In the world, 39 million are legally blind. Approximately 2 million patients suffer from vision loss due to mutated inherited genes. A genetic mutation is basically damaged or changed DNA. Therefore, the expression of the DNA is altered: silencing, overexpression, altered function of a protein. This dysfunction is passed from generation to generation in inherited disorders. Today, no effective treatment exists for genetic diseases like Retinitis Pigmentosa, Stargardt disease or Leber Congenital Amaurosis (LCA). However, technological and scientific progress bring hope to find new ways to improve patients’ quality of life. Why are the eye and retinal diseases suitable for gene therapies? What are the challenges behind this genetic approach? How do companies fight to cure blindness?
The eye: an ideal target organ for gene therapy
Disorders leading to blindness are not the only type of inherited diseases. Why is gene therapy such a hot topic in the eye compared to other organs? The reason is that the eye presents an extremely opportune environment for examinations and for the therapy implementation.
First, the eye is an easily accessible organ. Examination and surgery are facilitated as interventions can be done from the outside, without invasive process. In fact, it is important to follow the disease progression and the treatment efficiency. For example, clinicians can observe the phenotype of the eye and picture the back of the eye with retinal imaging.
Second, the accessibility of the eye is also convenient for therapy delivery. Usually, a needle is inserted inside the eye. Although this is invasive, it is done without affecting other body parts.
Third, the eye is also an immune privileged site protected by the blood retinal barrier. This means it can tolerate the introduction of antigens without eliciting an inflammatory immune response.
Finally, the cells inside the eye that are targeted in the gene therapies are non-dividing. The treatment therefore lasts for life.
Genetic approach for curing blindness and retinal diseases: a scientific, clinical and business challenge
The basic idea to cure blindness is to provide a treatment acting at the genetic level to correct the alterations caused by mutations of the DNA in the eye. The development of a gene therapy to treat blindness is a challenge for the science, in the clinics and for the business.
Curing blindness: a scientific challenge
The scientific challenge is to find the appropriate strategy to correct the mutation of a specific gene. About 270 genes cause inherited retinal disorders, such as RPE65, CEP290 or RHO that are genes studied in clinical trials. Each of them is altered in a particular way. A convenient type are loss-of-function mutations where a gene is silenced. In this case, an appropriate therapy is to insert a normal copy of the gene to replace the mistaken one. This approach is the most studied option but has a major limitation. It can only be used for small genes, as the vehicle to insert the gene into the eye has limited space. The famous gene editing technology CRISPR-Cas9 might therefore be an alternative to correct the mutations instead. This revolutionary technology can also be used to regulate the gene expression which is necessary in other types of mutation.
Curing blindness: a clinical challenge
Once the appropriate strategy is developed, the therapy must be injected into the eye in a surgical intervention. A needle is inserted into the eye to deliver the treatment, which is associated with at least three main clinical challenges :
- Previous clinical trials failed as they faced the challenge of inflammation. The presence of a foreign molecule injected for the treatment can cause an immune reaction in the eye.
- An example of another challenge is that many inherited disorders appear at early stages of life which makes surgery difficult. The eyes of infants are physically smaller, and kids are too young to express their consent.
- Another hurdle for trials is that several diseases progress slowly, which implies long term trials.
Curing blindness: a business challenge
On the business side, the main challenge is that genes cannot be considered as an intellectual property. A gene mutated in a disease can therefore not be licenced. Companies licence technologies instead, which are the strategies and technique to correct a mutation. Therefore, a lot of competition is ongoing around different genes, as they can be explored by anyone.
The outlook for genetic and alternative treatments to cure blindness and retinal diseases
Genetic treatment is a coveted topic in inherited retinal disorders as the FDA recently approved the first gene therapy targeting the gene RPE65 in LCA by Spark Therapeutics. Companies are now looking for novel genes and disorders to target with innovative technologies and strategies.
While looking for ideal gene targets, alternative approaches are also part of the competition. Antisense therapy is promising against RHO genes in Retinitis Pigmentosa retinal disease or CEP290 in Leber Congenital Amaurosis (LCA) retinal diseases. This approach can be considered gene therapy, but the difference is that it acts at a different level inside the cell. So called Antisense Oligonucleotides influence the expression messenger RNA, the transcription product of DNA. The goal is however similar: to silence or modulate protein expression, the final product of a gene.
Finally, pharmacological approaches treating the disease with small molecules, cell therapies and implants are also contributing with promising treatments to cure blindness.
In the fight against blindness and retinal diseases, gene therapy is a promising growing biotechnology. The eye presents an opportune environment thanks to its physical properties. Inherited ocular disorders are caused by many genes. The first challenge consists in finding the right gene with an adapted therapeutic strategy. Once in clinical trials, the challenges are to avoid inflammation in the eye after therapy delivery, to handle very young patients and the slow disease progression. Although there are hurdles during development, gene therapy is a competed field in ocular medicine. In addition to gene therapy, pharmacological, cellular therapies and implants are also being explored by healthcare companies. The payoff will certainly be high for companies who will succeed. And the impact on the quality of life for blind people will hopefully be considerable.
If your company is active in the field of gene therapy, exploring such opportunities in ocular and other disorders could be a great opportunity. Alcimed is here to support you!
About the authors
Christina, Consultant, and Quentin, Project Manager in Alcimed’s Healthcare team in Switzerland
Benjamin, Great Explorer Digital Health in Alcimed’s Healthcare team in France
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