Molecular neurology

Molecular neurology group

Molecular neurology

 

Principal investigator: F. Javier Rodriguez

E-mail: fjrodriguez@sescam.jccm.es

 

The Molecular Neurology Group (GNM) was founded in 2004 with the aim of identifying new therapeutic targets and developing combined therapies to induce neuroprotection and promote neural repair. This broad experimental approach to the neural repair challenge is tackled through multidisciplinary research, from its most molecular aspects to its functional and histological correlation, in clinically relevant animal models of injury or damage to the nervous system.

 

Our main finding has been the first description of the expression of most members of the Wnt protein family in the adult spinal cord and their involvement in the response to traumatic injury or neurodegeneration, attempting to ensure that the results obtained in animal experimental models have a correlation and thus potential therapeutic relevance in samples obtained from healthy and pathological human donors. Our current interest is focused on identifying Wnt targets for the development of therapeutic strategies based on protein engineering and recombinant biomaterials, which allow for specific biological effects and versatility in the routes of administration for spinal cord injuries and amyotrophic lateral sclerosis.

 

The GNM has also contributed to the field of cell therapy with the description of a novel source of autologous stem cells in the leptomeninges of the adult spinal cord, and has generated proof of concept and efficacy of human adipose mesenchymal cell transplants in acute spinal cord injuries.

 

The GNM currently has two research projects funded for the period 2023-2027 by the Spanish National Research Agency and the Research and Innovation Agency of Castilla-La Mancha, and accounts with a consolidated research line in the field of neural repair.

 

 

Selected publications

 

1. González-Fernández C&, González P, Maqueda A, Pérez V, Rodríguez FJ& (& Co-Corresponding authors). Enhancing motor functional recovery in spinal cord injury through pharmacological inhibition of Dickkopf-1 with BHQ880 antibody. Biomed Pharmacother (2024), Jul;176:116792.

 

2. González P&, González-Fernández C, Maqueda A, Pérez V, Escalera-Anzola S, Rodríguez de Lope A, Arias FJ, Girotti A, Rodríguez FJ& (& Co-Corresponding authors). Silk-Elastin-like Polymers for Acute Intraparenchymal Treatment of the Traumatically Injured Spinal Cord: A First Systematic Experimental Approach. Pharmaceutics (2022), 14(12):2713.

 

3. González P&, González-Fernández C, Javier Rodríguez F& (& Co-Corresponding authors). Effects of Wnt5a overexpression in spinal cord injury. J Cell Mol Med (2021), 25(11):5150-5163.

 

4. Mendibil X*, Gonzalez-Perez* F, Bazán X, Diez-Ahedo R, Quintana I, Rodríguez FJ, Basnett P, Nigmatullin R, Lukasiewicz B, Roy I, Taylor C, Glen A, Claeyssens F, Haycock J, Schaafsma W, González E, Castro B, Duffy P, Merino S. “A bioresorbable and mechanically optimized nerve guidance conduit based on a naturally derived medium chain length polyhydroxyalkanoate and poly(ε-caprolactone) blend”. (* Co-first authors). ACS Biomaterials Science & Engineering (2021), 7(2):672-68.

 

5. González P&, González-Fernandez C, Campos-Martín Y, Mollejo M, Carballosa-Gautam M, Marcillo A, Norenberg M, Rodríguez FJ& (& Co-Corresponding authors). Frizzled 1 and Wnt1 as new potential therapeutic targets in the traumatically injured spinal cord. Cell Mol Life Sci (2020), 77(22):4631-4662.

 

6. González P&, González-Fernández C, Rodríguez FJ& (& Co-Corresponding authors). Spatio-temporal and cellular expression pattern of PTK7 in the healthy rat and human spinal cord and after traumatic spinal cord injury in the rat. Cell Mol Neurobiol (2020), 40(7):1087-1103. 

 

7. González-Fernández C&, González P, Rodríguez FJ& (& Co-Corresponding authors). New insights into Wnt signaling alterations in amyotrophic lateral sclerosis: a potential therapeutic target? Neural Regen Res (2020), 15(9):1580-1589.

 

8. Maqueda A&, Rodríguez FJ& (& Co-Corresponding authors). Efficacy of human HC016 cell grafts in tissue preservation and functional recovery in a rat model of acute spinal cord injury. J Tissue Eng Regen Med (2020), 14(2):319-333.

 

9. González-Fernandez C, González P, Andrés-Benito P, Ferrer I, Rodríguez FJ. Wnt signaling alterations in the human spinal cord of amyotrophic lateral sclerosis cases: spotlight on Fz2, Fz5 and Wnt5a. Mol Neurobiol (2019), 56(10):6777-6791.

 

10. Duffy P , McMahon S, Wang X, Keaveney S, O'Cearbhaill ED, Quintana I, Rodríguez FJ, Wang W. Synthetic bioresorbable poly-α-hydroxyesters as peripheral nerve guidance conduits; a review of material properties, design strategies and their efficacy to date. Biomater Sci (2019), 7(12):4912-4943.

 

11. Dolci S, Pino A, Berton V, Gonzalez P, Braga A, Fumagalli M, Bonfanti E, Malpeli G, Pari F, Zorzin S, Amoroso C, Moscon D, Rodriguez FJ, Fumagalli G, Bifari F, Decimo I. High yield of adult oligodendrocytes lineage cells obtained from meningeal biopsy. Frontiers in Pharmacology (2017); 8:703.

 

12. González Fernández C, Arévalo Martín A, Paniagua Torija B, Ferrer I, Rodríguez FJ&, García Ovejero D&. (& Co-Corresponding Authors). Wnts are expressed in the ependymal region of the adult spinal cord. Molecular Neurobiology (2017); 54(8):6342.

 

13. González P, Rodríguez FJ. Analysis of the expression of the Wnt family of proteins and its modulatory role on cytokine expression in non-activated and activated astroglial cells. Neuroscience Research (2017); 114- 16-29.

 

14. González Fernández C, Mancuso R, del Valle J, Navarro X, Rodríguez FJ. Wnt Signaling Alteration in the spinal cord of Amyotrophic Lateral Sclerosis Transgenic Mice: Special Focus on Frizzled-5 Cellular Expression Pattern. PLoS One (2016); 11-5: e0155867.

 

15. González-Fernández C, Fernández-Martos CM, Arenas E, Rodríguez FJ. Wnts are expressed in the spinal cord of adult mice and are differentially induced after injury. J Neurotrauma (2014); 31(6): 565.

 

16. González P, Fernández-Martos CM, Rodríguez FJ. The Ryk Receptor Is Expressed in Glial and Fibronectin-Expressing Cells after Spinal Cord Injury. J Neurotrauma (2013); 30(10): 806-817.

 

17. González P, Fernández-Martos CM, González-Fernández C, Arenas E, Rodríguez FJ. Spatio-Temporal Expression Pattern of Frizzled Receptors after Contusive Spinal Cord Injury in Adult Rats. PLoS One (2012); 7(12): e50793.

 

18. Fernández-Martos CM, González P, Rodríguez FJ. Acute Leptin Treatment Enhances Functional Recovery after Spinal Cord Injury. PLoS One (2012); 7(4): e35594.

 

19. Fernandez-Martos CM, Gonzalez-Fernandez C, Gonzalez P, Maqueda A, Arenas A, Rodriguez FJ. Differential expression of Wnts after Spinal Cord Contusion Injury in adult rats. PLoS One (2011); 6 (11): e27000.

 

20. Decimo I; Bifari F, Rodríguez FJ, Malpeli G, Dolci S, Lavarini V, Vázquez S, Sciancalepore M, Montalbano A, Berton V, Krampera M, Fumagalli G. Nestin- and DCX-Positive Cells Reside in Adult Spinal Cord Meninges and Participate to Injury-Induced Parenchymal Reaction. Stem Cells (2011); 29(12): 2062-2076.

 

 

Personnel

 

  • F. Javier Rodríguez (PhD in Biological Sciences; Universitat Autònoma de Barcelona 1999).
  • Pau H. González (PhD in Biological Sciences; Universitat Autònoma de Barcelona 2009).
  • Alfredo Maqueda Fernández (PhD in Biological Sciences; Universidad Autónoma de Madrid 2007).
  • Virginia Pérez Jort (Lab Manager; BSc. In Biology).

 

 

External collaborations

 

  • Dr. F. Javier Arias and Dra. A. Girotti. Group BIOFORGE. Universidad de Valladolid (Spain).
  • Dr. Ángel Arévalo y Dr. Daniel García Ovejero. Group of Neuroinflammation. “Hospital Nacional de Parapléjicos” (Spain).
  • Dr. Óscar Gómez Torres. Faculty of Environmental Sciencies and Biochemistry. University of Castilla-La Mancha (Spain).

 

 

Research lines

 

1. Development of pharmacological therapies: Evaluation in vitro and animal models of neural damage of drugs commonly used in clinical practice, such as leptin, whose single or combined administration promotes neuroprotection and axonal/tissue regeneration.

 

2. Design of cell therapies: Development of new protocols for isolating, expanding, and instructing cell transplants obtained from autologous and easily accessible tissues, with the competence to promote neuroprotection, positive immunomodulation, axonal regeneration, and/or cell replacement (neurons and oligodendrocytes).

 

3. Search for new therapeutic targets: Characterization of new factors relevant to the pathophysiology of spinal cord injury using quantitative PCR, proteomics, and immunohistochemistry techniques. In this section, our main interest is focused on the Wnt family of proteins.

 

4. Development of new nanostructured and functionalized biomaterials to promote neuroprotection, axonal regeneration, and tissue repair. In this section, our interest is focused on biopolymers based on Elastin-Like Recombinamers.

 

 

Ongoing projects

 

1. SCI-WINNER: Development of a clinically relevant therapy for spinal cord injury based on the BHQ880 antibody and canonical Wnt modulation with elastin-like polymers. Funding: Ministry of Science and Innovation (PID22-1373260B-C21).
Experimental evidence provides solid support for the hypothesis that potentiation of the canonical Wnt signaling pathway, through exogenous administration of canonical Wnt ligands or blockade of their inhibitors, will reduce secondary damage and promote functional recovery through: 1) Neuroprotection; 2) Reduction of hematogenous inflammatory cell infiltration; 3) Restoring the blood-spinal cord barrier (BSCB) and thus homeostasis; 4) Resolving inflammation by promoting an M2 phenotype that facilitates tissue repair; 5) Functional recovery through the formation of new synapses and remyelination.
Our results have identified the Wnt1/Frizzled1 axis and the canonical inhibitor Dkk1 as potential therapeutic targets during the acute phase of spinal cord injury. However, Wnt therapies are limited by their short half-life and intrinsic risk of inducing carcinogenesis when administered systemically. Consequently, we propose the combined use of hydrogels developed by the Group “Smart Devices for Nanomedicine” (University of Valladolid), based on Elastin-like Recombinamers (ELR) designed to be injected into soft tissues, with neuroprotective and regenerative properties, and genetically modifiable to increase half-life and control the release of molecules such as Wnt proteins.
The ultimate goal is to develop a therapy with clinical potential based on the administration, single and intraparenchymal within 24 hours post-injury during decompression surgery, of an ELR hydrogel containing molecules capable of activating the canonical Wnt pathway or inhibiting Dkk1.
The proposed therapy aims to achieve a powerful neuroprotective effect, restoring the BSCB and a resolutive inflammatory response in the first weeks post-injury, facilitating both tissue and functional repair during the subacute and intermediate stages post-injury promoted by the ELR hydrogel injected into the epicenter of the damaged spinal cord.

 

2. MED-INMUNOPROTHECT: Acute Spinal Cord Injury: Immunomodulation and Neuroprotection using a Hydrogel of Elastin Recombinamer, Adipose Tissue Mesenchymal Cells and TGFβ. Funding: Research and Innovation Agency of Castilla-La Mancha (INNOCAM).
After spinal cord injury (SCI), an innate and tissue inflammatory response similar to that of other tissues with regenerative capacity is induced. However, prolonged compromise of the blood-spinal cord barrier (BSCB), insufficient early glial scar formation, and the induction of an exacerbated pro-inflammatory response lead to a chronic inflammatory response and secondary damage expansion, which is responsible for most of the functional sequelae resulting from SCI. In this regard, the unbalanced expression of certain anti-inflammatory factors, such as transforming growth factor beta 1 (TGFβ1), prevents the acquisition of anti-inflammatory phenotypes by microglia/macrophage (M2) cells and lymphocytes (Th2/T-Reg), necessary to promote a resolution stage of inflammation and spinal cord repair. The final result is the formation of a cystic cavity surrounded by a glial scar considered to limit axonal regeneration. However, recent studies indicate that glial scar formation is not inhibitory and that it is necessary, together with pro-regenerative stimuli, for the repair of injured tissue and the formation of new functional connections. 
The project proposes that intraparenchymal administration of a single dose within the first 48 hours post-injury of a therapy capable of promoting rapid restoration of the BSCB, rapid glial scar formation, and induction of a resolutive inflammatory response would reduce neural damage and promote functional repair.
To this end, we propose the use of a hydrogel developed by the Smart Devices for Nanomedicine Group at the University of Valladolid (SDN-UVA), which is composed of Elastin-Like Recombinamers (ELR) and silk protein (structural support), fibronectin RGD sequences (neuroprotective, anti-fibrotic, promoter of cell adhesion and migration), and a biomimetic TGFβ1 peptide (potent anti-inflammatory activity). The aim is to administer this hydrogel together with mesenchymal cell transplants from adipose tissue (neuroprotective, anti-fibrotic, anti-inflammatory, promoter of axonal regeneration and remyelination).