Transplantation of Schwann cell line clones secreting GDNF or BDNF into the retinas of dystrophic Royal College of Surgeons rats.
OBJECTIVE
To assess the capacity of a retrovirus-engineered Schwann cell line (SCTM41), transfected with either a glial cell line-derived neurotrophic factor (GDNF) construct or a brain-derived neurotrophic factor (BDNF) construct, to sustain visual function in the dystrophic Royal College of Surgeons (RCS) rat.


METHODS
Cell suspensions were injected into the subretinal space of the right eye of 3-week-old dystrophic RCS rats through a transscleral approach. The left eye remained as an unoperated control. Sham-surgery animals received injections of carrier medium plus DNase to the right eye. All animals were placed on oral cyclosporine. At 8, 12, 16, and 20 weeks of age, animals were placed in a head-tracking apparatus and screened for their ability to track square-wave gratings at various spatial frequencies (0.125, 0.25, and 0.5 cyc/deg). At the end of the experiment, the animals were perfused and processed for histologic assessment of photoreceptor survival.


RESULTS
Animals with SCTM41-GDNF-secreting cells, on average, head tracked longer than animals with SCTM41-BDNF-secreting cells, and both performed better than those injected with the parent SCTM41 line. All tracked longer than sham-surgery or nonsurgical dystrophic eyes. Each cell type demonstrated preservation of photoreceptors up to at least 4 months of age, over and above the sham-surgery control.


CONCLUSIONS
Engineered Schwann cells sustain retinal structure and function in the dystrophic RCS rat. Cells overexpressing GDNF or BDNF had a greater effect on photoreceptor survival than the parent line or sham surgery. This study demonstrates that ex vivo gene therapy and subsequent cell transplantation can be effective in preserving photoreceptors from the cell death that normally accompanies retinal degeneration.
Lawrence
Jean M
JM
Department of Pathology, Institute of Ophthalmology, London, United Kingdom. jean.lawrence@ucl.ac.uk
Keegan
David J
DJ
Muir
Elizabeth M
EM
Coffey
Peter J
PJ
Rogers
John H
JH
Wilby
Martin J
MJ
Fawcett
James W
JW
Lund
Ray D
RD
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D017690:Cell Transplantation; D002999:Clone Cells; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D019416:Head Movements / Q000502:physiology; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology; D051381:Rats; D011922:Rats, Mutant Strains; D012162:Retinal Degeneration / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D012190:Retroviridae / Q000235:genetics; D012583:Schwann Cells / Q000378:metabolism* / Q000637:transplantation*; D014785:Vision, Ocular / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors