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Cell Therapy for Parkinson's Disease

Scientists in Lund have pioneered the use of fetal dopamine neurons for transplantation in Parkinson´s Disease. This approach was developed from 1979-1983 in a series of animal experimental studies (publications 1 below), followed by more directed pre clinical work (publications 2 below) that provided the experimental and methodological basis for the first open-label clinical trials that were initiated at Lund University Hospital in 1987-1989 (publications 3 below). The results obtained in the Lund transplantation program have provided proof-of-principle that human fetal midbrain dopamine neurons can survive and function for many years (more than a decade) after transplantation to the striatum in patients with advanced Parkinson´s disease (publications 4 below). Although the clinical outcome so far has been highly variable, the trials have provided evidence that grafted dopamine neurons can restore regulated dopamine release and movement-related frontal cortical activation in the transplanted patients, and - at least in some cases - give rise to significant symptomatic relief (publications 5 below). Subsequent studies have shown that the transplants can provide sustained improvement over long time, up to 24 years after transplantation (publications 6 below). The brains from four of the grafted patients in the Lund program, who died 13-24 years after transplantation, have come to autopsy. Microscopic analysis of the 11-24 year old transplants (publications 7 below) showed large numbers of surviving dopamine neurons and the expected, widespread reinnervation of the host striatum. In addition, however, the analysis revealed that a portion of the grafted cells had developed the type of alpha-synuclein inclusions, Lewy bodies, that is a hallmark of cells affected by Parkinson´s disease. This striking finding has opened up new avenues for the study of the mechanisms underlying the progressive spread of the disease pathology in the affected brains (publications 8 below).

Current efforts in the Lund PD transplantation program are focused on the use of dopamine neurons derived from pluripotent stem cells, using a protocol that has been devloped here in Lund (publications 9 below).


References

Publications 1:


Reconstruction of the nigrostriatal dopamine pathway by intracerebral nigral transplants. A Björklund and U Stenevi. Brain Research, 177 (1979) 555 560

Reinnervation of the denervated striatum by substanita nigra transplants: Functional consequences as revealed by pharmacological and sensomonitor testing. A Björklund, S B Dunnett, U Stenevi, M E Lewis and S D Iversen. Brain Research, 199 (1980) 307-333

Behavioural recovery following transplantation of substantia nigra in rats subjected to 6-OHDA lesions of the nigrostriatal pathway. I. Unilateral lesions. S B Dunnett, A Björklund, U Stenevi and S D Iversen. Brain Research, 215 (1981) 147-161

Behavioral recovery following transplantation of substantia nigra in rats subjected to 6-OHDA lesions of the nigrostriatal pathway. II. Bilateral lesions. S B Dunnett, A Björklund, U Stenevi and S D Iversen. Brain Research, 229 (1981) 457-470

Functional reactivation of the deaffrented neostriatum by nigral transplants. A Björklund, U Stenevi, S B Dunnet, S D Iversen. Nature vol. 289 5 Feb (1981) 497-499

Aged Rats: Recovery of Motor Impairments by Intrastriatal Nigral Grafts. F H Gage, S B Dunnett, U Stenevi, A Bjorklund. Science vol. 221 966-968

Intracerebral grafting of neuronal cell suspensions II. Survival and growth of nigral cell suspensions implanted in different brain sites. A Björklund, U Stenevi, R H Schmidt, SB Dunnett and F H Gage. Acta physiol scand Suppl. 522, 9-18, (1983)

Intracerebral grafting of neuronal cell suspensions III. Activity of intrastriatal nigral suspension implants as assessed by measurements of dopamine synthesis and metabolism. H Schmidt, A Björklund, U Stenevi, S B Dunett and F H Gage. Acta physiol scand Suppl. 522, 19-28, (1983)

Intercerebral grafting of neuronal celle suspensions IV. Behavioral recovery in rats with unilateral 6-OHDA lesions following implantation of nigral cell suspensions in different forebrain sites. S B Dunnett, A Björklund, R H Schmidt, U Stenevi and S D Iversen. Acta physiol scand Suppl. 522, 29-38, (1983)

Intracerebral grafting of neuronal cell suspensions V. Behavioral recovery in rats with bilateral 6-OHDA lesions following inmplantation of nigral cell suspensions. S B Dunnett, A Björklund, R H Schmidt, U Stenevi and S D Iversen. Acta physiol scand Suppl. 522, 39-48, (1983)


Publications 2


Behavioural effects of human fetal dopamine neurons grafted in a rat model of Parkinson's disease. P. Brundin, O.G. Nilsson, R.E. Strecker, O. Lindvall, B. Astedt, and A. Björklund
Exp Brain Res (1986) 65:235-240

Human fetal dopamine neurons grafted in a rat model of Parkinson's disease: immunological aspects, spontaneous and drug-induced behaviour, and dopamine release. P. Brundin, R.E. Strecker, H. Widner, D.J. Clarke, O.G. Nilsson, B. Astedt, O. Lindvall and A. Björklund. Exp Brain Res (1988) 70:192-208

Human fetal dopamine neurons grafted in a rat model of Parkinson's disease: ultrastructural evidence for synapse formation using tyrosine hydroxylase immunocytochemistry. D.J. Clarke, P. Brundin, R.E. Strecker, O.G. Nilsson, A. Björklund, and O. Lindvall. Exp Brain Res (1988) 73:115-126


Publications 3


Fetal dopamine-rich mesenephalic grafts in Parkinson's disease. O Lindvall, B Åstedt, T Lindholm, S Rehncrona, P Brundin, H Widner, A Björklund, K L Leenders, R Frackowiak, J C Rothwell, C D Marsden, B Johnels, R Freedman, B J Hopper, G Steg, Å Seiger, I Strömberg, M Bygdeman, L Olson. The Lancet, Dec 24/31 1483-1484 (1988)

Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson's disease. O Lindvall, S Rehncrona, P Brundin, B Gustavii, B Åstedt, H Widner, T Lindholm, A Björklund, K L Leenders, J C Rothwell, R Frackowiak, D Marsden, B Johnels, G Steg, R Freedman, B J Hoffer, Å Seiger, M Bygdeman, I Strömberg, L Olson. Arch Neurol vol 46, (1989) 615-631

Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. O Lindvall, P Brundin, H Widner, S Rehncrona, B Gustavii, R Frackowiak, K L Leenders, G Sawle, J C Rothwell, C D Marsden, A Björklund. Science vol. 247, 574-577 (1990)


Publications 4


Transplantation of fetal dopamine neurons in Parkinson's disease: One-year clinical and neurophysiological observations in two patients with putaminal implants. O Lindvall, H Widner, S Rehncrona, P Brundin, P Odin, B Gustavii, R Frackowiak, K L Leenders, G Sawle, J C Rothwell, A Björklund, C D Marsden. Ann Neurol 1992:31: 155-165

Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson's disease. G K Wenning, P Odin, P Morrish, S Rehncrona, H Widner, P Brundin, J C Rothwell, R Brown, B Gustavii, P Hagell, M Jahanshahi, G Sawle, A Björklund, D J Brooks, C D Marsden, N P Quinn, O Lindvall. Ann Neurol 1997; 42:95-107

Sequential bilateral transplantation in Parkinson’s disease - Effects of the second graft. P. Hagell, A. Schrag, P. Piccini, M. Jahanshahi, R. Brown, S. Rehncrona, H. Widner, P. Brundin, J. C. Rothwell, P. Odin, G. K. Wenning, P. Morrish, B. Gustavii, A. Björklund, D. J. Brooks, C. D. Marsden, N. P. Quinn and O. Lindvall. Brain (1999), 122, 1121–1132

Cell Therapy in Parkinson’s Disease. Olle Lindvall and Anders Björklund. NeuroRx: The Journal of the American Society for Experimental NeuroTherapeutics, Vol. 1, 382–393, October 2004


Publications 5


Dopamine release from nigral transplants visualized in vivo in a Parkinson’s patient. Paola Piccini, David J. Brooks, Anders Björklund, Roger N. Gunn, Paul M. Grasby, Ornella, Rimoldi, Patrik Brundin, Peter Hagell, Stig Rehncrona, Håkan Widner and Olle Lindvall. Nature neuroscience • volume 2 no 12 • december (1999) 1137-1140

Delayed Recovery of Movement-Related Cortical Function in Parkinson’s Disease after Striatal Dopaminergic Grafts. Paola Piccini, Olle Lindvall, Anders Björklund, Patrik Brundin, Peter Hagell, Roberto Ceravolo, Wolfgang Oertel, Niall Quinn, Michael Samuel, Stig Rehncrona, Håkan Widner, and David J. Brooks. Annals of Neurology Vol 48 No 5 November (2000) 689-695

Factors affecting the clinical outcome after neural transplantation in Parkinson’s disease. Paola Piccini, Nicola Pavese, Peter Hagell, Jan Reimer, Anders Björklund, Wolfgang H. Oertel, Niall P. Quinn, David J. Brooks and Olle Lindvall. Brain (2005), 128, 2977–2986


Publications 6
 

Serotonergic neurons mediate dyskinesia side effects in Parkinson's patients with neural transplants. Politis M, Wu K, Loane C, Quinn NP, Brooks DJ, Rehncrona S, Bjorklund A, Lindvall O, Piccini P. Sci Transl Med. 2010 Jun 30;2(38):38-46.

Long-term Clinical Outcome of Fetal Cell Transplantation for Parkinson Disease: Two Case Reports. Kefalopoulou Z, Politis M, Piccini P, Mencacci N, Bhatia K, Jahanshahi M, Widner H, Rehncrona S, Brundin P, Björklund A, Lindvall O, Limousin P, Quinn N, Foltynie T. JAMA Neurology. 2013 Nov 11

Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Li W, Englund E, Widner H, Mattsson B, van Westen D, Lätt J, Rehncrona S, Brundin P, Björklund A, Lindvall O, Li JY. Proc Natl Acad Sci U S A. 2016 May 2.


Publications 7


Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation.  Li, J, Englund, E, Holton, JL, Soulet, D, Hagell, P, Lees, AJ, Lashley, T, Quinn, NP, Rehncrona, S, Bjorklund, A, Widner, H, Revesz, T, Lindvall, O, and Brundin, P. Nat Med. 2008 May;14(5):501-3

Characterization of Lewy body pathology in 12- and 16-year-old intrastriatal mesencephalic grafts surviving in a patient with Parkinson's disease. Li JY, Englund E, Widner H, Rehncrona S, Björklund A, Lindvall O, Brundin P. Mov Disord. 2010 Mar 2.

Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Li W, Englund E, Widner H, Mattsson B, van Westen D, Lätt J, Rehncrona S, Brundin P, Björklund A, Lindvall O, Li JY. Proc Natl Acad Sci U S A. 2016 May 2.


Publications 8


Research in motion: the enigma of Parkinson’s disease pathology spread. Patrik Brundin, Jia-Yi Li, Janice L. Holton, Olle Lindvall and Tamas Revesz. Nature Reviews Neuroscience vol 9 Oct (2008) 741-745

Chapter 11 - Neuropathology in transplants in Parkinson's disease: Implications for disease pathogenesis and the future of cell therapy. Patrik Brundin, Jeffrey H.Kordower. Progress in Brain Research, Volume 200, 2012, Pages 221-241


Publications 9
 

Generation of Regionally Specified Neural Progenitors and Functional Neurons from Human Embryonic Stem Cells under Defined Conditions. Kirkeby A, Grealish S, Wolf D A, Nelander J, Wood J, Lundblad M, Lindvall O, Parmar M. Cell Reports, 26 May 2012

Generation of high-purity human ventral midbrain dopaminergic progenitors for in vitro maturation and intracerebral transplantation. Nolbrant S, Heuer A, Parmar M, Kirkeby A. Nature Protocols 12, 31 August 2017


 

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