Forgot your password?
Document Actions
Marius Ader
Development of cell-based therapies for the treatment of retinopathies
Previous and current research
For my PhD I first went for 1.5 years to the ETH Zürich (Switzerland) to work on brain-derived stem cells and established techniques for their isolation, cultivation, and differentiation. The focus of my research was the use of neural stem cells for the remyelination of unmyelinated axons, which might be of benefit for patients suffering from demyelinating diseases like multiple sclerosis or leukodystrophies. Starting with transplantation experiments into the retina of wild-type mice (Ader et al., 2000) and continuing with the injection of neural stem cells into brains of a mouse model for myelin disease (Ader et al., 2001; at the ZMNH, University of Hamburg, Germany) we demonstrated that neural stem cells have the capacity to extensively remyelinate host axons after transplantation in vivo. A detailed morphological and anatomical analysis after neural stem cell transplantation showed that the majority of donor cells had differentiated into mature oligodendrocytes that myelinated host axons in diverse regions of the brain. Interestingly, the myelination capacity of grafted neural stem cells was not restricted to young mice during development but continued in adult animals (Pressmar et al., 2001; Ader et al., 2004). In cooperation with the groups of Michael Wegner (University of Erlangen-Nürnberg, Germany) and Dieter Riethmacher (University of Hamburg, Germany) we also used neural stem cells to clarify whether the transcription factor Sox10, or the neuregulin receptor erbB3, play essential roles in oligodendrocyte maturation. Null mutants of either Sox10 or erbB3 die at birth, making it impossible to analyse oligodendrocyte maturation and myelination in these mutants. By transplanting neural stem cells isolated from embryonic brains of either of the mutants into our demyelination models, we could show that the maturation of oligodendrocytes depends on Sox10 but not erbB3 (Stolt et al., 2002; Schmucker & Ader et al., 2003).
My most recent research has been the application of stem cell therapies for the treatment of retinal disorders affecting the light-absorbing cells of the eye, the photoreceptors. Although we have shown that neural stem cells better integrate into dystrophic retinas when compared to wild-type retinas (Pressmar et al., 2001) their potential to replace degenerating photoreceptors is severely limited. Thus, we are now testing (at the Department of Genetics, Trinity College Dublin, Ireland) the potential of stem/progenitor cells isolated from the retina itself to differentiate into photoreceptors in vitro and after transplantation in vivo. Preliminary data from our lab shows that a sub-fraction of precursors isolated from the developing retina indeed have the potential to integrate into the adult retina of mice after transplantation and differentiate into mature photoreceptors.
In addition to cell-therapeutic strategies for the treatment of retinal dystrophies I am currently involved in developing a gene-therapeutic approach for such diseases. Using retinal explants and injections into mice we have shown that mutation–independent suppression by RNA interference technology and simultaneous expression of a replacement gene in photoreceptor cells might be a possible strategy for the development of therapies targeting dominant retinal diseases (Kiang et al., 2005; Palfi et al., 2006, O’Reilly et al., 2007).
Integration of cells isolated from the retina of postnatal EGFP-transgenic mice 2.5 weeks after subretinal transplantation into an adult mouse. EGFP-positive donor cells (green) integrated into the outer nuclear layer (ONL), differentiated into mature photoreceptors, and developed axonal enlargements that terminated in close proximity to dendrites of endogenous PKCα-positive bipolar cells (red). OS: outer segments; IS: inner segments; ONL: outer nuclear layer; OPL: outer plexiform layer; INL: inner nuclear layer; IPL: inner plexiform layer; RGC: retinal ganglion cell layer
Future prospects and goals
For the development of cell-based therapeutic treatments of retinopathies work will be focused on the following key elements:
1. extrinsic and/or intrinsic stimulation of expandable stem/progenitor cells for the generation of photoreceptors
2. characterization of best integrating cell-type by analysis of primary retinal cells isolated at different developmental stages
3. manipulation of host tissue to enhance cell integration
4. transplantation of cells into mouse models of retinopathies
5. analysis of integrated cells: morphology, expression patterns, synaptic connections, functionality
About
 |
|
Selected publications
Bartsch U, Oriyakhel W, Kenna PF, Linke S, Richard G, Petrowitz B, Humphries P, Farrar GF, Ader M.: Retinal cells integrate into the outer nuclear layer and differentiate into mature photoreceptors after subretinal transplantation into the adult mouse. Submitted
Palfi A, Ader M, Kiang AS, Millington-Ward S, Clark G, O’Reilly M, McMahon HP, Kenna PF, Humphries P, Farrar GJ (2006): RNAi-based suppression and replacement of rds/peripherin in retinal organotypic cuture. Hum Mut 27(3):260-8
Ader M, Schachner M, Bartsch U (2004): Integration and differentiation of neural stem cells after transplantation into the dysmyelinated central nervous system of adult mice. Eur J Neurosci 20(5):1205-10.
Pressmar S, Ader M, Richard G, Schachner M, and Bartsch U (2001): The fate of heterotopically grafted neural precursor cells in the normal and dystrophic adult mouse retina. Invest Ophthalmol Vis Sci 42, 3311-9.
Ader M, Meng J, Schachner M, and Bartsch U (2000): Formation of myelin after transplantation of neural precursor cells into the retina of young postnatal mice. Glia 30, 301-310.