science
A Revolution
in Pain Medication
Unmet Needs of Pain Medication
Pain is a universal human experience. It can manifest in various forms, including physical, emotional, or psychological pain.
Every single human is, has or will experience pain at some point of his/her life.
Multiple forms
Pain has many forms, generally classified as acute or chronic. Acute pain is short-lived and essential for the maintenance of our physical integrity, whereas chronic pain persists beyond the normal time of healing and adversely affects well-being. Pain can also be classified according to its intensity: mild, moderate, or severe.
Mild pain is usually treated with analgesics that are considered safe, such as paracetamol. However, more intense pain requires stronger analgesics, such as opioids, which are effective but have significant drawbacks and potential risks, including addiction, overdose, respiratory depression and withdrawal symptoms.
Severe Consequences
Untreated pain can have far-reaching effects extending beyond immediate discomfort: sleep disorders, depression, social isolation. Most importantly, inadequately treated pain can contribute to the development of chronic pain, which affects 20% of the world’s population, constituting a substantial economic burden.
Severe adverse effects of current pain medication
Current pain medication is plagued by severe adverse effects. Mild analgesics, such as paracetamol, are generally considered safe within a well-defined dosing regimen, but opioids present risks of addiction even at low doses, leading many patients to refuse them and just put up with the pain. This generally delay full recovery, by hindering physical therapy, for example. Certain antiepileptic drugs widely used in the treatment of neuropathic pain can also lead to misuse and abuse.
A classic case: opioids
Opioids account for 32% of the pain medication market. They meet some of the overall need, but clearly illustrated the issues to be resolved:
Tolerance: The efficacy of opioids gradually decreases with repeated use, due to the development of tolerance, which renders them woefully inadequate for the treatment of chronic pain (20% of the population are
estimated to suffer from various kinds of chronic pain), and increases the risk of addiction, as patients end up having to increase the dose to maintain an equivalent level of pain management.
Addiction: Opioids, such as morphine, fentanyl, and the less potent tramadol, are well-known to be highly addictive, just like the opium from which this group derives its name. This leads to major health issues of addiction, substance abuse, overdose, and death. The US is currently in the grip of a so-called “Opioid Crisis”, in which opioid-related overdoses alone account for the deaths of over 50,000 people annually. This is a rapidly growing phenomenon.
There is an urgent need to develop new solutions for pain medication and management, based on novel approaches.
This is the mission of Tafalgie Therapeutics.
Pain: The Gate Control Theory
Gating Neurons
- According to the Gate Control Theory of pain, the propagation of touch and pain information to the central nervous system is strongly modulated by a particular class of spinal cord interneurons, the gating neurons.
- At the heart of this theory is the notion that injury decreases the efficacy of these gating neurons, allowing both innocuous and noxious stimuli to trigger pain. This results in phenomena of allodynia (pain triggered by innocuous stimuli) and hyperalgesia (extreme pain triggered by noxious stimuli).
Ground-breaking discoveries
Ground-breaking work from the team of Dr Aziz Moqrich in Marseille has elucidated the mechanism underlying the decrease in gating neuron activity triggered by injury and has demonstrated that TAFA4 blocks injury-induced pain hypersensitivity by restoring normalgating neuron activity..
These discoveries demonstrated the potential of TAFA4 as a disease-modifying biologic drug. TAFA4 has been shown to be an effective painkiller in a broad spectrum of pain conditions, including inflammatory, postoperative and neuropathic pain conditions.
The TAFA4 Protein
Modulating the activity of gating neurons
TAFA4 is a small endogenous neurokinin secreted by C low-threshold mechanoreceptors (C-LTMRs).
Initially characterized in 1939, C-LTMRs were thought to mediate only pleasant touch sensations. The Moqrich team identified TAFA4 as a molecular marker of C-LTMRs, and demonstrated that this molecule is a strong modulator of pain transmission.
Inhibition of Pain Propagation
TAFA4 loss leads to an exacerbation of injury-induced mechanical and chemical pain and its long-term maintenance. Exogenous TAFA4 administration enhances the spinal inhibitory tone under physiological conditions, strongly reversing the injury-induced decrease in the inhibitory function of gating neurons.
Excellent Safety Profile
This endogenous protein is inherently safe (no toxicity). Moreover, preclinical studies have shown that its efficacy is not diminished by repeated administration (no development of tolerance).
This makes TAFA4 ideally suited for all kinds of pain, including chronic pain.
Pain Relief
In preclinical studies, Tafalgie Therapeutics has demonstrated that TAFA4 and its peptide derivatives:
Effectively block the propagation of injury-induced pain, even for moderate-to-severe pain.
Display no toxicity
Remain effective after repeated administrations (no development of tolerance)
Revolution in Pain Medication
The ground-breaking combination of high efficacy and an absence of tolerance phenomena makes TAFA4 and its derivatives (our portfolio of lead molecules) perfect candidates to lead a genuine revolution in pain medication, a safe alternative to the current unsatisfactory options.
Moreover, the total absence of tolerance phenomena, in particular, renders TAFA4 particularly suitable for the treatment of chronic pain
Market Access Strategy
In addition to producing “mass-market” molecules, which aim to provide pain relief to populations suffering from a wide range of pain conditions (pain with different etiologies, such as neuropathic pain, osteoarthritis, and low back pain), we will also target “niche” indications with specific requirements. These indications include hospital markets (for severe postoperative pain, for example) and rare painful diseases for which few, if any, effective treatments are currently available.
Bibliography
List of Publications Aziz Moqrich and Stephane Gaillard
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- Malapert, A., Robert, G., Brunet, E., Chemin, J., Bourinet, E and Moqrich, A. (2023) A novel Nav1.8-FLPo driver mouse line for intersectional genetics to study the functional specialization of primary sensory neurons. iScience (accepted)
- Reynders, A., Jhumka, A., Gaillard, S., Hoeffel, G., Mantilleri, A. Malapert, P., Salio, C., Ugolini, S., Castets, F., Saurin, A., Serino, M. And Moqrich, A. (2023) Gut microbiota promotes pain chronicity in Myosin1A deficient male mice. (Under revision) Brain, Behavior and Immunity.
- Charron, A., Pepino, L., Malapert, P., Debrauwer, V., Castets, F., Salio, C., and Moqrich, A. (2023). Sex-related exacerbation of injury-induced mechanical hypersensitivity in GAD67 haplodeficient mice. Pain.
- Pepino, L., Malapert, P., Saurin, A.J., Moqrich, A., and Reynders, A. (2023). Formalin-evoked pain triggers sex-specific behavior and spinal immune response. Sci Rep 13, 9515.
- Clerc N and Moqrich, A. (2022). Diverse roles and modulations of IA in spinal cord pain circuits. Cell Rep 38, 110588.
- Middleton, S.J., Perini, I., Andreas, C.T., Weir, G.A., McCann, K., Barry, A.M., Marshall, A., Lee, M., Mayo, L.M., Bohic, M., Baskozos, G., Morrison, I., Löken, L., McIntyre, S., Nagi, S., Staud, R., Sehlstedt, I., Johnson, R., Wessberg, J., Wood, J., Woods, C., Moqrich, A., Olausson, H. and Bennett D. (2022). Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice. Brain.
- Bertoni, A., Schaller, F., Tyzio, R., Gaillard, S., Santini, F., Xolin, M., Diabira, B., Vaidyanathan, R., Matarazzo, V., Medina, I., Hammock, E., Zhnag, J., Chini, B., Gaiarsa, J-L and Muscatelli, F. (2021) Oxytocin administration in neonates shpaes hippocampal circuitry and restores social behavior in a mouse model of autism. Molecular Psychiatry, Dec; 26(12), 7582-7595.
- Runge, K., Mathieu, R., Bugeon, S., Lafi, S., Beurrier, C., Sahu, S., Schaller, F., Loubat, A., Herault, L., Gaillard, S., Cahuc, M., Pallesi-Pocachard, E., Montheil, A., Bosio, A., Rosenfeld, J.A., Hudson, E., Lindstrom, K., Mercimek-Andrews, S., Jeffries, L., Van Haeringen, A., Vanakker, O., Pichon, B., Van Hecke, A., Amrom, D., Küry, S., Ratner, C., Jethva, R., Gambler, C., Jacq, B., Fasano, L., Santpere, G., Lorente-Galdos, B., Sestan, N., Gelot, A., Giacuzz, S., Goebbels, S., Represa, A., Cardoso, C., Cremer, H. and De Chevigny, A. (2021) Disruption of NEUROD2 causes a neurodevelopmental syndrome with autistic features via cell-autonomous defects in forebrain glutamatergic neurons. Molecular Psychiatry. Nov; 26(11), 6215-6148.
- Yoo, S. Santos, C., Reynders, A., Marics, I., Malapert, P., Gaillard, S., Ugolini, S., Rossignol, R., El Khallouqi, A., Springael, J-Y., Parmentier, M., Saurin, A.J., Goaillard, J-M., Castets, F., Clerc, N. and Moqrich, A. (2021) TAFA4 relieves injury-induced mechanical allodynia through LRP1 and modulation of spinal A-type potassium currents. Cell Reports, Oct-26 vol 37, issue 4, 109884.
- Salio, C., Aimar, P., Malapert, P., Moqrich, A., and Merighi, A. (2021). Neurochemical and Ultrastructural Characterization of Unmyelinated Non-peptidergic C-Nociceptors and C-Low Threshold Mechanoreceptors Projecting to Lamina II of the Mouse Spinal Cord. Cell Mol Neurobiol 41, 247-262.
- Pierrelee, M., Reynders, A., Lopez, F., Moqrich, A., Tichit, L., and Habermann, B.H. (2021). Introducing the novel Cytoscape app TimeNexus to analyze time-series data using temporal MultiLayer Networks (tMLNs). Sci Rep 11, 1.
- Hoeffel, G., Debroas, G., Roger, A., Rossignol, R., Gouilly, J., Laprie, C., Chasson, L., Barbon, P.V., Balsamo, A., Reynders, A., et al. (2021). Sensory neuron-derived TAFA4 promotes macrophage tissue repair functions. Nature 594, 94-99.
- Filtjens, J., Roger, A., Quatrini, L., Wieduwild, E., Gouilly, J., Hoeffel, G., Rossignol, R., Daher, C., Debroas, G., Henri, S., et al. (2021). Nociceptive sensory neurons promote CD8 T cell responses to HSV-1 infection. Nat Commun 12, 2936.
- Delay, L., Barbier, J., Aissouni, Y., Jurczak, A., Boudieu, L., Briat, A., Auzeloux, P., Barrachina, C., Dubois, E., Ardid, D., et al. (2021). Tyrosine kinase type A-specific signalling pathways are critical for mechanical allodynia development and bone alterations in a mouse model of rheumatoid arthritis. Pain.
- Chaumette, T., Delay, L., Barbier, J., Boudieu, L., Aissouni, Y., Meleine, M., Lashermes, A., Legha, W., Antraigue, S., Carvalho, F.A., et al. (2020). c-Jun/p38MAPK/ASIC3 pathways specifically activated by nerve growth factor through TrkA are crucial for mechanical allodynia development. Pain 161, 1109-1123.
- Bohic, M., Marics, I., Santos, C., Malapert, P., Ben-Arie, N., Salio, C., Reynders, A., Le Feuvre, Y., Saurin, A.J., and Moqrich, A. (2020). Loss of bhlha9 Impairs Thermotaxis and Formalin-Evoked Pain in a Sexually Dimorphic Manner. Cell Rep 30, 602-610 e606.
- Wang, Y., Wu, H., Fontanet, P., Codeluppi, S., Akkuratova, N., Petitpre, C., Xue-Franzen, Y., Niederreither, K., Sharma, A., Da Silva, F., et al. (2019). A cell fitness selection model for neuronal survival during development. Nat Commun 10, 4137.
- Candelas, M., Reynders, A., Arango-Lievano, M., Neumayer, C., Fruquiere, A., Demes, E., Hamid, J., Lemmers, C., Bernat, C., Monteil, A., et al. (2019). Cav3.2 T-type calcium channels shape electrical firing in mouse Lamina II neurons. Sci Rep 9, 3112.
- Kambrun, C., Roca-Lapirot, O., Salio, C., Landry, M., Moqrich, A., and Le Feuvre, Y. (2018). TAFA4 Reverses Mechanical Allodynia through Activation of GABAergic Transmission and Microglial Process Retraction. Cell Rep 22, 2886-2897.
- Fromy, B., Josset-Lamaugarny, A., Aimond, G., Pagnon-Minot, A., Marics, I., Tattersall, G.J., Moqrich, A., and Sigaudo-Roussel, D. (2018). Disruption of TRPV3 Impairs Heat-Evoked Vasodilation and Thermoregulation: A Critical Role of CGRP. J Invest Dermatol 138, 688-696.
- Bautzova, T., Hockley, J.R.F., Perez-Berezo, T., Pujo, J., Tranter, M.M., Desormeaux, C., Barbaro, M.R., Basso, L., Le Faouder, P., Rolland, C., et al. (2018). 5-oxoETE triggers nociception in constipation-predominant irritable bowel syndrome through MAS-related G protein-coupled receptor D. Sci Signal 11.
- Gaillard*, S., Urien*, L. Lo-Re, L., Malapert, P., Bohic, M., Reynders, A. and Moqrich, A. (2017) Genetic ablation of GINIP-expressing primary sensory neurons strongly impairs formalin-evoked pain. Scientific Reports, 7, 43493.
- Reynders, A., Mantilleri, A., Malapert, P., Rialle, S., Nidelet, S., Laffray, S., Beurrier, C., Bourinet, E., and Moqrich, A. (2015). Transcriptional Profiling of Cutaneous MRGPRD Free Nerve Endings and C-LTMRs. Cell Rep 10, 1007-1019.
- Reynders, A., and Moqrich, A. (2015). Analysis of cutaneous MRGPRD free nerve endings and C-LTMRs transcriptomes by RNA-sequencing. Genom Data 5, 132-13.
- Francois, A., Schuetter, N., Laffray, S., Sanguesa, J., Pizzoccaro, A., Dubel, S., Mantilleri, A., Nargeot, J., Noel, J., Wood, J.N., et al. (2015). The Low-Threshold Calcium Channel Cav3.2 Determines Low-Threshold Mechanoreceptor Function. Cell Rep 10, 370-382.
- Moqrich, A. (2014). Peripheral pain-sensing neurons: from molecular diversity to functional specialization. Cell Rep 6, 245-246.
- Gaillard*, S., Lo-Re*, L., Mantilleri, A., Urien, L., Malapert, P., Alonso, S., Deage, M., Kambrun, C., Landry, M., Low, S.A, Scherrer, G., Alloui, A., Le Feuvre, Y., Bourinet, E. and Moqrich, A. (2014) GINIP, a new Gai interacting protein, functions as a key modulator of peripheral GABAB receptor-mediated analgesia. Neuron, Oct 1;84(1):123-136.
- Marics, I. Malapert, P., Reynders, A., Gaillard, S. and Moqrich, A. (2014) Acute heat-evoked temperature sensation is impaired but not abolished in mice lacking TRPV1 and TRPV3 channels. Plos One, Jun 12;9(6):e99828.
- Gorokhova, S, Gaillard, S., Urien, L., Malapert, P., Legha, W., Baronian, G., Desvignes, J-P., Alonso, S. and Moqrich, A. (2014). Uncoupling of molecular maturation from peripheral target innervation in nociceptors expressing a chimeric TrkA/TrkC receptor. Plos Genetics. Feb 6;10(2):e1004081.
- Delfini, M-C., Mantilleri, A., Gaillard, S., Hao, J, Reynders, A., Malapert, P., Alonso, S., François, A., Barrere, C., Seal, R., Landry, M., Eschallier, A., Alloui, A., Bourinet, E., Delmas, P., Le Feuvre, Y. and Moqrich, A. (2013). TAFA4, a chemokine-like protein, modulates injury-induced mechanical and chemical pain hypersensitivity in mice. Cell Reports vol 5, pp378-388.
- Bouhadfane, M., Tazerart, S., Moqrich, A., Vinay, L., and Brocard, F. (2013). Sodium-mediated plateau potentials in lumbar motoneurons of neonatal rats. J Neurosci 33, 15626-15641.
- Gaillard*, S., Gascon*, E., Malapert, P., Liu, Y., Rodat Despoix, L., Samokhvalov, I.M, Delmas, P., Helmbacher, F., Maina, F. and Moqrich, A. (2010). HGF-Met signaling is required for Runx1 extinction and peptidergic differentiation in primary nociceptive neurons. J. Neurosc. vol 30(37), pp12414-12423.
- Legha, W., Gaillard, S., Gascon, E., Malapert, P., Hocine, M., Alonso, S. and Moqrich, A. (2010) stac1 and stac2 genes define discrete and distinct subsets of dorsal root ganglia neurons. Gene Expression Patterns, vol 10, pp368-375.
- Gascon, E., and Moqrich, A. (2010). Heterogeneity in primary nociceptive neurons: from molecules to pathology. Arch Pharm Res 33, 1489-1507.
- Gorokhova, S., Gaillard, S. and Gascon, E. (2009). (journal club). Spindle-Derived NT3 in Sensorimotor Connections: Principal Role at Later Stages. J. Neurosc. vol 29(33), pp10181-10183.
- Mandadi, S., Sokabe, T., Shibasaki, K., Katanosaka, K., Mizuno, A., Moqrich, A., Patapoutian, A., Fukumi-Tominaga, T., Mizumura, K., and Tominaga, M. (2009). TRPV3 in keratinocytes transmits temperature information to sensory neurons via ATP. Pflugers Arch 458, 1093-1102.
- Gaillard, S., Jacquet, H., Vavasseur, A., Leonhardt, N. and Forestier, C. (2008). AtMRP6/AtABCC6, an ATP-binding cassette transporter gene expressed during early steps of seedling development and up-regulated by cadmium in Arabidopsis thaliana. BMC Plant Biol. vol 8, p22-32.
- Gaillard, S., Bailly, Y., Benoist, M., Rakitina, T., Kessler, J-P., Fronzaroli-Molinières, L., Dargent, B. and Castets, F. (2006). Targeting of the members of the striatin family to dendritic spines: role of the coiled-coil domain. Traffic. vol.7, pp 74-84.
- Benoist, M., Gaillard, S. and Castets, F. (2006). The striatin family: a new signalling platform in dendritic spines.J. Physiol. Paris.vol 99, pp 146-153.
- Moqrich, A., Hwang, S.W., Earley, T.J., Petrus, M.J., Murray, A.N., Spencer, K.S., Andahazy, M., Story, G.M., and Patapoutian, A. (2005). Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science 307, 1468-1472.
- Moqrich, A., Earley, T.J., Watson, J., Andahazy, M., Backus, C., Martin-Zanca, D., Wright, D.E., Reichardt, L.F., and Patapoutian, A. (2004). Expressing TrkC from the TrkA locus causes a subset of dorsal root ganglia neurons to switch fate. Nat Neurosci 7, 812-818.
- Blondeau, C., Gaillard, S., Ternaux, J-P., Monneron, A. and Baude A. (2003). Expression and distribution of phocein and members of the striatin family in neurons of rat peripheral ganglia. Histochemistry and Cell Biology. vol 119, pp 131-138.
- Su, A.I., Cooke, M.P., Ching, K.A., Hakak, Y., Walker, J.R., Wiltshire, T., Orth, A.P., Vega, R.G., Sapinoso, L.M., Moqrich, A., et al. (2002). Large-scale analysis of the human and mouse transcriptomes. Proc Natl Acad Sci U S A 99, 4465-4470.
- Peier, A.M., Moqrich, A., Hergarden, A.C., Reeve, A.J., Andersson, D.A., Story, G.M., Earley, T.J., Dragoni, I., McIntyre, P., Bevan, S., et al. (2002a). A TRP channel that senses cold stimuli and menthol. Cell 108, 705-715.
- Peier, A.M., Reeve, A.J., Andersson, D.A., Moqrich, A., Earley, T.J., Hergarden, A.C., Story, G.M., Colley, S., Hogenesch, J.B., McIntyre, P., et al. (2002b). A heat-sensitive TRP channel expressed in keratinocytes. Science 296, 2046-2049
- Baillat, G., Gaillard, S., Castets, F. and Monneron, A. (2002). Interactions of phocein with nucleoside-diphosphate kinase, Eps15 and dynamin I. J. Biol. Chem. vol 277, pp 18961-18966.
- Baillat, G., Moqrich, A., Castets, F., Baude, A., Bailly, Y., Benmerah, A., and Monneron, A. (2001). Molecular cloning and characterization of phocein, a protein found from the Golgi complex to dendritic spines. Mol Biol Cell 12, 663-673.
- Gaillard, S., Bartoli, M., Castets, F. and Monneron, A. (2001). Striatin, a calmodulin-dependent scaffolding protein, directly binds caveolin-1. FEBS letters vol 508, pp 49-52.
- Castets, F., Rakitina, T., Gaillard, S., Moqrich, A., Mattei, M. G. and Monneron, A. (2000). Zinedin, SG2NA and striatin are calmodulin-binding, WD-repeat proteins principally expressed in brain. J. Biol. Chem. vol 275, pp 19970-19977.
- Moqrich, A., Mattei, M.G., Bartoli, M., Rakitina, T., Baillat, G., Monneron, A., and Castets, F. (1998). Cloning of human striatin cDNA (STRN), gene mapping to 2p22-p21, and preferential expression in brain. Genomics 51, 136-139.
- Tomasello, E., Olcese, L., Vely, F., Geourgeon, C., Blery, M., Moqrich, A., Gautheret, D., Djabali, M., Mattei, M.G., and Vivier, E. (1998). Gene structure, expression pattern, and biological activity of mouse killer cell activating receptor-associated protein (KARAP)/DAP-12. J Biol Chem 273, 34115-34119.
- Castets, F., Bartoli, M., Barnier, J.V., Baillat, G., Salin, P., Moqrich, A., Bourgeois, J.P., Denizot, F., Rougon, G., Calothy, G., et al. (1996). A novel calmodulin-binding protein, belonging to the WD-repeat family, is localized in dendrites of a subset of CNS neurons. J Cell Biol 134, 1051-1062.