Seminar – Kenneth L. Madsen

Venue: Centre Broca

Kenneth L. Madsen

Department of Neuroscience 
University of Copenhagen

Invited by David Perrais (IINS)

Title

A peripherally restricted PICK1 inhibitor for treatment of chronic pain

Abstract

Kathrine L. Jensen^1,2, Sara E. Jager², Carolyn M. Goddard², Marco Kowenicki¹, Andreas T. Sørensen^1,2, Kenneth L. Madsen^1,2

¹ Zyneyro, Hørsholm, Denmark

²Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, University of Copenhagen, Denmark

Worldwide 1.5 billion people suffer from chronic pain. Whereas pain is crucial for our survival, maladaptive pain serves no biological function, and leads to comorbidities such as anxiety, depression, poor sleep, and high prescription drug use. We have developed and characterized a bivalent lipid-conjugated peptide, mPD5, designed to bind to the PDZ domain of the scaffold protein PICK1 (Protein Interacting with C-kinase 1). mPD5 relieves both ongoing and evoked hypersensitivity in multiple mouse models of pain in both female and male mice. Current treatment options for chronic pain entail severe dose-limiting side effects originating from their action on the CNS. However, we have data suggesting that the distribution of mPD5 is restricted to peripheral tissues. Clearing of brain and spinal column tissue of mice injected with labelled mPD5 in combination with mass spectrometry data of brain tissue, spinal cord tissue, plasma, and CSF of mice injected with unlabelled mPD5 indicate that mPD5 is peripherally restricted. mPD5 was present in dorsal root ganglions (DRGs) and plasma, but undetected in CSF, spinal cord, or brain. While PICK1 is well described in the CNS, we lack knowledge about the role of PICK1 in the PNS. By extracting mRNA data from a publicly accessible database, we have confirmed the presence of PICK1 along the somatosensory nociceptive pathway of both human and mouse, including DRGs. In addition, we have used mPD5 mimicking peptides to successfully pull down PICK1 from both spinal cord and DRG tissue from male and female humandonors, substantiating that PICK1 is indeed a relevant therapeutic pain target in humans as well. Lastly, other peripherally acting drugs such as botox, lidocaine patches, and capsaicin patches lead to impaired acute nociception. We have used a hot water tail immersion test (49 ^oC) and a capsaicin paw-lick test revealing normal sensory perception of mice treated with mPD5. Relieving chronic pain, without limiting the sensitivity to potential harmful stimuli of everyday life would be a great benefit for patients. In conclusion, mPD5 alleviates hypersensitivity through a novel mechanism offering a unique option for further investigation that could provide valuable insight into the biology of pain.

Selected publications

• Fadahunsi N et al. (2024) Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment. Science Advances 10:eadg2636.
• Jensen KL et al. (2024) Peripherally restricted PICK1 inhibitor mPD5 ameliorates pain behaviors in murine inflammatory and neuropathic pain models. JCI Insight 9
• Andersen RC et al. (2022) Coding variants identified in patients with diabetes alter PICK1 BAR domain function in insulin granule biogenesis. J Clin Invest 132
• Christensen NR, Pedersen CP, Sereikaite V, Pedersen JN, Vistrup-Parry M, Sørensen AT, Otzen D, Teilum K, Madsen KL, Strømgaard K (2022) Bidirectional protein–protein interactions control liquid–liquid phase separation of PSD-95 and its interaction partners. iScience 25