Gene Therapy
A wide range of faulty genes cause retinitis pigmentosa (RP) and other inherited retinal diseases (Finding and Treating the Cause and Genetics and Retinitis Pigmentosa and Other Inherited Retinal Diseases).
Several research teams around the world are investigating techniques to
correct these genetic faults (gene therapy). In the first instance,
animal models of inherited retinal disease (animals which have similar
faulty genes and retinal disease) are being used to develop these gene
therapies prior to testing these treatments in people. The first human
clinical trials commenced in 2007 in the UK (LCA Gene Therapy Trial). There are now further multiple on-going gene therapy clinical trials in Europe and the USA. (Gene Therapy Trials)
Different forms of RP can result from a person inheriting one or two faulty genes, depending on the type of RP (Inheritance Patterns of RP and Basic Rules of Genetics). In general, in the types of RP caused by two faulty genes (both the maternal and paternal copies of the gene are faulty) (Autosomal Recessive Inheritance and Basic Rules of Genetics), it is found that these two genes are often either non-functional or have significantly reduced function. Researchers are developing techniques to replace these faulty genes with fully functional genes by an injection into the retina of a harmless virus or "vector" to carry the specifically required gene into the retinal cells. It is hoped that this will lead to the restoration of normal function or improved function in the cells that receive the replacement gene. Potential Gene Therapy for X-linked RP is likely to be similar to that outlined herein for Autosomal Recessive RP in that gene replacement is also likely to be sufficient.
The situation in which RP is caused by one faulty gene is paradoxically more challenging to treat (Autosomal Dominant Inheritance). In general, in these types of RP, either the faulty gene inhibits the function of the remaining normal copy of the gene (a 'dominant-negative' effect) or the faulty copy of the gene fails to produce a functional protein and the remaining normal copy of the gene is insufficient to alone provide for the normal needs of the retinal cells ('haploinsufficiency'). Therefore, in order to design gene therapies for autosomal dominant disease, the mechanism(s) by which the faulty gene causes disease needs to be established – 'dominant-negative' or 'haploinsufficiency'. In forms of RP resulting from a dominant-negative mechanism, the faulty copy of the gene needs to be 'silenced' – that is to say the faulty copy needs to be 'switched off’' so that it can no longer harm the retinal cells or prevent the other normal gene from functioning adequately. Effective and reliable 'silencing' is technically very challenging - although great progress has been made in the last 5 years, resulting in gene therapy trials being anticipated in the near future. In situations where haploinsufficiency is the problem, therapy is more straightforward in that a replacement functional gene for the faulty gene needs to be inserted to restore normal function – in a similar fashion to that for autosomal recessive conditions.
Different forms of RP can result from a person inheriting one or two faulty genes, depending on the type of RP (Inheritance Patterns of RP and Basic Rules of Genetics). In general, in the types of RP caused by two faulty genes (both the maternal and paternal copies of the gene are faulty) (Autosomal Recessive Inheritance and Basic Rules of Genetics), it is found that these two genes are often either non-functional or have significantly reduced function. Researchers are developing techniques to replace these faulty genes with fully functional genes by an injection into the retina of a harmless virus or "vector" to carry the specifically required gene into the retinal cells. It is hoped that this will lead to the restoration of normal function or improved function in the cells that receive the replacement gene. Potential Gene Therapy for X-linked RP is likely to be similar to that outlined herein for Autosomal Recessive RP in that gene replacement is also likely to be sufficient.
The situation in which RP is caused by one faulty gene is paradoxically more challenging to treat (Autosomal Dominant Inheritance). In general, in these types of RP, either the faulty gene inhibits the function of the remaining normal copy of the gene (a 'dominant-negative' effect) or the faulty copy of the gene fails to produce a functional protein and the remaining normal copy of the gene is insufficient to alone provide for the normal needs of the retinal cells ('haploinsufficiency'). Therefore, in order to design gene therapies for autosomal dominant disease, the mechanism(s) by which the faulty gene causes disease needs to be established – 'dominant-negative' or 'haploinsufficiency'. In forms of RP resulting from a dominant-negative mechanism, the faulty copy of the gene needs to be 'silenced' – that is to say the faulty copy needs to be 'switched off’' so that it can no longer harm the retinal cells or prevent the other normal gene from functioning adequately. Effective and reliable 'silencing' is technically very challenging - although great progress has been made in the last 5 years, resulting in gene therapy trials being anticipated in the near future. In situations where haploinsufficiency is the problem, therapy is more straightforward in that a replacement functional gene for the faulty gene needs to be inserted to restore normal function – in a similar fashion to that for autosomal recessive conditions.
Gene therapy for optic nerve disease.AbstractPURPOSE:There has been recent interest in the potential use of gene therapy techniques to treat ocular disease. In this article, we consider the optic nerve diseases that are potentially most amenable to gene therapy.METHODS:We discuss the recent success of gene transfer experiments in animal models of glaucoma, optic neuritis, Leber's hereditary optic neuropathy (LHON), and optic nerve transection, and we assess the possibility of using similar techniques to treat human disease in the future.RESULTS:We have achieved highly efficient transfection of retinal ganglion cells in a rat model of glaucoma following a single intravitreal injection of adeno-associated virus (AAV). In our model, we have found that AAV-mediated gene therapy with brain-derived neurotrophic factor has a significant neuroprotective effect compared to saline or control virus injections. Guy and co-workers have successfully used AAV-mediated gene therapy to replace the defective mitochondrial enzyme subunit in cells derived from human patients with LHON. Gene therapy techniques have also shown promise in animal models of optic neuritis and optic nerve trauma.CONCLUSIONS:Human diseases with single-gene defects such as LHON may soon be treated successfully by gene therapy, assuming that vectors continue to improve and are well tolerated in the human eye. Other optic nerve diseases such as glaucoma that do not have a single-gene defect may also benefit from gene therapy to enhance RGC survival. In all cases, the risks of treatment will need to be balanced against the potential benefits. |
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