Gene Therapy for Inherited Retinal Degenerations: Extrapolation from Proof
of Principle in Animal Models to Treatment of Human Disease
Albert M. Maquire, Gene Bennet (USA-Philadelphia,
Pa)
F. M. Kirby Center
for Molecular Ophthalmology, Scheie Eye Institute, Department of Ophthalmology,
University of Pennsylvania,
51 N. 39th Street and Myrin Circle; Philadelphia PA 19104-2689
Recent
success in delivering vision to a canine model of a severe, early onset
blinding disease, Leber congenital Amaurosis (LCA) (Acland et al, 2001,
Nature Genetics 28:92) invites speculation that the human disease could
be treated similarly. There are many variables which may affect success,
however, and part of the challenge in planning a human clinical trial
relates to identification of these variables in preclinical testing. Such
variables include age of treatment, dose of therapeutic material, target
area of the retina, cellular specificity of the treatment, and previous
immunological history of the subject. Equally important in preclinical
studies, is evaluation of the potential toxicity of the treatment. The
toxic limits should be well delineated so that they can be avoided in
human studies. Furthermore, methods should be designed which could be
used to treat any complication which may develop. Finally, in anticipation
of evaluating success in humans, it will be necessary to develop methodology
with which to detect and quantify any potential therapeutic effects over
time by non-invasive testing. Examples of efforts in these directions
will be described. Additional retinal diseases which may be good targets
for gene therapy in future studies will be described. The challenges inherent
to developing treatments for these particular diseases will be discussed
with respect to the success in the canine model for LCA.