VISION

We aim to bring to the clinic disease-modifying therapies for brain diseases
Neurological disorders are the leading cause of disability and the second leading cause of death worldwide. Most of them lacking causative explanation and being chronic, the need to develop effective disease-modifying strategies is imperative. We are determining this route.

FOCUS

We are targeting a multi-acting nuclear receptor
Nurr1 (NR4A2) has been a long-thought therapeutic target for brain diseases. It has a genetic link to Parkinson’s disease, while it is expressed in both neurons and glia and it is both neuroprotective and anti-inflammatory. Recently, the therapeutic potential and druggability of Nurr1 has been validated in vivo with robust results. We highly prioritize Nurr1 as a pleiotropic therapeutic target for brain diseases.

PLAN

We are developing a portfolio of clinical standards therapeutics
We are targeting the heterodimer of Nurr1 with RXRa. We have implemented a multi-round iterative MedChem program to explore the chemical space of binding in order to optimize potency and selectivity for the target. We have developed different series of several proprietary molecules that we are further assessing besides potency and selectivity, for safety. The most promising therapeutics will enter the clinic in 2023.

Argo Therapeutics Small Molecules Development Pipeline

YOUR CONTACT PERSONS

Dr. Athanasios Spathis

Dr. Athanasios Spathis
PhD (CEO/Co-Founder)

EMBO Fellow at Imperial College, MRC, London, and National Fellow at Medical School of the University of Padova, to study the pathophysiology of Parkinson’s disease being awarded by the European Society for Neurosciences. RIKEN Fellow, Brain Sciences Institute, Tokyo, Japan.

His translational research resulted in a potential therapeutic for Parkinson’s disease and is protected through a patent application.

EIT fellow (multiple) and awarded, Niarchos fellow.

Under his leadership Argo was awared a grant by BaseLaunch in 2019.

SCIENCE

We have developed a novel therapeutic for Parkinson’s disease (PD) showing multiple both disease-modifying and symptomatic efficacy1. The target of our developing PD therapeutic is Nurr1, a nuclear receptor required for the development of dopaminergic neurons2 that has been implicated in both dopamine biosynthesis and dopaminergic neuron survival. Nurr1 was shown to be involved in the activation of tyrosine hydroxylase (TH)3 and GTP cyclohydrolase I (GCH1)4 that are critical enzymes for DA synthesis.

Furthermore, Nurr1 decreased levels are strongly associated with PD and reduced dopaminergic neuron survival. Nurr1 mutations decreasing its mRNA were found in PD patients5 while Nurr1 protein levels are reduced in the SN of PD brains6. Nurr1 ablation in adult mice leads to loss of striatal dopamine and behavioral features of parkinsonism during aging7.

Finally, reduced Nurr1 levels in mice result in increased microglial activation and augmented inflammatory response that is further amplified by astrocytes leading to death of neurons in SN8. Given the potential of Nurr1 to be a PD target, our rational was to pharmacologically activate it and then test its efficacy in PD models. However, Nurr1 lacks a classical ligand binding pocket. Since in midbrain dopaminergic neurons, Nurr1 forms heterodimers with RXRa, we postulated that targeting Nurr1:RXRa heterodimers with synthetic ligands that bind to the RXRa binding pocket could be a potential therapeutic strategy for PD.

Indeed, we have developed Nurr1:RXRa selective compounds and validated their therapeutic potential in vivo. Importantly, we have shown that our ligands also apply to other therapeutic indications as well. We are currently further optimizing them to bring them to the clinic and deliver a novel treatment for Parkinson’s and other brain diseases.

REFERENCES

1) Spathis A.D.a1, Asvos X, Ziavra D, Karambelas T, Topouzis S, Cournia Z, Alexakos P, Smits L, Dalla C, Schwambornd JS, Tamvakopoulos C, Fokas D, Vassilatis DK. Nurr1:RXRα Heterodimer Activation as Monotherapy for Parkinson’s Disease. (2017) PNAS 114(15): 3999-4004.

2)  Zetterström RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T. (1997) Dopamine neuron agenesis in Nurr1-deficient mice. Science 276(5310):248–250.

3) Kim KS, Kim CH, Hwang DY, Seo H, Chung S, Hong SJ, Lim JK, Anderson T, Isacson O. (2003). Orphan nuclear receptor Nurr1 directly transactivates the promoter activity of the tyrosine hydroxylase gene in a cell-specific manner. J Neurochem 85(3):622-634.

4) Gil M, McKinney C, Lee MK, Eells JB, Phyillaier MA, Nikodem VM. (2007) Regulation of GTP cyclohydrolase I expression by orphan receptor Nurr1 in cell culture and in vivo. J Neurochem 101(1):142-150.

5) Le WD, Xu P, Jankovic J, Jiang H, Appel SH, Smith RG, Vassilatis DK. (2003). Mutations in NR4A2 associated with familial Parkinson disease. Nat Genet 33(1):85-89.

6) Chu Y, Le W, Kompoliti K, Jankovic J, Mufson EJ, Kordower JH. (2006). Nurr1 in Parkinson’s disease and related disorders. J Comp Neurol 494(3):495-514.

7)  Kadkhodaei B, Alvarsson A, Schintu N, Ramsköld D Volakakis N, Joodmardi E, Yoshitake T, Kehr J, Decressac M, Björklund A, Sandberg R, Svenningsson P, Perlmann T. (2013) . Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons. Proc Natl Acad Sci U S A. 110, 2360-2365

8) Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK. A Nurr1/CoREST transrepression pathway attenuates neurotoxic inflammation in activated microglia and astrocytes. Cell, 2009; 137 (1): 47-59.

AT HOME IN SWITZERLAND

Argo Therapeutics GmbH
c/o Switzerland Innovation Park
Gewerbestrasse 24
CH-4123 Allschwil