Patience is certainly not one of my strong qualities, but when I think of the suffering of patients with hereditary or age-related eye diseases who are eagerly awaiting a possible treatment, my own impatience pales in comparison. Therefore, I think it is wiser to exercise restraint and be pleased that our collaboration with Antje Grosche's lab at LMU Munich has yielded success after at least seven years of intense effort (from conception to publication). We have shown that gene therapy in the eye, aimed at modulating the activity of the complement system, is a viable way to counteract acute degeneration.
But let's take it slowly and step by step. PhD students Josef Biber (Grosche lab) and Yassin Jabri (Pauly lab) have produced recombinantly truncated forms of the complement regulator FH that have been shown to retain all critical functions of FH in vitro, compared to native FH. These constructs were cloned into AAVs that preferentially target only Müller cells in the retina and induce expression and secretion of the truncated FH variants specifically in activated Müller cells.
In mice with acute retinal damage due to ischemia, we have shown that administration of these AAV expressing truncated FH variants leads to several positive outcomes: (i) increased detection of FH in the retina, (ii) altered degradation of the central complement protein C3, (iii) influence on local gene expression of complement transcripts depending on the AAV used, (iv) better preservation of the inner nuclear and inner plexiform layers, and (v) decreased macrophage reactivity due to AAVs expressing the truncated FH variants.
This collaboration has been an incredible journey with fantastic partners. I am very grateful to everyone who has made this journey possible. New paths require time and patience, perhaps even when reading the manuscript, but it is undoubtedly worth it. Our work not only highlights the importance of patience and perseverance in the face of scientific challenges, but also shows the potential of gene therapy as a transformative approach to tackling eye diseases.
Find the full publication here.
Diana