Genetics of retinal degenerations. Clinical prerequisites to go from bench
to bedside
Birgit Lorenz (D-Regensburg)
Dept.of Paediatric Ophthalmology, Strabismology and Ophthalmogenetics,
Klinikum, University of Regensburg, Regensburg, Germany
www.paedeye.de
To date,
about 130 genes have been localised and 60 genes cloned known to be associated
with retinal degenerations (http://www.retina-international.org/sci-news/,
http://www.sph.uth.tmc.edu/Retnet/).
Depending on the genes involved, 20% to close to 100% of hereditary retinal
diseases such as various forms of retinitis pigmentosa, ABCA4 associated
Stargardt disease, X-linked retinoschisis, Norrie disease and stationary
cone dystrophies can be diagnosed on a molecular genetic level to date.
Disclosing the underlying pathophysiology allows to test various therapeutic
approaches in an increasing number of naturally occurring animal models
as well as in genetically engineered animals. These include gene replacement
therapy in recessive diseases, elimination of the mutant gene product
in dominant diseases, introduction of growth factors and dietary supplementation.
Depending on the treatment modality and the disease stage, therapy can
be expected to cause reversal of the dysfunction i.e. complete cure, arrest
of the disease process, or only slowing of the disease progress. Different
from the animal models where high numbers of genetically identical animals
can be tested, human clinical trials will have to take into account inter-
and intrafamilial variability even in the presence of an identical mutation
of the disease causing gene. Furthermore, different immunological reactions
may occur. Also, many genes show enormous genetic heterogeneity e.g. more
than 100 different rhodopsin mutations have been reported to date. Therefore,
longitudinal studies are needed prior to any clinical trial in addition
to already now in some instances available cross-sectional studies,. High
resolution morphological and functional methods have to be employed to
precisely describe the phenotype both in space and over time. To compare
data from different centres standardisation of the various methods would
be highly desirable. To minimise data error, the reliability of the various
tests has to be quantified. Legal issues must be addressed. Standardised
databases of the genetic and clinical data must be established to allow
time- and cost-effective recruitment of patients eligible for future trials.
Examples of efforts in this direction will be demonstrated.