Protective and regenerative therapies of the CNS

Fernando Pitossi - Fundación Instituto Leloir

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The mayor interest of our Laboratory is to provide information for the development of protective or regenerative therapies for Parkinson ´s Disease (PD). Protective therapies focus on delaying or bring to an end the progression of the disease. On that path, we have discovered that inflammation could worsen the development of PD, and we are currently studying the molecules that must be modulated in order to protect the neurons from degeneration. The purpose of regenerative therapies is to restore functionalities lost because of neuronal death. For this purpose, we are able to produce induced pluripotent stem cells from blood or a little piece of skin. In the future, these stem cells could be differentiated into neurons that could be transplanted into the brain, in order to improve altered brain function, in PD patients. We also study the effects of inflammation in Multiple Sclerosis. Finally, we use cell reprogramming to study other diseases such as epilepsy and Huntington ´s Disease.  
  • Objective 1: Identification of modulatory molecules that mediate the toxic effect of neuroinflammation in PD.
We use animal models that have been developed in our lab (Neurobiology of Disease, 2006 Oct;24(1):183-93; Brain, 2008, 131:1880-94, Neurobiology of Disease, 2010, 37(3):630-40 J Neuroimmunol. 2010, May;222(1-2):29-39 y Exp Neurol. 2011 Feb;227(2):237-51) and functional genomics, in order to identify a candidate molecule that could promote dopaminergic neurons death, which are compromised in PD. We use Drosophila melanogaster, rodents and cellular models in order to determine the functional role of this new molecule in PD.  
  • Objective 2: Cellular Therapy Pre-clinical studies for PD.
We aim to test, in animal models of PD, the therapeutic effect along with the safety of neuronal transplantation of dopaminergic neurons derived from human reprogramed stem cells. Likewise, we focus to improve the safety and efficacy of one anti-inflammatory protocol, and/or the gene expression related with inflammation derived from our current studies ( Gene Ther. 2019 Apr 16. doi: 10.1038/s41434-019-0077-4; FEBS Lett. 2015 Nov 14;589(22):3396-406.).  
  • Objective 3: Modeling disease with cellular reprogramming.
We are using induced pluripotent stem cells to develop neurons from stem cells reprogramed from skin samples of patients with Epilepsy or Huntington Disease, in order to discover the underlying mechanisms of the disease to be able to use this information for future therapies.  
  • Objective 4: Study the functional role of inflammation in Multiple Sclerosis (MS).
We have observed that a sustained peripherical inflammation, aggravates MS. We are currently studying potential therapeutical approaches in MS models developed at our lab (American Journal of Pathology, 2004 Nov;165(5):1827-37; Brain Behav Immun. 2018 Mar;69:515-531), including non-pharmacological interventions such as enriched environment.  

Wenker SD, Pitossi FJ. Cell therapy for Parkinson's disease is coming of age: current challenges and future prospects with a focus on immunomodulation. Review. Gene Ther. 2019 Apr 16. doi: 10.1038/s41434-019-0077-4

Galeano P, Leal MC, Ferrari CC, Dalmasso MC, Martino Adami PV, Farías MI, Casabona JC, Puntel M, Do Carmo S, Smal C, Arán M, Castaño EM, Pitossi FJ, Cuello AC, Morelli L. Chronic Hippocampal Expression of Notch Intracellular Domain Induces Vascular Thickening, Reduces Glucose Availability, and Exacerbates Spatial Memory Deficits in a Rat Model of Early Alzheimer. Mol Neurobiol. 2018 Nov;55(11):8637-8650.

Silva BA, Leal MC, Farías MI, Avalos JC, Besada CH, Pitossi FJ, Ferrari CC. A new focal model resembling features of cortical pathology of the progressive forms of multiple sclerosis: Influence of innate immunity. Brain Behav Immun. 2018 Mar;69:515-531

Rosato-Siri MV, Marziali L, Guitart ME, Badaracco ME, Puntel M, Pitossi F, Correale J, Pasquini JM. Iron Availability Compromises Not Only Oligodendrocytes But Also Astrocytes and Microglial Cells. Mol Neurobiol. 2017 Jan 14. doi: 10.1007/s12035-016-0369-2

Miraglia MC, Costa Franco MM, Rodriguez AM, Bellozi PM, Ferrari CC, Farias MI, Dennis VA, Barrionuevo P, de Oliveira AC, Pitossi F, Kim KS, Delpino MV, Oliveira SC, Giambartolomei GH. Glial Cell-Elicited Activation of Brain Microvasculature in Response to Brucella abortus Infection Requires ASC Inflammasome-Dependent IL-1β Production. J Immunol. 2016 May 1;196(9):3794-805.

Wenker SD, Leal MC, Farías MI, Zeng X, Pitossi FJ. Cell therapy for Parkinson׳s disease: Functional role of the host immune response on survival and differentiation of dopaminergic neuroblasts. Brain Res. 2016 May 1;1638(Pt A):15-29. Review

Wenker SD, Casalía M, Candedo VC, Casabona JC, Pitossi FJ. Cell reprogramming and neuronal differentiation applied to neurodegenerative diseases: Focus on Parkinson's disease. FEBS Lett. 2015 Nov 14;589(22):3396-406. Review

Palma V, Pitossi FJ, Rehen SK, Touriño C, Velasco I. Stem cell research in Latin America: update, challenges and opportunities in a priority research area. Regen Med. 2015;10(6):785-98. Review  

Radice PD, Mathieu P, Leal MC, Farías MI, Ferrari C, Puntel M, Salibe M, Chernomoretz A, Pitossi FJ. Fibulin-2 is a key mediator of the pro-neurogenic effect of TGF-beta1 on adult neural stem cells. Mol Cell Neurosci. 2015 Jun 5;67:75-83

Murta V, Farías MI, Pitossi FJ, Ferrari CC. Chronic systemic IL-1β exacerbates central neuroinflammation independently of the blood-brain barrier integrity. J Neuroimmunol. 2015 Jan 15;278:30-43

Solomon S, Pitossi F, Rao MS. Banking on iPSC--is it doable and is it worthwhile. Stem Cell Rev. 2015 Feb;11(1):1-10. Review

Pitossi FJ, Podhajcer OL. Current status of stem cells and regenerative medicine research in Argentina. Stem Cells Dev. 2014 Dec;23 Suppl 1:17-9. Review





Fernando Pitossi
Head of Laboratory - fpitossi@leloir.org.ar



Shirley Wenker
Assitant Research - CONICET



María Celeste Leal
Assistant Research - CONICET



Berenice Silva
PhD Student - Fundación René Baron



Juan Cruz Casabona
Reserch - CONICET



Brenda Erhardt
Ph.D. Student - CONICET



Esteban Miglietta
Ph.D. Student - CONICET



María Isabel Farias
Technical assistant



Carina Ferrari