 
| Group leaderPhilippe Hantraye (DR2-CNRS)
|
Evaluation of innovative pre-clinical therapeutic strategies
The aim of this line of research is to propose,
develop and evaluate innovative pre-clinical therapeutic strategies for neurodegenerative diseases like Parkinson's, Huntington's and Alzheimer's. Different translational approaches are currently under evaluation, aiming at either protecting and preventing disease progression or replacement and repair strategies. This can be achieved by various means including
cell-, gene- and drug-based therapies
in vivo in pertinent
validated disease models (in rodents and non-human primates).
The development of these preclinical studies need the use of predictive animal models (d'Orange et al., 2017) and a major activity of the group is to develop and characterize the rodent and non human primate animal models.
The major concern is to assess the efficacy of these approaches applying non-invasive techniques, like
behavioral tests (Aron Badin et al., 2016), PET, and MRS/MRI, that are comparable and/or directly applicable in the clinical set-up (Lavisse et al., 2015; Gaura et al. 2017).
This working strategy has already been successfully applied in various clinical trials like cell therapy for Parkinson's (Gaura
et al., 2004) and Huntington's disease (Bachoud-Levi
et al, 2006) and
ex vivo gene therapy in Huntington's disease; (Bloch
et al., 2004).
A permanent collaboration with clinical teams in SHFJ (CEA), Henri Mondor (Neurosurgical & Neurological departments) and the Bicêtre Hospital allows a
continuous bench-to-bedside feedback that we believe is the key to translational research. This is what makes our unit attractive to both clinical and industrial partners in France, Europe and overseas. In parallel, our teams are involved in the development of new non-invasive monitoring technics with functional imaging (Galineau et al., 2017) and electroencephalography in order to use them as biomarkers for early detection in prodromal animal models of neurodegenerative diseases (Parkinson, Huntington, Tauopathy).
This translational research strategy was already succesfully applied in various clinical trials of cell therapy for Parkinson Disease (Gaura et al., 2004) or Huntington Disease (Bachoud-Levy et al., 2006 and 2010) but also in gene therapy ex vivo for Huntington Disease (Bachoud Levy et al., 2004) and in vivo for the Parkinson Disease (Jarryaya et al., 2009; Palfi et al., 2014)
Research approaches
Recent & ongoing collaborative projects include using cell-, gene- and drug-based therapies for the treatment of Parkinson's and Huntington's disease similarly to Pharmacological treatments to slow down disease progression or provide symptomatic relief for chronic, progressive neurodegenerative disorders. These strategies rely heavily on the accuracy of the symptomatology of the disease models used and on the use of appropriate non-invasive follow-up techniques to detect and quantify changes over time.
1) The Pharmacological approach
This approch can be used to slow down disease progression or provide symptomatic relief for chronic, progressive neurodegenerative disorders. These strategies rely heavily on the accuracy of the symptomatology of the disease models used and on the use of appropriate non-invasive follow-up techniques to detect and quantify changes over time.
Some of the laboratory’s most recent research projects have resulted in clinical applications of the tested drugs:
- Evaluation of the antidyskinetic efficacy of a novel drug in a model of Parkinson’s disease with motor complications (IPSEN-Beaufour).
- Neuroprotective effect of the granulocyte-colony stimulating factor (G-CSF) in a model of Parkinson’s disease (Michael J Fox Foundation).
-
In vivo longitudinal imaging and behavioral assessment of the efficacy of a novel neuroprotective treatment in an animal model of Huntington’s disease (Servier).
2) The cellular approach
The
basis of cellular approaches is to repair a deficient neuronal network that underlies pathological symptoms by grafting
embryonic or stem cells and reconstituting the circuitry. Our research focuses on the efficacy of different types of cells (embryonic , stem cells, IPS cells), their safety and immunogenicity, and the in vivo follow-up necessary to assess graft functionality. Some examples are listed below:
Examples of ongoing projects:
- In vivo functional characterization of IPS cell allografts and xenografys in a primate model of HD using longitudinal MR imaging and behavioral assessments (RepairHD, FP7, in collaboration with A Perrier, I-Stem; Anne Roser and Steve Dunnett, Cardiff University)
-
In vivo PET imaging of dopaminergic and serotoninergic grafts in parkinsonian animals (NeuronE FP7, NeX, in collaboration with D Kirik, Lund University)
-
In vivo PET and MR imaging signature of stem cell fate following transplantation in PD and HD animal models (Neurostemcell, FP7, NeX, in collaboration with A Perrier, I-Stem; Malin Palmar, Lund University)
- PET, behavioral and histopathological characterization of intrastriatal embryonic dopaminergic pig xenografts in parkinsonian animals (Xenome, FP7, NeX, in collaboration with E Cozzi, University of Padova; B Vanhove, ITERT Nantes)
- MRI and histopathological evaluation of a 'safety switch' to control overgrowth after cell transplantation using the TK suicide gene strategy in an animal model of HD (ANR TKSafe, LTK Pharma; A Perrier, I-Stem; J Cohen, R Lemoine, Pitié Salpétrière)
- Pre-clinical evaluation of cell-based therapy in HD using pluripotent stem cells (ANR HD-SCT, A Perrier, I-Stem; D Sourdive, Cellectis)
-
In vivo PET, MR imaging and behavioral longitudinal assessment of stem cell allo- and xeno-therapy for Huntington's disease (Repair-HD, FP7, NeX, S Dunnett, University of Cardiff; Roslin Institute Edinburgh; A Perrier, I-Stem; AC Bachoud-Lévi, Henri Mondor Hospital).
3) Gene therapy approaches
Gene
therapy approaches consist of
using modified viral vectors to over-express therapeutic genes in adult
neurons. The efficacy of this strategy has been demonstrated in animal models of
Parkinson’s disease where dopamine synthesis was restored in the brain after the injection of the ProSavin® vector (Oxford Biomedica). An ongoing clinical trial in Henri Mondor Hospital yields encouraging results in Parkinsonian patients (PI: S. Palfi, Henri Mondor Hospital).
Examples of ongoing projects:
- In vivo behavioral and PET imaging assessment of the efficacy of gene therapy for Parkinson’s disease after administration of the ProSavin® lentiviral vector (Oxford BioMedica, UK and S. Palfi, Henri Mondor Hospital).
- Pre-clinical safety and efficacy of an enhanced dopamine replacelent gene therapy strategy (OXB-102) in a primate model of Parkinson's disease using behavioral and PET imaging assessments (Oxford BioMedica, UK and S. Palfi, Henri Mondor Hospital).
- Neuroprotective effect of over-expressing the ciliary neurotrophic factor (CNTF) in adult neurons in an animal model of Huntington’s disease and patients (AFM, Généthon, AC Bachoud-Levi, Henri Mondor Hospital).
- PET imaging longitudinal assessment of dopamine production in rodent models of Parkinson’s disease after lentiviral gene transfer (D Kirik, Lund University).
18F-FluoroMethylTyrosine PET imaging in a NHP (non-human primate) model of Parkinson disease
(normal, Parkinson NHP and Parkinson-treated NHP)
Members of the laboratory associated with these projects
Collaborations
- Oxford BioMedica, UK,
- Hôpital Henri Mondor (Stéphane Palfi, Philippe Remy, Anne-Catherine Bachoud-Levy)
- Lund University (D Kirik et Malin Palmar)
- University of Padova (E Cozzi)
- ITERT Nantes (B Vanhove)
- I-Stem (A Perrier)
- Hôpital de la Pitié Salpétrière (J Cohen, R Lemoine)
- Cellectis (D Sourdive)
- University of Cardiff (S Dunnett)
- Institute of Edimburgh (Roslin)
Recent publications
Cell therapy for Parkinson's disease: A translational approach to assess the role of local and systemic immunosuppression
Aron Badin R, Vadori M, Vanhove B, Nerriere-Daguin V, Naveilhan P, Neveu I, Jan C, Lévèque X, Venturi E, Mermillod P, Van Camp N, Dollé F, Guillermier M, Denaro L, Manara R, Citton V, Simioni P, Zampieri P, D'avella D, Rubello D, Fante F, Boldrin M, De Benedictis GM, Cavicchioli L, Sgarabotto D, Plebani M, Stefani AL, Brachet P, Blancho G, Soulillou JP, Hantraye P, Cozzi E.
Am J Transplant. 2016, Jan 8.
IRC-082451, a novel multitargeting molecule, reduces L-DOPA-induced dyskinesias in MPTP Parkinsonian primates
Aron Badin R, Spinnewyn B, Gaillard MC, Jan C, Malgorn C, Van Camp N, Dolle F, Guillermier M, Boulet S, Bertrand A, Savasta M, Auguet M, Brouillet E, Chabrier PE, Hantraye P
PLoS One 2012 8:e52680.
Delivery of the Human Wild-type Tau Protein Mediates a Slow and Progressive Neurodegenerative Tau Pathology in the Rat Brain
Caillierez R, Begard S, Lecolle K, Deramecourt V, Zommer N, Dujardin S, Loyens A, Dufour N, Auregan G, Winderickx J, Hantraye P, Deglon N, Buee L, Colin M Lentiviral
Mol Ther 21 2013 :1358-1368.
Restricted transgene expression in the brain with cell-type specific neuronal promoters
Delzor A, Dufour N, Petit F, Guillermier M, Houitte D, Auregan G, Brouillet E, Hantraye P, Deglon N
Hum Gene Ther Methods 2013 23:242-254.
Reactive astrocytes overexpress TSPO and are detected by TSPO positron emission tomography imaging
Lavisse S, Guillermier M, Herard AS, Petit F, Delahaye M, Van Camp N, Ben Haim L, Lebon V, Remy P, Dolle F, Delzescaux T, Bonvento G, Hantraye P, Escartin C
J Neurosci 2012 32:10809-10818.
Dopamine gene therapy for Parkinson's disease in a nonhuman primate without associated dyskinesia
Jarraya B, Boulet S, Ralph GS, Jan C, Bonvento G, Azzouz M, Miskin JE, Shin M, Delzescaux T, Drouot X, Herard AS, Day DM, Brouillet E, Kingsman SM, Hantraye P, Mitrophanous KA, Mazarakis ND, Palfi S
Sci Transl Med 2009 1:2ra4.