Open-label Investigation of the Safety and Clinical Effects of NTCELL in Patients With Parkinson's Disease

• the safety of xenotransplantation of NTCELL [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
  measured by the incidence of adverse events, clinical laboratory tests (including xenogeneic viral analysis), physical examination, review by infectious disease physician
  
  

• Brain metabolism as demonstrated on PET with [18F]-fluorodopa measured at 26 weeks post-implant 1 compared with baseline [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
  
• Brain metabolism as demonstrated on PET with [11C]-tetrabenazine measured at 26 weeks post-implant 1 compared with baseline [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
  
• Scores measured by the Unified Parkinson's Disease Rating Scale (UPDRS Parts I, II, III, IV - Parts II and III will be performed in the 'off' and 'on' state) over 26 weeks post-implant 1 compared with the baseline scores [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
  
• Modified Hoehn and Yahr stages over 26 weeks post-implant 1 compared with the baseline stages [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
  
• Scores measured by the Unified Dyskinesia Rating Scale (UDysRS Parts I, II, III, IV - Parts III and IV will be performed in the 'off' and 'on' state) over 26 weeks post-implant 1 compared with the baseline scores [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
  
• Times for hand-arm movement between 2 points (tapping test) in accordance with the CAPSIT-PD protocol (Defer et al. 1999) over 26 weeks post-implant 1 compared with the baseline times [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
  
• Scores measured by the modified walking test in accordance with the CAPSIT-PD protocol (Defer et al. 1999) (walking 4.5m back and forth instead of 7m back and forth) over 26 weeks post-implant 1 compared with the baseline scores [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
  
• Scores measured by the Parkinson's Disease Questionnaire (PDQ-39) over 26 weeks post-implant 1 compared with the baseline scores [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
  
• Scores measured by neuropsychological tests at 26 weeks post-implant 1 compared with the baseline scores [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]

  TESTS USED

  • National Adult Reading Test
  • Speed and Capacity of Language Processing Test
  • Boston Naming Test
  • Trail Making Test A
  • Trail Making Test B
  • WMS IV Logical Memory I
  • WMS IV Logical Memory II
  • RAVLT List Learning
  • RAVLT Short Delay Recall
  • RAVLT Long Delay Recall
  • Rey Complex Figure Copy
  • Rey Complex Figure Delayed Recall
  • WAIS IV Digit Span
  • WAIS IV Matrix Reasoning
  • WAIS IV Symbol Search
  • WAIS IV Coding
  • DKEFS Word Fluency
  • DKEFS Category Fluency
  • DKEFS Category Switching
  • DKEFS Colour Naming
  • DKEFS Word Reading
  • DKEFS Inhibition
  • DKEFS Inhibition/switching
  • Mini Mental State Examination
  • Montreal Cognitive Assessment
  • HADS Anxiety
  • HADS Depression
  
  
• Psychiatric assessment at 26 weeks post-implant 1 compared with the baseline psychiatric assessment [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
  

• Following the decision point at Week 26 post-implant 1 for each of the patients, a protocol amendment will be written to describe the secondary endpoints to be tested over the remainder of the study. [ Time Frame: 26 weeks-52weeks ] [ Designated as safety issue: No ]
  

Parkinson's disease is characterised by widespread neural degeneration, particularly in the substantia nigra and its projections to the basal ganglia. Current therapy for Parkinson's disease is purely symptomatic. There is a pressing need for a treatment that reverses or slows the degeneration of the nigrostriatal pathway.

Numerous transplant-based therapies have attempted to support, repair or replace the degenerating nigrostriatal neurons. These have included the transplantation of foetal and other neuronal stem cells, gene transfers, and the implantation of devices releasing neural growth factors. All these have been shown to have some effectiveness in animal models, but have been generally disappointing in human studies.

Intracranial choroid plexus cell transplantation has the potential to deliver biological neural agents for the treatment of Parkinson's disease which cannot be achieved by conventional treatment. The overall aim of delivering neural proteins and compounds over many months to the basal ganglia of the brain is to enhance neural repair currently not possible with antiparkinsonian medication or deep brain stimulation (DBS).

As animal-derived tissues have to be protected from immune rejection when transplanted into humans, transplants are usually accompanied by immunosuppressive therapy. However, porcine choroid plexus cells are preferably implanted without the use of immunosuppressive drugs which cause significant morbidity. To protect them from immune rejection, the cells can be encapsulated in alginate microcapsules which permit the inward passage of nutrients and the outward passage of biologic neural proteins and compounds normally secreted by choroid plexus cells. Alginate-encapsulated porcine choroid plexus cells implanted into the brain without immunosuppressive drugs have survived rejection for many months in animal studies.

NTCELL comprises neonatal porcine choroid plexus cells encapsulated in alginate microcapsules. NTCELL has been safely implanted in rats, and non-human primates. Following NTCELL implants, animals with chemically-induced Parkinson's-like lesions showed improvement of functional neurological motor abnormalities that was associated with histologic changes consistent with amelioration of the lesion.

The initial dose for intracranial implantation of the current NTCELL preparation for the treatment of Parkinson's disease in humans is based on the effective dose in a non-human primate (rhesus monkey) model.

Parkinson's disease patients will be followed up for 26 weeks after receiving an implantation of NTCELL administered into the putamen of the corpus stratium on the side contralateral to the greatest clinical deficit.

Based upon the data obtained during the 26-week follow-up period a decision will be made as to whether the patient will receive:

• an implantation of a second dose of NTCELL
• unilateral DBS
• bilateral DBS
• no further intervention

The data will be reviewed by the investigators and the Data Safety Monitoring Board (DSMB), the data will consist of clinical outcomes and clinimetric data, an MRI scan, PET scanning, and adverse events.

Irrespective of the decision made, all patients will be followed up for a further 26 weeks.