title: Cyclosporin promotes neurorestoration and cell replacement therapy in pre-clinical models of Parkinson's disease.
abstract: BACKGROUND
  The early clinical trials using fetal ventral mesencephalic (VM) allografts in Parkinson's disease (PD) patients have shown efficacy (albeit not in all cases) and have paved the way for further development of cell replacement therapy strategies in PD. The preclinical work that led to these clinical trials used allografts of fetal VM tissue placed into 6-OHDA lesioned rats, while the patients received similar allografts under cover of immunosuppression in an α-synuclein disease state. Thus developing models that more faithfully replicate the clinical scenario would be a useful tool for the translation of such cell-based therapies to the clinic.
  
  
  RESULTS
  Here, we show that while providing functional recovery, transplantation of fetal dopamine neurons into the AAV-α-synuclein rat model of PD resulted in smaller-sized grafts as compared to similar grafts placed into the 6-OHDA-lesioned striatum. Additionally, we found that cyclosporin treatment was able to promote the survival of the transplanted cells in this allografted state and surprisingly also provided therapeutic benefit in sham-operated animals. We demonstrated that delayed cyclosporin treatment afforded neurorestoration in three complementary models of PD including the Thy1-α-synuclein transgenic mouse, a novel AAV-α-synuclein mouse model, and the MPTP mouse model. We then explored the mechanisms for this benefit of cyclosporin and found it was mediated by both cell-autonomous mechanisms and non-cell autonomous mechanisms.
  
  
  CONCLUSIONS
  This study provides compelling evidence in favor for the use of immunosuppression in all grafted PD patients receiving cell replacement therapy, regardless of the immunological mismatch between donor and host cells, and also suggests that cyclosporine treatment itself may act as a disease-modifying therapy in all PD patients.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Tamburrino
authors.affiliation: Veterans Hospital/Research Services/Portland and Department of Behavioral Neuroscience Oregon Health &, Science University, Portland, OR, USA.
authors.forename: Madeline J
authors.initials: MJ
authors.lastname: Churchill
authors.affiliation: Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, Lund, Sweden.
authors.forename: Oi W
authors.initials: OW
authors.lastname: Wan
authors.affiliation: Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, Lund, Sweden.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Colino-Sanguino
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Ippolito
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
authors.forename: Sofie
authors.initials: S
authors.lastname: Bergstrand
authors.affiliation: Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, Lund, Sweden.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Wolf
authors.affiliation: Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Houston, USA.
authors.forename: Niculin J
authors.initials: NJ
authors.lastname: Herz
authors.affiliation: Veterans Hospital/Research Services/Portland and Department of Behavioral Neuroscience Oregon Health &, Science University, Portland, OR, USA.
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Sconce
authors.affiliation: Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Björklund
authors.affiliation: Veterans Hospital/Research Services/Portland and Department of Behavioral Neuroscience Oregon Health &, Science University, Portland, OR, USA.
authors.forename: Charles K
authors.initials: CK
authors.lastname: Meshul
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy. m.decressac@tigem.it.
authors.forename: Mickael
authors.initials: M
authors.lastname: Decressac
mesh_terms: D000818:Animals; D017690:Cell Transplantation / Q000379:methods*; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000209:etiology / Q000628:therapy; D016572:Cyclosporine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology / Q000637:transplantation; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000150:complications / Q000188:drug therapy* / Q000209:etiology / Q000601:surgery*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D051844:alpha-Synuclein; D016572:Cyclosporine; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase