The long-term objective is to provide a comprehensive pre-clinical background for neuroprotective therapies, using gene therapy delivery systems developed by European biotechnology companies, in patients with neurodegenerative diseases. Experimental studies have pointed to the trophic factors CNTF and GDNF as potential neuroprotective agents for striatal and nigral neurons, respectively. In parallel, gene therapy systems to deliver these proteins directly to the brain are developed in Europe. A systematic analysis of the parameters that must be specified for clinical application will be performed, in order to determine the safety conditions, the quantify of proteins released for therapeutic effects, their spread away from the site of production and the time-course of release, the final goal being to provide clinicians with therapeutic tools to be applied in patients with Huntington's or Parkinson's diseases.
Description of the work
The work will be assembled in seven workpackages ordered to take all preparatory steps to be taken before therapeutic protocols are experimented in non-human primates. Three gene therapy delivery systems for the ciliary neurotrophic factor (CNFTF) and the glial cell line-derived neurotrophic factor (GDNF), with neuroprotective capacity for striatal and nigral neurons respectively, will be experimented in parallel, based upon HSV-1, immortalized human cells or encapsulated genetically-modified cell lines.
WP1 will define conditions for safe delivery to the brain. In parallel, WP2 will establish imaging protocols to assess neuroprotective effects by in vivo quantitation of neurons and evaluation of function. WP3 and 4 will examine temporal and spatial characteristics of the delivery of CNTF and GDNF.
Experimental therapeutic procedures will then be defined and applied to non-human primate models of Huntington's (WP5) and Parkinson's disease (WP6). The final WP7 is set to analyse the data for each delivery system and conclude upon their advantages and limitations. These analyses will be translated into optimized clinical procedures that, subsequently, may be used for clinical trials in HD or PD patients.
Maximal tolerated doses, number of simultaneous and of repeated administrations into the rat brain will be determined for each of the delivery system (WP1). In vivo imaging will make use of magnetic resonance spectroscopy, positron emission tomography and SPECT (WP2). Biological parameters will be evaluated biochemically after administrations into tissue cultures or into the rat brain (WP3/4).
Therapeutic efficacy will be looked for after administration into the brain of non-human primates specifically treated by neurotoxins, the effects of which mimics the neurodegeneration observed in HD or PD patients (WP5/6).
The main outcomes will be clinically applicable procedures.
The first milestone (+12 months) will be the maximal tolerated dose for each system (MTD-N). WP3/4 will determine the optimal conditions for delivery of CNTF and GDNF. The safety (WP1), imaging (WP2) and biological results (WP3/4) will allow us to set the optimal experimental procedures (OEP-N) (+24 months). WP5/6 will appreciate the therapeutic efficiency of OEP-N in non-human primate and the final workpackage, WP7, the optimised clinical procedures (OCP-N) (+36 months), for clinical trials.
Funding SchemeCSC - Cost-sharing contracts
221 00 Lund