The clinical trials showed variable results from fetal cell transplants for Parkinson's disease. Good outcomes require around 100,000 surviving dopamine neurons on each side and reinnervation of the striatum. Problems include variable results, immune response issues, and graft-induced dyskinesia. Gene therapy is a promising alternative being tested in clinical trials. While dopamine neuron transplants can improve function, serotonin neurons may worsen L-DOPA induced dyskinesia through abnormal dopamine release. Future cell therapies require standardized preparations.

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

5. 19

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

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

17. 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 Sahin et al., unpublished data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