. Gene silencing or overexpression technologies are employed to elucidate which genes and pathways directly or indirectly influence the pathogenesis of the protein aggregation².

Since the technologies employed are designed for high-capacity studies, our module can be used for studies ranging from detailed evaluation of the function of a single to a few genes, where the capacity is utilized to generate statistical power in a multitude of readouts, to thousands of genes, where the capacity is used in a more traditional screening context³.

Gain access to advanced in vitro systems

We have profound knowledge in the development and standardization of advanced co-cultures and have created a collection of in vitro systems that can be used for the creation of a broad range of disease models. These include rodent, humanized and chimeric models where cell types and composition of e.g. neurons, astrocytes and microglia can be tailored to answer the question at hand.

In vitro disease modeling strategies

We create highly relevant disease models using different strategies to recapitulate various aspects of neurodegeneration and neuroinflammation. Idiopathic-like disease models can be created by e.g. addition of protofibrils to induce endogenous protein aggregation, or by the addition of inflammatory mediators to simulate chronic neuroinflammation. Genetic models can be created from transgenic animals, in vitro genetic modulation tools or by humanized disease cell lines.

Gene modulation at scale

Through the use of target modulation and expression technologies, we can interrogate gene and pathway function in a disease-relevant setting at scales ranging from single target testing to high throughput genetic screening², ³.

Highly innovative readouts

We monitor progression and modulation of protein aggregation, as well as subtle morphological changes associated with neurodegeneration, with high content imaging and super-resolution methodologies where our proprietary high-capacity microfluidic platforms can be used to further decipher mechanisms⁴. Optical electrophysiology and advanced data analysis methodologies are employed to detect alterations in synaptic function, stemming from neurodegenerative processes, in a truly phenotypic manner.
Johan Pihl
CSO

Your partner for neurodegenerative disease drug discovery

“We engage with our Clients to establish research programs aimed at achieving novel drug discovery options for neurodegenerative diseases. With our unique discovery platform, we are positioned to support the advancement of the neuroscience research field.”
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Case studies

As the ND service module is designed for high-capacity testing, it is most powerful for early drug discovery applications. These include target identification and target validation, where defined targets are explored for their capability to affect neuronal function and morphology. In addition, the platform is highly suitable for screening of test compound libraries and further characterization of novel molecules. For example, the technology has been successfully used in Client projects for target validation programs.


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References

1. S. LARDELL, L. MOLL, C. NODIN, L. STRID ORRHULT, J. PIHL;
CELLECTRICON AB, CELLECTRICON AB, MÖLNDAL, SWEDEN. DEVELOPMENT OF AN IN VITRO Α-SYNUCLEIN AGGREGATION ASSAY IN PRIMARY CORTICAL CULTURES FOR TARGET DISCOVERY AND VALIDATION. PROGRAM NO. 703.02. 2022 NEUROSCIENCE MEETING PLANNER. SAN DIEGO, CA: SOCIETY FOR NEUROSCIENCE, 2022. ONLINE

2. LINNEA STRID ORRHULT1, EMMY RANNIKKO2, ANNE VUORENPÄÄ2, JOHAN PIHL3, PAUL KARILA1, ANDRII DOMANSKYI2, IBRAHIM MALIK2;
1 CELLECTRICON AB, DISCOVERY, MÖLNDAL, SWEDEN; 2 ORION CORPORATION, DISCOVERY, TURKU, FINLAND; 3 CELLECTRICON AB, R&D, MÖLNDAL, SWEDEN. PROGRAM NO. P0805 / #624. AD/PD 2023 INTERNATIONAL CONFERENCE ON ALZHEIMER’S AND PARKINSON’S DISEASES; GOTHENBURG, SWEDEN.

3. S. LARDELL1, Å. JÄGERVALL1, A. BACK1, J. SJÖHOLM1, M. SVEDMAN1, T. BELLANDE2,3, R. MELKI2, J. TÄGER4, P. HEUTINK4, C. VOLBRACHT5, G. K. TOFARIS6, J. PIHL1;
1 CELLECTRICON AB, MÖLNDAL, SWEDEN; 2 CEA, INST. FRANÇOIS JACOB (MIRCEN), FONTENAY-AUX-ROSES, FRANCE; 3 CNRS, LAB. OF NEURODEGENERATIVE DIS., FONTENAY-AUX-ROSES, FRANCE; 4 CTR. FOR NEURODEGENERATIVE DIS. (DZNE), TÜBINGEN, GERMANY; 5 NEUROSCI., H. LUNDBECK A/S, VALBY, DENMARK; 6 NUFFIELD DEPT. OF CLIN. NEUROSCIENCES, UNIV. OF OXFORD, OXFORD, UNITED KINGDOM. VALIDATION OF AN IN VITRO ALPHA-SYNUCLEIN AGGREGATION ASSAY IN PRIMARY CORTICAL CULTURES FOR HIGH THROUGHPUT RNA INTERFERENCE SCREENING. PROGRAM NO. 703.10. 2022 NEUROSCIENCE MEETING PLANNER. SAN DIEGO, CA: SOCIETY FOR NEUROSCIENCE, 2022. ONLINE.

4. L. STRID ORRHULT1, N. ARBEZ2, P. DELAGRANGE3, J. PIHL1, M. KARLSSON1;
1 CELLECTRICON AB, CELLECTRICON, MÖLNDAL, SWEDEN; 2 CELL. SCI. DEPT., 3 NEUROL. AND INFLAMMATION THERAPEUT. AREA, INST. DE RECHERCHES SERVIER, CROISSY SUR SEINE, FRANCE. DEVELOPMENT OF AN ASSAY FOR COMPOUNDS MODULATING TYROSINATION AND DE-TYROSINATION IN MOUSE CORTICAL CULTURES USING MICROFLUIDIC CO-CULTURE PLATES. PROGRAM NO. 085.10. 2022 NEUROSCIENCE MEETING PLANNER. SAN DIEGO, CA: SOCIETY FOR NEUROSCIENCE, 2022. ONLINE.