cell and gene therapy for parkinson’s disease - part 2
DESCRIPTION
Presentation by Prof Deniz Kirik, MD, PhD at the Parkinson's UK Research Conference, November 2010 in York. With introduction by Dr Oliver Bandmann. Part 1: http://www.slideshare.net/ParkinsonsResearchUK/cell-and-gene-therapy-for-parkinsons-disease-part-1TRANSCRIPT
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
18F-DOPA PET
19
11C-Raclopride PET
11C-Raclopride PET + metamphetamine
11C-Raclopride PET
25
Carta et al., 2007
Role of the serotonin system in L-DOPA-induced dyskinesia
Carta et al., 2007
Role of the serotonin system in L-DOPA-induced dyskinesia
Role of the grafted serotonin neurons on L-DOPA induced dyskinesia
Carlsson et al., 2007
Role of the grafted serotonin neurons on
L-DOPA induced dyskinesia
Carlsson et al., 2007
Role of the grafted serotonin neurons on L-DOPA induced dyskinesia
Carlsson et al., 2007
Role of the grafted serotonin neurons on L-DOPA induced dyskinesia
Online microdialysis
Dopamine release
!"!#
$!!"!#
%!!!"!#
%$!!"!#
&!!!"!#
&$!!"!#
'!!!"!#
'$!!"!#
(!!!"!#
($!!"!#
$!!!"!#
)*+,#-./01# )2#304.+# $536304.+#!"#$%&'(&%)*)%+&,-.
"%/&"*)0&12&.
34+&
!"#$%&'(&0)%)$+)&$5)0&67'89(&
%+/#78#9:411;.<;#
&.=#78#9:411;.<;#
!"!#
$!"!#
%!"!#
&!"!#
'!"!#
(!!"!#
($!"!#
(%!"!#
(&!"!#
('!"!#
($")
#$)
"!#
*+")
#)!
"!#
&$")
#+)
"!#
'+")
#(!
!"!#
(($"
)#($
)"!#
(*+"
)#()
!"!#
(&$"
)#(+
)"!#
('+"
)#$!
!"!#
$($"
)#$$
)"!#
$*+"
)#$)
!"!#
$&$"
)#$+
)"!#
$'+"
)#
!"#$%&'$(
)*"+(
,-(.+$+/0+(
,-./#01234#
,5#6371.#
)86#6371.#
1st K+ challenge
2nd K+ challenge
L-DOPA
Sahin et al., unpublished data
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
Carlsson et al., 2007
How does the serotonin system respond to local continuous DOPA synthesis in the gene therapy setting?
Björklund et al., 2010
Reversal of motor impairments after gene therapy
Reversal of dyskinesia after gene therapy
L-DOPA induced dyskinesias
AIM = Abnormal involuntary movement
0
Pre 4 8 12
100
200
300
Inte
gra
ted
AIM
sco
re
Viral Injection Weeks
*
*
Carlsson et al., 2005
Björklund et al., 2009
Dopamine synthesis after gene therapy
Target cell
TyrosineTyrosine
TH
DOPADOPA
5-HT55555555555555555-------HHHHHHHHHHHHHHHHHHHHTTTTTTTTTTTTTTTTTTTT5-HT
5-HT
receptors
5-HT
receptors
Dopamine
receptorsrrrrrrrrrrrrrreeeeeeeeeeeeeeeeeeccccccccccccccceeeeeeeeeeeeeeeeeppppppppppppppppppppttttttttttttttttttoooooooooooooooooorrrrrrrrrrrrrrrrrrrrrsssssssssssssss
DDDDDDDDDDDDDDDDDDDDooooooooooooooooooooooppppppppppppppppppppppppppaaaaaaaaaaaaaaaaaaaammmmmmmmmmmmmmmmmmmiiiiiiiiiiiiiiinnnnnnnnnnnnnnnnneeeeeeeeeeeeeeeeeeeeeeepppaaaaaaaaaaammmmmmDopamine
receptors
5-HT5555555555555555------HHHHHHHHHHHHHHHHHHHTTTTTTTTTTTTTTTTTT5-HT
Serotonin
terminal
Serotonin
terminal
DOPA
DopamineoooooooooooooooooooopppppppppppppppppppppaaaaaaaaaaaaaaaaaammmmmmmmmmmmmmmmmmmmiiiiiiiiiiiiiiiinnnnnnnnnnnnnnnnnnnneeeeeeeeeeeeeeeeeeeeeeepppppppppppppppppppaaaaammmmmDopamine
DDDDDDDDDDDDDDDDDDDDDDOOOOOOOOOOOOOOOOOOOOOOPPPPPPPPPPPPPPPPPPPPPPPPPPPAAAAAAAAAAAAAAAAAAAAAAAAAADOPA
AADC
TTTTTTTTTTTTTTTTTTTTTTTaaaaaaaaaaaaaaaaaaaaaaaaaarrrrrrrrrrrrrrrrrrrrrrgggggggggggggggggggggggggggeeeeeeeeeeeeeeeeeeeeeeeeeeeetttttttttttttttttttttttt ccccccccccccccccceeeeeeeeeeeeeeeeeeeeeeeeellllllllllllllllllllllllllllllllllllTarget cell
Target cellTarget cell
55555555555555------HHHHHHHHHHHHHHHHHHHTTTTTTTTTTTTTTTTTTT5-HT5555555555
cccccccccceeeeeeeeeeeeeeeeeeeppppppppppppppppppppppppttttttttttttttttttoooooooooooooooooorrrrrrrrrrrrrrrrrrrrssssssssssssssceptorscccccccccccccccc
TTTTTTTTTTTTTTTTTTTTTTTTaaaaaaaaaaaaaaaaaaaaaaaaaarrrrrrrrrrrrrrrrrrrrrrrggggggggggggggggggggggggggggggeeeeeeeeeeeeeeeeeeeeeeeeeeeeetttttttttttttttttttttttt cccccccccccccccceeeeeeeeeeeeeeeeeeeeeeeellllllllllllllllllllllllllllllllllllllTarget cell
nnnnnnnnnnnnnnnnnnnnnnnniiiiiiiiiiiiiiiiiiiiiiiiiiinnnnnnnnnnnnnnnnnnnnnnnninSSSSSSSSSSSSSSSSSSSSSSSSSeeeeeeeeeeeeeeeeeeeeeeeeeeeeerrrrrrrrrrrrrrrrrrrrrrrrrrrrooooooooooooooooooooooooottttttttttttttttttttttttttttooooooooooooooooooooooonnnnnnnnnnnnnnnnnnnnnnSeroton
nnnnnnnnnnnnnnnnnnnaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaallllllllllllllllllllllnaltttttttttttttttttttttttttttteeeeeeeeeeeeeeeeeeeeeeeeeerrrrrrrrrrrrrrrrrrrrrrrrmmmmmmmmmmmmmmmmmmmmmmmmmiiiiiiiiiiiiiiiiiiiiiiinnnnnnnnnnnnnnnnnnnntermin
TTTTTTTTTTTTTTyyyyyyyyyyyyyyyyyyyyyyrrrrrrrrrrrrrrrooossssssiiiiiiiiiiiiiiiiiinnnnnnnnnnnnnnnnnnneeeeeeeeeeeeeeeeeeeeTyrosine
T
DDDDDDDDDDDDDDDDDDDDDOOOOOOOOOOOOOOOOOOOODOGTPPPPPPPPPPPGTP
CytoplasmCyCyCyCyCyCyCyCyCyCyCyCyCyCyCyCyCyCyCyCyCytototototototototototototototototototoplplplplplplplplplplplplplplplplplplplplplplplplasasasasasasasasasasasasasasasasasmmmmmmmmmmmmmmmmmmmCytoplasm
NucleusNucleus
BH4BBBBBBBBBBBBBBBBBBHHHHHHHHHHHHHHHHHHHHHHHH4444444444444444444444BH4
Host striatal cell
GC
H1
GGGGGGGGGGGGGGGGGGCCCCCCCCCCCCCCCCCCCCC
HHHHHHHHHHHHHHHHHHHHH11111111111111
GC
H1
44444444444444
DDDDDDDDDDDDDDDDDDDoooooooooooooooooooDo
TH
OOOOOOOOOOOOOOOOOOOOOPPPPPPPPPPPPPPPPPPPPPPPPPAAAAAAAAAAAAAAAAAAAAAAAAOPA
TH gene
GCH1 geneGCH1 gene
TTTTTTTTTTTTTTTTTTTTyyyyyyyTy
PPPPPPPPPPPPPPPPPPPPP
NuNuNuNuNuNuNuNuNuNuNuNuNuNuNuNuNuNuNuNuNuNuNuNuclclclclclclclclclclclclclclclclclclclclclcleueueueueueueueueueueueueueueueueueueueueussssssssssssssssssssNucleus
TH genegH
HHHHHHHHHHHHHH1111111111111H1GGGGGGGGGGGGGGGGGGCCCCCCCCCCCCCCCCCCCHHHHHHHHHHHHHHHGCH gggggggggggggggggggggggeeeeeeeeeeeeeeeeennnnnnnnnnnnnnnnnnnneeeeeeeeeeeeeeeeeee gene
GGGGGGGGGGGGGGTTTTTTTTTPPPPPGTPGGGGGGGGGGGGGGGTTTTTTTTTTTTPPPPPPPPGTP
rrrrrrrrrrrrrooooooooooooooooossssssssssssssssiiiiiiiiiirosioooooooooooo
Modi�ed from Björklund et al.,
Science Translational Medicine 2009
MMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMooooooooooooooooooooooodddddddddddddddddddddddddddddddddiiiiiiiiiiiiiiiiiiiiiiiii���������������������������������eeeeeeeeeeeeeeeeeee jjjjjjjjjjjjjjjjjjjjjjjjöööööööööööööööööööööööööööööörrrrrrrrrrrrrrrrrrrrrrrrrkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkklllllllllllllllllllluuuuuuuuuuuuuuuuuuuuuuunnnnnnnnnnnnnnnnnnnnnnnndddddddddddddddddddddddddddddddd BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBjjjjjjjjjjjjjjjjjjjjjjjjjöööööööeeeeeeeeeeeeeeeeeeeeeeeeeeedddddddddddddddddddddddddddddddd ffffffffffffffffffffffffffffffrrrrrrrrrrrrrrrrrrrrrrrroooooooooooooooooooooooooooooooooooooooooooommmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmm mmmmmmmmmooooooooommmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmm eeeeeeeeeeeeeeeeeeeeeeeeeeeeeettttttttttttttttttttttttt aaaaaaaaaaaaaaaaaaaaaaallllllllllllllllllllllllll.........,,,,,,,,,,,,,,,,
SSSSSSSSSSSSSSSSSSSSSSSSSSSSScccccccccccccccccccciiiiiiiiiiiiiiiiiiiiiiiiieeeeeeeeeeeeeeeeeeeeeeeeeeennnnnnnnnnnnnnnnnnnnnnnccccccccccccccccccccccceeeeeeeeeeeeeeeeeeeeeeee oooooooooooooooooooooonnnnnnnnnnnnnnnnnnnnnnaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaallllllllllllllllllllll MMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMeeeeeeeeeeeeeeeeeeeeeeeeeeeeedddddddddddddddddddddddddddddddddiiiiiiiiiiiiiiiiiiiiiiiiiicccccccccccccccccccciiiiiiiiiiiiiiiiiiiiiiiiiiinnnnnnnnnnnnnnnnnnnnnnneeeeeeeeeeeeeeeeeeeeeeeeeeeeeee 222222222222222222222222222220000000000000000000000000000000000000000000000000000000000999999999999999999999999999999tttttttttttttttttttttttttiiiiiiiiiiiiiiiiiiiiiioooooooooooooooooooeeeeeeeeeeeeeeeeeeeeeeeeeeeee TTTTTTTTTTTTTTTTTTTTTTTTTTTTTrrrrrrrrrrrrrrrrrrrraaaaaaaaaaaaaaaaaaaaaaaaaaaaaannnnnnnnnnnnnnnnnnnnnnnsssssssssssssssssssssssssssssssssssssssssllssssllllllllllllllllllllllaaaaaaaaaaaaaaaaaaaaaaaaaattttttttttttttttttaaaattttttttttttttttttttttttssssssssssssssslllllllllllllllllllllllllllllllllllllllaaaaaaaaaaaaaaaaa
Modi�ed from Björklund et al.,
Science Translational Medicine 2009
eeeeeeeeeeee
rrrrrrrrrrrrrrrreeeeeeeeeeeeeeeeeeecccccccccccrec
Björklund et al. 2010
Requirement of striatal 5-HT innervation for behavioral recovery
Pre 5,7-DHT lesion
@ 23 wks
Post 5,7-DHT lesion
@ 26 wks
125
100
75
50
25
0
Left
fo
reh
an
d s
tep
s (%
of
inta
ct)
Stepping test
*
*
Pre 5,7-DHT lesion
@ 23 wks
Post 5,7-DHT lesion
@ 26 wks
60
50
40
30
20
10
0
Le
ft f
ore
lim
b t
ou
ch
es
(% o
f to
tal)
Cylinder test
Les-Sham
TH+GCH1*
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
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
Collaborators at Lund UniversityAnders Björklund
Angela Cenci-NilssonCarl Rosenblad
Clinical transplantation teamOlle Lindvall
Håkan WidnerPeter Hagell
Stig Renchona
Brain Repair and Imaging
in Neural Systems (BRAINS)
Erik Ahlm Cederfjäll Tomas BjörklundNathalie Breysse
Thomas CarlssonManolo Carta
Hélène Hall Gurdal Sahin
Charlotte SonesonSimon Stott
Lachlan ThompsonAyse Ulusoy
Christian WinklerLiselijn Wisman
Björn Anzelius Anneli JosefssonUlla Jarl Elsy LingHongyan Liu Bengt Mattsson Ulla Samuelsson Ulrika Sparrhult-Bjork