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.

Pain takes multiple forms

Pain is commonly 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 is classified into three main levels based on its intensity: mild, moderate, and severe.

While mild pain is usually treated with «safe» analgesics such as paracetamol, higher levels of pain require 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 beyond the immediate discomfort: sleep disorder, depression, social isolation. Most importantly, inadequately treated pain can contribute to development of chronic pain; a condition that affects 20% of the world population with a substantial economic burden.

Current Medications induce Severe Adverse Effects

Pain medication is plagued with severe adverse effects. While mild analgesics such as paracetamol are generally considered safe within a well-defined dosing regimen, opioids present risks of addiction even at low doses, leading many patients to decline opioids and instead deal with the pain (which in turn usually delays full recovery, for example by impeding physical therapy). Some antiepileptic drugs, widely used in the treatment of neuropathic pain can also lead to misuse and abuse.

A Well-Known Example: Opioids

Opioids represent 32% of the pain medication market. They are a part of the overall need, but are highly representative of the issues to be solved:

Despite their initial efficacy, opioids lose efficacy when administered repeatedly (an issue called tolerance), which make them woefully unsuited to treating chronic pain (20% of the population are
estimated to suffer from various kinds of chronic pains), and increase the risk of addiction as the patients increase dosage to maintain an equivalent level of pain management.

Addiction: opioids such as morphine, fentanyl, or the less-potent tramadol, are well-known to be highly addictive, just as their namesake is (opium). This leads to major health issues of addiction, substance abuse, overdoses, and death. The so-called «Opioid Crisis» in theUSA kills over 50,000 people each year, from opioid-related overdoses only. It is a fast-accelerating phenomenon.

There is an urgent need to develop new solutions for pain medication and management, based on a new approach.
This is Tafalgie’s mission.

Pain: The Gate Control Theory

Gating Neurons

The Gate Control Theory of pain stipulates that propagation of touch and pain information to the central nervous system, is strongly modulated by a particular class of spinal cord interneurons called « Gating Neurons ».
The core of this theory predicts that injury induces a disruption in the efficacy of these gating neurons, allowing both innocuous and noxious stimuli to access the pain pathway. These phenomena are called allodynia (pain evoked by innocuous stimuli) and hyperalgesia (extreme pain evoked by noxious stimuli).

Ground-breaking discoveries

Ground-breaking work from the team of Dr Aziz Moqrich in Marseille identified the mechanism underlying the injury-induced diminished activity of the gating neurons and demonstrates that TAFA4 blocks injury-induced pain hypersensitivity by restoring normal activity of the gating neurons.

These discoveries demonstrate that TAFA4 is a disease-modifying biologic drug. Its pain-killing efficacy has been demonstrated in a large spectrum of pain conditions, including inflammatory, post-operative and neuropathic pain conditions.

The TAFA4 Protein

Modulating the Gating Neurons’ Activity

TAFA4 is a small endogeneous neurokinin protein secreted by C-low threshold mechanoreceptors (C-LTMRs).

Initially characterized in 1939, C-LTMRs were previously thought to only mediate pleasant touch sensation. Research by 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

Specifically, the loss of TAFA4 leads to exacerbation and long-lasting injury-induced mechanical and chemical pain. Exogenous administration of TAFA4 enhances the spinal inhibitory tone under physiological conditions, and strongly reverses the injury-induced diminished inhibitory function of the 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 tolerance).

This makes TAFA4 ideally suited for all kinds of pain, including chronic pain.

Pain Relief

Tafalgie’s preclinical studies have demonstrated that TAFA4 and its peptide derivatives

Effectively block the propagation of injury-induced pain, even for moderate to severe pain.

Exhibits no toxicity

Keeps its efficacy when repeatedly administred (no tolerance)

Revolution in Pain Medication

The ground-breaking combination of high efficacy and absence of tolerance, mean that TAFA4 and its derivatives (our Portfolio of Leads) are perfect candidates for a genuine revolution in pain medication; a safe alternative to the current unsatisfactory options.

Moreover, the specific absence of tolerance particularly boost TAFA4’s ability to address chronic pain.

Market Access Strategy

In addition to ‘mass market’ molecules which aim to provide pain relief to populations suffering from a wide range of pain situations (pain from different origins such as neuropathic pain, osteoarthritis, low back pain…), we will also target ’niche’ indications with specific requirements. These indications include hospital markets (for example, severe post-operative pain), or painful rare diseases (for which there are few, if any, therapeutic options).

Bibliography

List of Publications Aziz Moqrich and Stephane Gaillard

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.

our Pipeline

A Revolution in Pain Medication