cell and gene therapy for parkinson’s disease - part 2

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

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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Sahin et al., unpublished data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

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Science Translational Medicine 2009

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Requirement of striatal 5-HT innervation for behavioral recovery

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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