Cell and gene therapy for Parkinson’s disease - part 2

1. Results of the clinical trials Good therapeutic effect requires: - ~100 000 surviving DA-neurons on each side - Recovery of putaminal FD-uptake to ~50% of normal - Reinnervation of a major part of the striatal volume Problems associated with cell transplantation: - the results are too variable - the delayed immune response must be controlled - graft-induced dyskinesia is a problem that must be solved - the use of fetal tissue is unsatisfactory

3. 18F-DOPA PET

6. 11C-Raclopride PET

7. 11C-Raclopride PET + metamphetamine

10. 11C-Raclopride PET

11. 25

12. Role of the serotonin system in L-DOPA-induced dyskinesia Carta et al., 2007

13. Role of the serotonin system in L-DOPA-induced dyskinesia Carta et al., 2007

14. Role of the grafted serotonin neurons on L-DOPA induced dyskinesia

15. Role of the grafted serotonin neurons on L-DOPA induced dyskinesia Carlsson et al., 2007

18. Online microdialysis Dopamine release 1st K+ 2nd K+ challenge challenge

20. L-DOPA

21. Sahin et al., unpublished data

22. Dyskinesias induced by serotonergic hyperinnervation in the grafted striatum are effectively suppressed by a 5-HT1A agonist in transplanted PD patients Politis et al., 2010

23. How does the serotonin system respond to local continuous DOPA synthesis in the gene therapy setting? Carlsson et al., 2007

24. Reversal of motor impairments after gene therapy Björklund et al., 2010

25. Reversal of dyskinesia after gene therapy L-DOPA induced dyskinesias 300 Integrated AIM score 200 100 * * 0 Pre 4 8 12 Viral Injection Weeks AIM = Abnormal involuntary movement Carlsson et al., 2005

26. Dopamine synthesis after gene therapy Björklund et al., 2009

27. TH g H gene Seroton Serotonin nin Serotonin Nucleus Nucleus Nucleus cleu termin terminal nal terminal Tyrosi Tyrosine Tyrosine 5-HT 5-HT GCH1 gene GCH1 gene GCH H1 DOPA DOPA TH T AADC GTP GTP DOPA DO DOPA OPA Do Dopamine Dopamine GC H1 H1 H H H H H H H H1 H1 H1 H1 H1 H1 H1 H1 H1 H1 H1 H1 H1 H1 BH4 BH4 Cytoplasm Cytoplas Cytoplasm toplasm Host striatal cell 5-HT 5-HT 5-HT 5-HT receptors rec receptors ceptors Target cell Target cell Dopamine Dopamine Modi ed from Björklund et al., Modi ed from Björklund et al., Target cell Target cell receptors receptors Science Translational Medicine 2009 Science Translational Medicine 2009

28. Requirement of striatal 5-HT innervation for behavioral recovery Stepping test Cylinder test * 125 * Les-Sham Left forelimb touches (% of total) Left forehand steps (% of intact) 60 TH+GCH1 * 100 50 40 75 30 50 20 25 10 0 0 Pre 5,7-DHT lesion Post 5,7-DHT lesion Pre 5,7-DHT lesion Post 5,7-DHT lesion @ 23 wks @ 26 wks @ 23 wks @ 26 wks Björklund et al. 2010

29. Key points - 1 •Clinical results using fetal cell transplants have been mixed: Some patients showed substantial beneﬁts while others had unsatisfactory results or even side effects • Cell transplants from ventral mesencephalic tissue restore function in the parkinsonian brain mainly by restoring dopamine neurotransmission • However, serotonin neurons present in the tissue mixture can aggravate L-DOPA induced dyskinesias via a mechanism that involves abnormal DA release •Success of cell replacement therapy in the clinics will depend on the development of standardized and well-characterized cell preparations

30. Key points - 2 • The pre-clinical data on multiple independent approaches have given very strong indication on the potential of gene therapy • Viral vector mediated therapeutic gene transfer is now entering into clinical trials phase and holds great promise for making a difference in the quality of life of Parkinson’s patients • If successful, clinical application of gene therapy in Parkinson’s will set the stage for other neurological diseases that can be treated with this uniquely powerful tool

31. Brain Repair and Imaging in Neural Systems (BRAINS) Erik Ahlm Cederfjäll Björn Anzelius Tomas Björklund Anneli Josefsson Nathalie Breysse Ulla Jarl Thomas Carlsson Elsy Ling Manolo Carta Hongyan Liu Hélène Hall Bengt Mattsson Gurdal Sahin Ulla Samuelsson Charlotte Soneson Ulrika Sparrhult-Bjork Simon Stott Lachlan Thompson Ayse Ulusoy Christian Winkler Liselijn Wisman Collaborators at Lund University Anders Björklund Angela Cenci-Nilsson Carl Rosenblad Clinical transplantation team Olle Lindvall Håkan Widner Peter Hagell Stig Renchona

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