Molecular neurology

Molecular neurology group

Molecular neurology

 

Principal investigator: F. Javier Rodriguez

E-mail: fjrodriguez@sescam.jccm.es

 

 

The Group of Molecular Neurology (GMN) was created in 2005 with the objective of identifying new therapeutic targets and developing combined therapies for inducing neuroprotection and promoting neural repair. Such broad experimental approach to the neural repair challenge is tackled through multidisciplinary research ranging from very molecular aspects to the correlation in motor and sensory functional outcome, electrophysiology and histology in clinically relevant rodent models of injury or disease of the nervous system.

 

Our main finding has been the description for the first time of the expression of most of members of the Wnt family of proteins in the adult spinal cord and its implication in the response to traumatic injury or neurodegeneration, aiming that the results obtained in experimental models had a correlate and thus potential therapeutic relevance in samples obtained from healthy and pathological human donors. In this context, our most immediate interest pursues the continuous identification of new Wnt targets and the beginning of their application to the development of therapeutic strategies,with current focus on traumatic spinal cord injuries and a diffuse neurodegenerative pathology such as Amyotrophic Lateral Sclerosis. To that end, our efforts are focused on the development of Wnt therapies based on recombinant protein and biomaterial engineering, which will allow for specific biological effects and versatility in the administration routes (systemic or in the damaged tissue itself).

 

Besides, our group has also contributed to the cell therapy field with the description of a novel source of autologous stem cells located in the adult spinal cord leptomeninges with the potential to generate new neurons and oligodendrocytes, and generated the proof of concept and efficacy of human adipose mesenchymal cell transplants in acute spinal cord injuries, and whose results have contributed to the design and onset of an ongoing clinical trial (https://clinicaltrials.gov/ct2/show/NCT02917291). Likewise, we are also interested in the development of new drug-based therapies currently used in clinics, such as leptin with important interactions with the Wnt family of proteins. Finally, our group has been part of a European consortium focused on the development of new prostheses for the regeneration of damaged peripheral nerves, and collaborates with expert groups in biomaterials for the development of tools that allow an administration adapted to each type of pathology of pharmacological, molecular or cellular treatments found effective. The ultimate goal is to determine the molecular and cellular mechanisms underlying neural damage and develop new reparative therapies with translational potential.

 

The GMN currently has 3 research projects funded for the 2019-2023 period by the Ministry of Science, Innovation and Universities, the Institute of Health Carlos III and the Ministry of Education, Culture and Sports;1 post-doctoral scholarship from the Health Service of Castilla-La Mancha; and a consolidated background in the field of Neural repair.

 

 

Selected publications (last 10 years)

 

1- González P*&,González-Fernández C*&, RodríguezFJ&.“Effects of Wnt5a Overexpression on Spinal Cord Injury”. (* Co-first authors;&Co-corresponding authors). JournalofCellular and Molecular Medicine, In Press. Doi: 10.1111/jcmm.16507.

 

2- 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.

 

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

 

4- González P&, González-Fernández C, Rodríguez FJ&(& Co-Correspondingauthors). 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 MolNeurobiol (2020), 40(7):1087-1103.

 

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

 

6- 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 TissueEngRegenMed (2020), 14(2):319-333.

 

7- 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. MolNeurobiol (2019), 56(10):6777-6791.

 

8- 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.BiomaterSci (2019), 7(12):4912-4943.

 

9- 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.

 

10- 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.

 

11- 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.

 

12- 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.

 

13- 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.

 

14- 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.

 

15- 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.

 

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

 

17- Fernandez-MartosCM, Gonzalez-FernandezC,GonzalezP, MaquedaA, ArenasA, RodriguezFJ. Differential expression of Wnts after Spinal Cord Contusion Injury in adult rats.PLoS One (2011); 6 (11): e27000.

 

18- 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; UniversitatAutònoma de Barcelona 1999).
  • Pau H. González (PhD in Biological Sciences; UniversitatAutònoma de Barcelona 2009).
  • Alfredo Maqueda Fernández (PhD in Biological Sciences; Universidad Autónoma de Madrid 2007).
  • Carlos González-Fernández (PhD in Biochemistry, Molecular Biology and Biomedicine; Universidad Complutense de Madrid 2015).
  • 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. Isidre Ferrer. Institute of Neuropathology, Unit of Pathological Anatomy, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona (Spain).
  • Dr. Xavier Navarro and  Dr. Rubén López-Valés. Group of Neuroplasticity and Regeneration. Department of Cell Biology, Physiology and Immunology. UniversitatAutònoma de Barcelona (UAB, España).
  • Dr. Ernest Arenas. Molecular Neurobiology Unit. Department of Medical Biochemistry and Biophysics.KarolinskaInstitute (Sweden).
  • Consortium NEURIMP: IK4-Tekniker and HISTOCELL (Spain); ContiProPharma (Czech Republic), Vornia (Ireland), University of Sheffield and University of Westminster (UK), Qserve Consultancy (Netherlands).

 

 

Research lines

 

  1. Pharmacological therapies: Assessment in “in vitro” and animal models of Neural Damage of drugs currently in use in clinic, such as minocycline, lithium, ibuprofen or leptin, whose single or combined administration will promote neuroprotection, and axonal/tissue regeneration.
  2.  Cell therapies: Development of new protocols to isolate, expand and instruct cell transplants obtained from autologous and easy access tissues, with capacity to promote neuroprotection, positive immunomodulation, axonal regeneration and/or cell replacement (neurons and oligodendrocytes).
  3. Seek and identification of novel therapeutic targets: Characterization of new key factors on neural damage by means of quantitative PCR, proteomics and immunohistochemistry. In this aim our main research interests are focused on the Wnt family of proteins.
  4. Development of new biomaterials nanostructured and functionalized to promote neuroprotection, axonal regeneration and tissue repair.

 

 

Ongoing projects

 

1- WINSPIRE: Development of a therapy based on selective activation of the Wnt canonical pathway for the treatment of acute spinal cord injury. (Ministry of Science, Innovation and Universities: RTI2018-097775-B-I00).

Experimental evidence provides strong support for the hypothesis that the potentiation of the Wnt canonical signaling pathway, by exogenous administration of canonical Wnt ligands or blocking their inhibitors, will reduce secondary damage and promote functional recovery through: 1) Neuroprotection; 2) Reduce the infiltration of hematogenous inflammatory cells; 3) Restore the Blood Spinal Cord Barrier (BSCB) and hence homeostasis; 4) Resolution of inflammation via promotion of an M2 phenotype that facilitates tissue repair; 5) Functional recovery by formation of new synapses and remyelination.

Our results have allowed us to identify 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 to induce carcinogenesis when administered systemically. Consequently, we propose the combined use of hydrogels developed by the BIOFORGE Group (Univ. Valladolid), based on Elastin-LikeRecombinamers (ELR) designed to be injected into soft tissues, with neuroprotective and regenerative properties, and genetically modifiable to increase the half-life and control the release of molecules such as the Wnt proteins.

The ultimate goal is the development of a therapy with clinical potential based on the administration, unique and intraparenchymal at 24 hours post-injury during decompression surgery, of an ELR hydrogel containing Wnt1 and an anti-Dkk1 antibody.

The proposed therapy pursues a potent neuroprotective, restorative effect of the BSCB and a resolving inflammatory response in the first weeks post-injury, which will facilitate both tissue and functional repair during the subacute and intermediate post-injury stages by the ELR hydrogel injected into the epicenter of the damaged spinal cord.

 

2- SCI-IMMUNOPROTECT: Acute Spinal Cord Injury: IMMUNOmodulation&NeuroPROTection by means of Elastin-Like Recombinamers and Wnt Canonical Signaling Trigger. (Institute of Health Carlos III for Technological Development in Health,in coordination with the Group BIOFORGE from the University of Valladolid: DTS19/00129 and DTS19/00162).

Our group, together with other authors, have demonstrated the involvement of the Wnt family of proteins in Spinal Cord Injury (SCI), as well as the activation of its canonical signaling pathway could be a promising therapy. However, the therapeutic potential of Wnt proteins is limited by their short half-life, technical difficulty and high cost of production, and the intrinsic risk of causing carcinogenesis when administered systemically.

The main objective is the development of a new technological platform based on genetic engineering of Elastin-LikeRecombiners and Wnt derivatives, with the capacity to overcome the limitations that currently limit the clinical translation of Wnt therapies, despite the constant increase in preclinical evidence that implies Wnt signaling deregulation in SCI andother pathologies of the CNS ordifferent tissues/organs.

The specific objective is the application of this technology to develop a Wnt therapy with clinical potential for SCI, which couldbe administered as a single intraparenchymal injection into the epicenter during decompression surgery in the acute phase after the injury, when the potential for inducing a potent therapeutic effect is higher, and is competent to promote a prominent primary neuroprotection along with a tissue response capable of stimulating neural repair. The new technologies developed will be evaluated in a clinically relevant model of rat SCI.

 

3. SCI-WINTHERAPY: Acute treatment of spinal cord injury by combined therapy with elastin hydrogels and recombinant activating proteins of the canonical Wnt pathway. (Councilof Education, Culture and Sports of the Regional Government of Castilla-La Mancha: SBPLY/19/180501/000275).

The general objective of the project presented is the development of a Wnt therapy for Spinal Cord Injury (SCI)with clinical potential, which includes as main features the possibility of being administered as a single intraparenchymal injection in the epicenter of the lesion in the acute post-injury phase, when the potential to induce an effective therapeutic effect is higher, and has thecapacityto induce a prominent primary neuroprotection along with a tissue response capable of promoting neural repair in the subacute and intermediate stages.

In this context, the core of the proposal is to evaluate the therapeutic efficacy of recombinant proteins with the ability to mimic the biological activity of Wnt1. For this, we will use the same experimental model of SCIin which we have demonstrated the therapeutic efficacy of Wnt1.

Besides, we will determine the potential benefit of combining the administration of the proposed canonical Wnt pathway recombinant proteins with an injectable hydrogel based on Elastin-LikeRecombinamers (ELRs). The proposed combination therapy aims to promote a prominent neuroprotective effect in the acute phase, followed by an early restoration of the Blood Spinal Cord Barrier(BSCB) and a resolution of the inflammatory response in the first weeks post-injury which, together with the generation of a physical supportby the hydrogel in the epicenter, we aimto generate a long-term functional regeneration and recovery promoting environment.