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Development of xenogeneic donor tissue for neural grafting in neurodegenerative diseases

Objective

Overall goals are to explore the preconditions for the use of embryonic brain tissue derived from pigs for the repair of neurological deficits in patients with Parkinson's disease.

Specific objectives include:
To determine the optimal conditions for breeding, collection, preparation and implantation of non-modified and transgenic embryonic pig neurons.
To determine the expression of carbohydrate antigens on pig donor tissue, and analyse if pig neural tissue is lysed by human serum and complement factors.
To determine the critical factors that elicit inflammatory and immunology responses against discordant xenogeneic grafts in small animal models of neural grafting into the brain.
To determine the capacity of embryonic pig neurons to restore function to parkinsonian rats, pigs and non-human primates and to determine the need for additional immunosuppression.
To produce detailed protocols for the optimal recipient treatment and necessary safety monitoring for donor animals and patients to be included in a possible future clinical trial with xenogeneic pig derived donor tissue in patients with Parkinson's disease.

Neural tissue grafting for neurodegenerative disorders is a potential, novel therapeutic alternative for a number of neurological disorders. The most robust functional improvements have been observed with neuronal tissue grafts, which reinnervate the brain. Due to neurobiological constraints the donor tissue need to be immature, necessitating the use of donor tissue from human aborted embryos. The risks for transfer of infections and the ethical constraints preclude the wider application of this treatment modality in several European countries. The use of embryonic neural tissue derived from other species, xenografts, is one alternative, provided the donor tissue can be made to survive, and that safety concerns for trans-species pathogen transfer is mastered. One major obstacle is the prompt rejection of xenogeneic donor tissue. For pig tissue and organs grafted to humans this rejection is believed to be due to the existence of naturally occurring antibodies to pig cell surface carbohydrate antigens, and by direct human complement activation on the grafted cells, in addition to the cellular immune responses against pig antigens. This project will explore the possibility of grafting pig embryonic neural tissue to patients with donor tissue and recipient treatments aiming at overcoming the obstacles based on animal experiments.
The project will describe and determine the characteristics of normal and transgenically modified embryonic pig neuronal donor tissue, for their ability to activate human complement and their ability to fix antibodies directed against pig-specific antigens. Also, the many inflammatory and immunological constraints for acceptance of discordant xenografts in the brain, will be explored by performing a series of experiments in small animals (mice, rats and guinea pigs) and deduce from this the crucial factors for successful discordant neural tissue xenografts. The need for additional immunosuppressive drug treatment will be determined. The optimal treatment of the donor tissue in order to achieve maximal numbers of cells to survive the implantation will be defined, and the function of grafted neurons in animal models of parkinsonism in rats, pigs and in a limited number of non-human primates will be tested.
The final result of the project will be a series of protocols for the optimal design of a possible transgenic modification of the donor species, the conditions for breeding, the optimal procurement protocol and any pre-treatment of the donor tissue needed. Also, the optimal evaluation technique of patients, immunosuppressive treatment and the optimal safety monitoring for avoiding microbiological transfer will be produced.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Lund University
Address
17,Sflvegatan
223 62 Lund
Sweden

Participants (7)

KAROLINSKA INSTITUTE
Sweden
Address
Huddinge University Hospital
141 86 Huddinge
NEUROSEARCH AS
Denmark
Address
Pederstrupvej 93
Ballerup
THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
United Kingdom
Address
Robinson Way, Forvie Site
CB2 2PY Cambridge
UNIVERSITY OF AARHUS
Denmark
Address
44,Ny Munkegade
8000 C Aarhus C
UNIVERSITY OF SOUTHERN DENMARK - UNIVERSITY OF ODENSE
Denmark
Address
19,Winslíwparken 21
5000 Odense
University of Goteborg
Sweden
Address
16,Bruna Straaket
413 45 Gøteborg
Uppsala University
Sweden
Address
17,Akademiska Sjukhuset
751 85 Uppsala