Drug discovery in the peripheral nervous system

Targeting diseases such as ALS and Chronic pain, our PNP service module was developed for everything from mechanistic studies to large-scale target and lead discovery projects. Our native neuronal disease models are fully validated and can easily be customized to suit your specific needs.

Our PNP service module is relevant for several diseases

A large fraction of the human population is diagnosed with peripheral neuropathy. The unmet medical need, and the increasing understanding of the etiology, offers an attractive opportunity for drug development. To aid our Clients in identifying new, safe and efficacious medicines, we have developed the PNP service module.

There are many potential causes of peripheral neuropathies, including trauma, autoimmune diseases or viral and bacterial infections. Diabetic neuropathy is among the most common causes of peripheral neuropathy affecting 30% of diabetic patients.

Despite the fundamental difference between these insults, the development of peripheral neuropathies shares some common mechanisms. For example, both inflammatory processes associated with conditions like autoimmune neuropathies and infections can result in the release of pro-inflammatory molecules.

Patients with peripheral neuropathy suffer from abnormal signal transduction between the peripheral nerves and the central nervous system, often caused by changes in neuronal excitability. Common symptoms are numbness, tingling, muscle weakness and pain. Paradoxically, also a loss of sensation can occur which will lead to a reduced ability to perceive environmental insults¹.

lydia moll
external collaborations manager

We have extensive expertise in creating models of peripheral neuropathies

“We have developed a range of high-quality in vitro models which have been validated with industry Clients. Combining functional and morphological readouts in native neuronal models, as well as microfluidic technology, we can support everything from detailed studies on mechanism of action to high-capacity screening campaigns for Target and Lead Discovery.”

Physiological relevance

Our module is based on advanced in vitro models derived from native tissue or human stem cells where relevant proteins are expressed and functional. Neuronal stimulation paradigms are employed and combined with integrated functional and morphological readouts to facilitate data interpretation.

Versatility

The possibility to utilize both native and human iPSC-based disease-in-a-dish models enables us to select the most relevant, cost-efficient model for each scientific question. The diversity of our assays facilitates translation of data to both in vivo and clinical testing phases.

Capacity and scalability

Using our high-capacity platform, we exclusively work in 384- and 96-well formats. We therefore have sufficient throughput to support everything from detailed studies on mechanism of action to medium throughput screening campaigns for Target and Lead Discovery.

Quality

Our high-quality in vitro models generate highly reproducible results between repeat measurements and over extended time. This enables detection also of modest effects of drugs and target manipulation. The data we produce will truly aid your decision-making.

A versatile module for drug discovery in the peripheral nervous system

Our PNP module is based on a set of in vitro disease models where the effect of manipulating targets can be assessed with both functional and morphological readouts. The module is designed to be useful in the early stages of the Drug Discovery process – from target discovery and HTS, and all the way to mechanistic studies of advanced compounds before progressing to Development.

As one of the key changes that occur are alterations in neuronal excitability, we have established a range of validated peripheral neuronal hyperexcitability models. These models are applied in our proprietary high-capacity optical electrophysiology platform where we quantify changes in excitability, caused either by genetic modulation of targets of interest or by the addition of test compounds, in a highly reproducible manner.

The immense validation data generated in our labs over the past ten years show that targets relevant for chronic pain are present and can be modulated in rodent native neuronal peripheral ganglia models²^, ³^,⁴^,⁵ as well as in human iPSC-derived neuronal models⁶^,⁷. The module is also highly suitable for peripheral aspects of modeling ALS such as the neuromuscular junction.

Broad range of in vitro models

We have established a range of advanced peripheral neuronal models where hyperexcitability is induced by chemicals, such as nerve growth factor (NGF), inflammatory mediators and chemotherapy drugs, or through nerve lesions. The models are either based on rodent native neuronal peripheral ganglia, such as DRGs, or human iPSC-derived peripheral neurons.

Functional readouts

Using our proprietary high-capacity optical electrophysiology platform we can quantify changes in excitability caused either by genetic modulation of targets of interest or by the addition of test compounds. For more detailed follow-on studies, multielectrode array (MEA) technology can be applied.

Morphological readouts

We are using state-of-the-art HCA systems to quantify changes in morphological parameters such as neurite outgrowth and Wallerian degeneration. High content imaging can either be used stand-alone or in combination with our optical electrophysiology platform to become even more powerful.

Compartmentalized co-cultures

When disease is caused by malfunctioning intercellular communication, as in ALS where the communication between motor neurons and striated muscle is impaired, it is valuable to be able to isolate the two cell types. To enable rational study of such interactions, we have developed a proprietary high-capacity microfluidic co-culture plate⁸, ¹⁰.

Jennie Svensson Dalén
Director of Marketing

Your partner for peripheral neuropathy drug discovery

“With our peripheral neuropathy service module, we are well equipped to support our Clients’ drug discovery efforts targeting important diseases such as chronic pain and ALS. We are the ideal partner for conducting functional and morphological screening in neuronal models of the peripheral nervous system for Target and Lead Discovery, and mechanistic studies of advanced compounds before progressing into Development.”

Case studies

As the PNP module is designed for high-capacity testing, it is most powerful for early drug discovery applications. These include target identification (i.e. genome screening) and target validation where typically a defined list of targets are explored for their capability to affect neuronal function ¹¹. It also includes screening of test compound libraries and further characterization of novel molecules. For example, the technology has been successfully used in Client projects for target-based screening programs where up to in the order of hundred thousand molecules have been screened to identify sodium channel modulators⁹. In addition, the module has been applied in phenotypic screening programs of up to ten thousand molecules where compounds affecting neuronal excitability in the spinal cord were identified.

Download Case Study (PDF)

References

1. Marchettini P, Lacerenza M, Mauri E, Marangoni C. Painful peripheral neuropathies. Curr Neuropharmacol. 2006 Jul;4(3):175-81. doi: 10.2174/157015906778019536. PMID: 18615140; PMCID: PMC2430688.

2. Nodin et al., 2017; Development of a high capacity assay for identification of rnai or small molecule-mediated effects on excitability in pain conducting sensory neurons. 6th International Congress on Neuropathic Pain.

3. Sidders B, Karlsson A, Kitching L, Torella R, Karila P, Phelan A. Network-Based Drug Discovery: Coupling Network Pharmacology with Phenotypic Screening for Neuronal Excitability. J Mol Biol. 2018 Sep 14;430(18 Pt A):3005-3015. doi: 10.1016/j.jmb.2018.07.016. Epub 2018 Jul 18. PMID: 30030026.

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1 Neurosci., Genentech Inc, South San Francisco, CA; 2 Dept. of Neurosci., 3 Genentech, Inc., South San Francisco, CA; 4 Neurosci., Genentech, South San Francisco, CA; 5 Cellectricon AB, Mölndal, Sweden. A transgenic model with humanized TRPA1 pore domain enables study of human-selective TRPA1 inhibitors in the rat. Program No. 483.25. 2019 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2019. Online.

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6. Karila, P et al., 2017; A humanized screening platform for chronic pain; 6th International Congress on Neuropathic Pain.

7. Tams, D., Karila, P. & Barnes, A. A humanized phenotypic screening platform for chronic pain. Nat Methods 14, 636 (2017). https://doi.org/10.1038/nmeth.f.401

8. L. MOLL1,2, C. NODIN1, C. I. SVENSSON2, P. KARILA1;
1 Cellectricon AB, Mölndal, Sweden; 2 Karolinska Institutet, Solna, Sweden. A high-capacity in vitro co-culture platform for the study of synaptic transmission. Program No. 128.09. 2022 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2022. Online.

9. P. KARILA1, E. P. LEBOIS2, Å. JÄGERVALL1, P. SPRATT4, K. BENDER4, D. LAL5, M. WEÏWER2, J. CAMPBELL2, H.-R. WANG2, S. CHOI2, A. GHOSHAL2, D. BAEZ2, M. FITZGERALD2, M. FLEISHMAN2, Z. FU2, S. IQBAL2, K. PEREZ DE ARCE2, J. SACHER2, Q. XU2, G. FENG2, Y.-L. ZHANG3, E. SCOLNICK2, J. PAN2, J. PIHL1, F. WAGNER2, J. COTTRELL2;
1 Cellectricon AB, Cellectricon AB, Mölndal, Sweden; 2 Stanley Ctr. Therapeut., 3 Ctr. for the Develop. of Therapeut., Broad Inst., Cambridge, MA; 4 Dept. of Neurol., UCSF Weill Inst. for Neurosciences, San Francisco, CA; 5 Cleveland Clin., Cleveland, OH. Discovery of positive modulators for treating SCN2A-related disorders such as autism spectrum disorder. Program No. 440.03. 2022 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2022. Online.

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