A major advance in gene therapy for Retinitis Pigmentosa

A paper published in Nature Communications sheds light on why, until now, it has not been possible to effectively restore vision in rd1 mice – the world’s major model for retinitis pigmentosa (RP). This research also demonstrates how a particular type of mutation in this mice was the cause of failure of previous gene therapy attempts.

The rd1 mouse is a model of retinitis pigmentosa caused by defects in the PDE6B gene. The model was first described back in 1924 and is the oldest and most widely used model of retinal degeneration in the world. When light enters the eye and hits the rod cells (a type of photoreceptor – the light sensing cells of the eye), PDE6B is required to help turn this stimulus into electrical signals that can be understood by the brain and translated into an image. In rd1 mice, the defect in PDE6B leads to a rapid degeneration of the retina within the first four weeks of life, which is characterised by the death of rod cells and a complete loss of vision.

Numerous attempts have been made to preserve and restore function to rod cells in rd1 mice in the hope that an approach towards developing a treatment for RP patients could be identified. Past attempts to restore vision in these mice using gene therapy (where the normal gene is put back into the effected cells by means of a harmless virus known as a vector) has had limited success. In this model, retinal degeneration happens appears to happen so quickly that there aren’t enough, if any, healthy rod cells left to treat.

In other animal models (such as dogs) where progression of retinal degeneration caused by defects in PDE6B is somewhat slower, a restoration of vision has been possible and has led to the conclusion that in rd1 mice, the degeneration happens too quickly to allow for a window of opportunity to treat. This has confused the issue around whether a gene therapy approach to treating this form of RP in people could be effective.

Recent work from the group in UCL in other more severe forms of retinal degeneration, specifically that of Leber Congenital Amaurosis Type 4 (LCA4 [caused by a defect in the gene AIPL1]), however, has cast doubts on this explanation of previous findings in rd1 mice. Using an AIPL1 gene therapy, the scientists in UCL have been able to rescue vision loss in an LCA4 mouse model, which experiences a complete loss of vision in the first three weeks of life; faster than in rd1 mice.

Using the latest in gene therapy vector technology, the team has successfully created a more efficient and rapid acting PDE6B gene therapy then had previously been possible to address the short window of opportunity to treat. This approach was able to not only preserve the rod cells but restore their function as well. However, despite this, the team found that these mice were still not responding to a light stimulus suggesting that somewhere in the pathway that carries signals from the rod cells to the brain there must be a second and currently unreported defect blocking the signal.

An analysis of the genetic code of rd1 mice has indeed identified a defect in a gene called GPR179 that had not previously been found in the rd1 mouse strain. This defect affects the retinal bipolar cells – specialised cells that help transmit signals from the photoreceptors of the eye to the nerve cells that carry signals up to the brain. This defect is likely to be found in most of the rd1 mice around the world today and could have been present in this mouse strain for as long as 65 years. Through a process of selective breeding of different mouse models the team have successfully removed the GPR179 defect from rd1 mice and been able to demonstrate that PDE6B gene therapy does indeed lead to the preservation and restoration of rod cell function and that these mice can still sense and respond to light a year after treatment.

This study provides strong evidence to support the potential of gene therapy for RP caused by defects in the PDE6B gene and future studies will be required to assess further the potential. This study by no means suggests that previous work in rd1 mice is not valid but instead highlights the need, where appropriate, to reassess past findings and ensure that future work considers if the presence of a GPR179 defect may be a contributing factor to the results.

Source: UCL Eyetherapy Blog, Nature Communications