Jeans for Genes

Dr. Julian Mitchell, University of Portsmouth

You can always change the make of your jeans, but can you change the nature of your genes? Impossible? Not now. Gene therapy provides ways to replace genes, so that inherited diseases can be cured. This provides hope to more people than you may think. Genetic disorders are commoner than is generally acknowledged. It is estimated that 65% of the population suffer from some form of genetic disorder, where 1 person in 50 are affected by a single gene disorder. With over 6000 genetic disordered described, finding a cure for any one can be difficult, but not impossible.

To effect a cure, a functioning gene has to be introduced and expressed in the patient, or be changed from its aberrant form, replacing the failing one. Scientists have developed techniques that do this over the last 20 years, leading to over 2600 gene therapy clinical trials that have been completed or are currently ongoing. These include immunological techniques that stimulate the immunity system against malfunctioning cells. Such approaches have also helped in the development of vaccines, such as the ones used against SARS-CoV-2. Genome sequencing has also been central to gene therapy development, providing the information needed to generate any gene synthetically.

So, which genetic diseases have been cured? Gene therapies have been primarily for single gene deficiencies like thalassemia, severe combined immunodeficiency (ADA-SCID), cystic fibrosis and Duchenne muscular dystrophy. Therapies targeting complaints controlled by a number of genes present a greater challenge. How can the defective genes be identified? This is possible using population-level genome sequencing information, where genetic differences between healthy individuals and sufferers can be detected. Identifying changes present only in suffers recognises the genes involved in the condition. Congenital blindness has been one group of inherited diseases where this approach has been successful.

Among the 350-plus hereditary eye diseases, focus has centred on the conditions Leber congenital amourosis (defective light gathering cells of the retina) and retinitis pigmentosa (progressive loss of photoreceptor cells). There are 27 genes implicated in causing Leber congenital amourosis (LCA), while there are an estimated 50 involved in causing retinitis pigmentosa. From population studies, one gene, RPE65 coding for the enzyme retinoid isomero-hydrolase, has been identified as one potential cause for both complaints. A gene therapy for RPE65-related diseases called Luxturna was granted approval by the U.S. Food & Drug Administration in 2017, where a working copy of the gene is injected in the retinal cells of the eye, delivered using an adenoviral vector (similar to the one used in the AstraZeneca vaccine). This therapy improved eyesight after one-year post-treatment, and is currently available on the NHS for LCA suffers.

Improving poor eyesight is wonderful but restoring sight to a blind person is miraculous. This is now possible using optogenetics, where ganglion in the eye can be stimulated to turn light signals into electric nerve pulses that can be registered in the brain. The therapy involves using a viral vector to deliver (1) a gene that codes for a protein (a microbial opsin) that absorbs light at a specific wavelength and (2) a gene that codes for a light sensor that allows the ganglion to fire a signal. This treatment has allowed a 58-year-old retinitis pigmentosa sufferer to see light using special goggles – somewhat like Geordi La Forge in Star Trek: the next Generation. Yes, science fiction has become science fact, and it is this that makes supporting Jeans for Genes so important.

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