Previous and current research

Loss of sight as a result of dysfunction/degeneration of retinal cells is a major cause of disability. Eye diseases caused by degeneration of photoreceptors include e.g. retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, or cone-rod dystrophy. The immense genetic heterogeneity that causes photoreceptor degeneration (e.g. for retinitis pigmentosa alone mutations in more than 40 genes with up to 150 different mutations in a single gene are known) makes it difficult to develop therapeutical interventions for these diseases.

One possible strategy to treat loss of photoreceptors involves cell-based approaches, which might be of more general use since in principle many different pathogenic mutations might be treatable by the same source of cells. Recently it has been demonstrated that precursors committed to the photoreceptor fate rather than stem cells have the potential to integrate into host retinas and differentiate into mature photoreceptors following transplantation into adult mice. Primary cells directly isolated from the developing retina were used in these experiments. Although primary retinal cells provide an excellent tool to test cell-therapeutic approaches for retinopathies, the use of these cells as a cell source for therapies in humans might be difficult due to significant problems associated with availability and logistics beside ethical concerns. Thus, an expandable cell source, like stem cells, that can be pre-differentiated in vitro into photoreceptor precursors might be ideal for the development of cell-based therapies for retinopathies.

We will use stem cells isolated from the developing or adult retina and stimulate their differentiation into photoreceptors by extrinsic factors given to the culture medium or by transfection of photoreceptor-specific transcription factors. The detailed characterization of primary retinal cells that have the potential to correctly integrate and differentiate into mature photoreceptors will enable the selection of the optimal cell-type from expandable stem cell sources for transplantation. Transplantation experiments into mouse models that are characterized by photoreceptor degeneration will be performed to test the potential of cell replacement strategies to restore visual function.

5 Future projects and goals

1. extrinsic and/or intrinsic stimulation of expandable stem/progenitor cells for the generation of photoreceptors
2. characterisation 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

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

Group Members

List of group members

Selected Publications

Tanner G, Glaus E, Ader M, Barthelmes D, Fleischauer J, Pagani F, Berger W, Neidhardt J (2009) Therapeutic strategy to rescue mutation-induced exon skipping in rhodopsin by adaptation of U1 snRNA. Hum Mut, 30(2):255-63.

Bartsch U, Oriyakhel W, Kenna PF, Linke S, Richard G, Petrowitz B, Humphries P, Farrar GF, Ader M. (2008) Retinal cells integrate into the outer nuclear layer and differentiate into mature photoreceptors after subretinal transplantation into the adult mouse. Exp Eye Res, 86(4):691-700.

Tam LC, Kiang AS, Kennan A, Kenna PF, Chadderton N, Ader M, Palfi A, Aherne A, Campbell M, Reynolds A, McKee A, Humphries MM, Farrar J, Humphries P (2008) Therapeutic benefit derived from RNAi-mediated ablation of IMPDH1 transcripts in a murine model of autosomal dominant retinitis pigmentosa (RP10). Hum Mol Genet 17:2084-2100

O'Reilly M, Palfi A, Chadderton N, Millington-Ward S, Ader M, Cronin T, Tuohy T, Auricchio A, Hildinger M, Tivnan A, McNally N, Humphries MM, Kiang AS, Humphries P, Kenna PF, Farrar GJ. (2007) RNA interference-mediated suppression and replacement of human rhodopsin in vivo. Am J Hum Genet 81(1):127-35.

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.

Stolt CC, Rehberg S, Ader M, Lommes P, Riethmacher D, Schachner M, Bartsch U, and Wegner M (2002) Terminal differentiation of myelin-forming oligodendrocytes depends on the transcription factor Sox10. Genes Dev 16, 165-70

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, Schachner M, and Bartsch U (2001) Transplantation of neural precursor cells into the dysmyelinated CNS of mutant mice deficient in the myelin-associated glycoprotein and Fyn tyrosine kinase. Eur J Neurosci, 14, 561-6.

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.