TREATING PARKINSON S AND HUNTINGTON S DISEASE WITH CELL THERAPIES- WHY BOTHER? Roger Barker John van Geest Centre for Brain Repair and Department of Neurology University of Cambridge rab46@cam.ac.uk
WHAT IS PARKINSON S DISEASE? MOVEMENT DISORDER Tremor Slowness of movement /Bradykinesia Rigid muscles and NON-MOTOR PROBLEMS And NON-NIGRAL DOPAMINE CELL LOSS
TREATING PARKINSON S WITH CELL THERAPIES: WHY BOTHER? PARKINSON S DISEASE REASONS FOR: Common; Incurable; Well defined dopamine nigral cell loss; Responds to dopamine drugs so will respond well to dopamine cell therapies; Drug therapies have long term side effects; Fetal VM trials have shown proof of principle data to support their efficacy REASONS AGAINST: Most people die with rather than from PD; Good dopamine therapies exist for it already; Trials show it does not work with fetal VM tissue; Pathology extends beyond the dopamine system and this causes more significant problems; Grafts acquire PD pathology!
Neural grafts HUMAN FETAL VM Replace dopamine cells CURE time spent in "off" (%) time spent in "off" (%) 8 0 6 0 4 0 2 0 0 8 0 6 0 4 0 2 0 T r a n s p l a n t a t i o n s u r g e r y S e l e g i l i n e 1 0 m g S e l e g i l i n e 1 0 m g P a t i e n t 3 P a t i e n t 4 C y c l o s p o r i n e 0 L - d o p a 0 Key pathology is known i.e. loss of dopaminergic cells in nigra 0-1 2-6 0 6 1 2 1 8 2 4 3 0 3 6 m o n t h s p r e - a n d p o s t - t r a n s p l a n t a t i o n Graft survival and functional improvement EXPERIMENTALLY SHOWN: Allografts of right fetal age survive; Make and receive connections from host; Release DA; Ameliorate most but not all behaviours OPEN LABEL STUDIES in PD PATIENTS: Fetal nigral transplants in PD patients
2001 RESULT No significant benefit at 1 year using global rating scale; SIDE-EFFECTS!! Graft induced dyskinesias (GIDs) seen in 15% of patients BUT nevertheless. 2003 RESULT No significant benefit at 2 year using standard assessment; GIDs seen in 54% of patients
Fetal neural cells into rat brain Cell suspensions used But THE OPEN LABEL STUDY FOLLOW UP CONTINUES 1970-72 1976 1979 1980 1981 1985 1988 1990 1995 1997 1999 2000 2001 2002 2009 SO WHAT have we learnt to date about cell based therapies for PD
And the data to date Fetal dopamine transplants for PD can be delivered safely- no neurosurgical or tumour concerns. Fetal dopamine transplants can work well for over 10 years in some patients to the extent that they can stop their medication. Fetal dopamine transplants do NOT work in ALL patients with PD. THE NEED FOR A NEW TRIAL?.TRANSEURO AND some patients develop GIDs but only a new where these are bad enough to have DBS and in those cases it works as well as for LIDS..and Pathology can develop in these grafts albeit in low numbers of dopaminergic cells.. Barker et al Lancet Neurology 2013
LUND CAMBRIDGE CARDIFF LONDON PARIS FREIBURG VIENNA OPTIMISED THE COLLECTION OF DOPAMINE CELLS FROM THE HUMAN FETAL BRAIN COLLECTED, STUDIED AND OPTIMISED THE ASSESSMENT OF A LARGE GROUP OF YOUNG PATIENTS WITH PD (N=150) OPEN LABEL STUDY; 20 GRAFTED WITH 3 YEAR FOLLOW UP and IMMUNOSUPPRESSION; 20 FOLLOWED WITH PET; 11O FOLLOWED CLINICALLY; ALL MOTOR ASSESSMENTS RATED BLINDLY 2010 OPTIMISED THE DELIVERY OF FETAL TISSUE INTO THE BRAIN 2014 STEPPING STONE TO STEM CELL TRANSPLANT TRIALS
TREATING PARKINSON S AND HUNTINGTON S DISEASE WITH CELL THERAPIES- WHY BOTHER? PARKINSON S DISEASE WHAT CAN WE SAY? Fetal VM transplants can work as well as best dopamine therapies; This therapeutic effect can last for >10 years; Currently very variable clinical response; Grafts can acquire a pathology but this is not a critical factor in the short term; This is not a CURE but may have a major impact on changing the natural history of treated PD
Huntington s Disease- An introduction Autosomal dominant driven by mutant huntingtin Starts between ages of 30-50 Progresses over about 20 years from onset Expanded CAG repeat Mutant huntingtin Interferes with transcription STRATEGIES TRIED AMONGST OTHERS: Environmental enrichment Creatine supplementation Caspase inhibitors (minocyline) Regulators of proteosome Histone deacetylase inhibitors Activators of autophagy (rapamycin) sirna therapy Recent interest in NMDA-R mediated htt processing Aggregation of mutant protein/ Formation of inclusions Removed by UPS/autophagy Cellular dysfunction Altering glutamate signalling Causing excitotoxicity Cell Death
TREATING HUNTINGTON S DISEASE WITH CELL THERAPIES: WHY BOTHER? HUNTINGTON S DISEASE REASONS FOR: Relatively common; Incurable; Most people die of HD; Well defined early striatal pathology; Experimental studies show you can repair the excitotoxically lesioned striatum with fetal striatal grafts; Some grafted patients have done well; No effective therapy for HD unlike PD REASONS AGAINST: Pathology involves many nonstriatal sites from disease onset; Transplant studies in Tg mice have failed; Trials show it does not work for the majority of cases; Grafts can acquire HD pathology! Better approach is to target the pathogenic pathway involving mutant gene and its product
Huntington s disease: TRANSPLANT APPROACH Take patient with a neurodegenerative disorder such as HUNTINGTON S DISEASE Identify key pathology i.e. loss of strital projection neurons Transplant in striatal cells CURE Name Number of patients Improvement Post-mortem data Kopyov et al 1998 3 Yes short term Yes 2, poor graft integration 6 years post implantation with mass effect in 1 case Bachoud-Levi et al 2000 and 2006 5 Yes in 3/5 but now getting worse Rosser et al 2002 4 (5) No No Hauser et al 2002 7 No Yes- 1, with good graft survival but no clinical improvement and another with poor integration Tai et al 2 Yes 1 long term No No
Name Number of patients Improvement Post-mortem data Kopyov et al 1998 3 Yes short term Yes 2, poor graft integration 6 years post implantation with mass effect in 1 case Bachoud-Levi et al 2000 and 2006 5 Yes in 3/5 but now getting worse Rosser et al 2002 4 (5) No No Hauser et al 2002 7 No Yes- 1, with good graft survival but no clinical improvement and another with poor integration Tai et al 2 Yes 1 long term No No
Name Number of patients Improvement Post-mortem data Kopyov et al 1998 3 Yes short term Yes 2, poor graft integration 6 years post implantation with mass effect in 1 case Bachoud-Levi et al 2000 and 2006 5 Yes in 3/5 but now getting worse Rosser et al 2002 4 (5) No No Hauser et al 2002 7 No Yes- 1, with good graft survival but no clinical improvement and another with poor integration Tai et al 2 Yes 1 long term No No
Clinical Transplant Trial-Cambridge UK..and in Transplant group PET measurement of disease progression in HD 1.9 Mean reduction 5%/yr (range ~2.3-7.7) 1.7 Total UHDRS Scores (higher =worse) 1.5 Raclopride BP 1.3 1.1 Rstriat Lstriat No significant benefit clinically or on imaging 0.9 0.7 0.5 Baseline T1 +1 T1 +2 T2 +1 Time
Name Number of patients Improvement Post-mortem data Kopyov et al 1998 3 Yes short term Yes 2, poor graft integration 6 years post implantation with mass effect in 1 case Bachoud-Levi et al 2000 and 2006 5 Yes in 3/5 but now getting worse Rosser et al 2002 4 (5) No No Hauser et al 2002 7 No Yes- 1, with good graft survival but no clinical improvement and another with poor integration Tai et al 2 Yes 1 long term No No
BUT a patient grafted at KCL.. 30 20 10 0-6 0 6 12 18 24 30-10 -20 Transplantation Subject 1 Subject 2 Controls Time (months) Total UHDRS Score 60 50 40 30 20 10 Kings 1 Vs Controls 0-6 6 18 30 42 54 66 78 90 Months Kings 1 Controls -30 6 months Baseline post Tx DB Male CAG-repeat length 43 HD manifested clinically at age 46 when he developed chorea, aggression and depression. Grafted at KCH, London 1999. Last follow up 13 years post transplantation Reuter et al JNNP 2009
TREATING PARKINSON S AND HUNTINGTON S DISEASE WITH CELL THERAPIES- WHY BOTHER? PARKINSON S DISEASE WHAT CAN WE SAY? Fetal VM transplants can work as well as best dopamine therapies; This therapeutic effect can last for >10 years; Currently very variable clinical response; Grafts can acquire a pathology but this is not a critical factor in the short term; This is not a CURE but may have a major impact on changing the natural history of treated PD HUNTINGTON S DISEASE WHAT CAN WE SAY? Fetal striatal transplants can work in the short term; Fetal striatal grafts may ultimately be lost because of pathology of HD affecting the transplant; This will never be a CURE and is unlikely to have a major impact on changing the natural history of HD given the widespread pathology and problem in HD
THE TEAM involved over the years includes....main players in work mentioned today.. Tom Foltynie Tim Harrower Caroline Williams Gray Jonathan Evans Sarah Mason Aileen Ho Natalie Valle Guzman Main Collaborations : Trevor Robbins; Maria Grazia Spillantini; Adrian Owen; Carol Brayne; James Rowe; Stephen Sawcer; Alastair Compston; John Sinclair ; Harvey McMahon; Anna Philpott; Barbara Sahakian; Jenny Morton; David Rubinzstein (Cambridge); David Burn, Patrick Chinnery, David Brooks, Paola Piccini and UK- NEST network; Malin Parmar, Anders Bjorklund, Ernest Arenas, Elena Cattaneo (EU) Francesca Cicchetti (Canada) Our work has been supported by: MRC; PDS; Cure PD; Patrick Bertoud Trust; Rosetrees Trust; Raymond and Beverley Sackler Trust; NIHR-BRC/BRU ; Wellcome Trust; CHDI; Evelyn Trust and SCI.