Advances in Gene Therapy: The End of the Era of Incurable Genetic Diseases?

Editing an individual’s DNA, to prevent or treat a genetic disease, at one time seemed an impossible task. Remarkably, we are now living in an age of medical development where decades of laboratory research have been successfully translated into gene therapies suitable for human use.

Gene therapy may, for example, involve the replacement of a faulty gene with a healthy copy, the inactivation of a faulty gene or the introduction of a missing gene into the body, all with the principle aim of providing curative treatments for diseases previously thought to be untreatable by restoring natural function.

In April 2019, it was reported that a group of US scientists at the St Jude Children’s Research hospital in Memphis, Tennessee, had used a de-activated version of the human immunodeficiency virus (HIV) to make a gene therapy that cured eight infants of severe combined immunodeficiency, or perhaps better known as ‘bubble boy’ disease due to the completely sterile conditions infants with this condition have to live in from birth. This rare disorder is caused by mutations in the IL2RG gene, a gene that encodes the common γ-chain which is shared by multiple cytokine receptors necessary for the development and function of lymphocytes. Consequently, infants born with this disorder have a severely compromised immune system, resulting in the most common of infections becoming potentially fatal.

The current gold standard for treatment in this field is the use of haematopoietic stem-cell transplants from a tissue-matched sibling donor. However, although this strategy is an effective one, this approach is available to less than 20 % of patients and the use of alternative donors (i.e. non tissue-matched) is associated with both graft-versus-host disease and incomplete immune reconstitution.

The scientists involved in this gene therapy trial were able to replace the mutated IL2RG gene with the corrected form, resulting in the production of T cells, B cells and natural-killer cells, all of which contribute to a properly functioning, healthy immune system and offering the chance of a normal life for these infants.

In a yet further remarkable case of the effective use of gene therapy, in February 2019 a woman at John Radcliffe Hospital in Oxford became the first person in the world to have undergone gene therapy in an attempt to halt the most common form of blindness in the Western world; age-related macular degeneration (AMD).

AMD is an eye condition which affects the central part of the retina, the macula, resulting in impaired central vision. In AMD, it is the cells associated with this part of the retina which become irreversibly damaged. The patient in this instance received an injection into the back of the eye containing a harmless virus, used as a carrier, to deliver a synthetic gene into the retinal cells. The delivered synthetic gene encodes a protein that prevents the immune system from attacking the retinal cells, in turn keeping the macula healthy and maintaining vision.

The eye is a particularly good target for gene therapy due to the reduced immune surveillance in this particular area. Accordingly, the viral DNA used for delivery of such therapies are able to ‘fly under the radar’ and remain active for significantly longer than in other areas of the body that are regularly patrolled by immune cells. This distinguishing feature has resulted in diseases of the eye being at the forefront of translational medicine in gene therapy. For example, Luxturna®, a drug developed by Spark Therapeutics, has gained both FDA and EMA approval as a gene therapy to correct mutations in the RPE65 gene, which causes blindness. Although Luxturna® has been shown to improve vision for at least 3 years from just a single injection into each eye, the eye-watering cost of $425,000 per eye may limit access to such cutting-edge treatments.

Whilst some gene therapies are at a relatively advanced stage of development, other pre-clinical technologies have taken centre stage, with the CRISPR-cas9 system leading the way. CRISPR technology harnesses components of the bacterial defence system against viruses, providing a beautifully simple method to allow for very precise genome editing of mammalian cells. This may lead to treatments for a wide range of diseases with limited side effects.

Research in this area is currently attracting large amounts of investment and holds great promise for patients with previously untreatable conditions. For example, a study conducted by researchers at Duke University in February 2019 showed that a single treatment of CRISPR in mice was able to correct the genetic defect associated with Duchenne muscular dystrophy, a life-limiting disease characterised by widespread muscle weakness, including that of the cardiac and respiratory systems. Likewise, CRISPR has been used in a mouse model of Huntington’s disease (a neurodegenerative disease) to show a reduction in the level of huntingtin protein aggregates and the associated toxicity within the brain. In April 2019, researchers at the Children’s Hospital of Philadelphia used mice to show that CRISPR technology could be applied in utero, resulting in the correction of a mutation which would normally result in a lethal lung disease and death shortly after birth.

Whilst current research is primarily focussed on ways in which genetic diseases may be treated, the application of CRISPR in the treatment of a variety of different diseases is a growing area of interest. For example, in July 2019, a group of scientists from the Lewis Katz School of Medicine at Temple University and the University of Nebraska Medical Center demonstrated that by using a newly developed antiretroviral therapy (ART) in combination with CRISPR, they could successfully eliminate HIV DNA from 30 % of infected mice. Additionally, CRISPR has great potential in the oncology field. In August 2019, a team of researchers at Boston Children’s Hospital were able to knock-out the Lipocalin 2 gene, a gene associated with triple-negative breast cancer, using CRISPR technology in a mouse model. As a result, tumour growth was slowed by 77 % and by using a nanoparticle delivery system directed to breast cancer cells, via the expression of ICAM-1, off-target side effects were avoided.

Yet a further example is the use of CRISPR technology in the fight against obesity. In August 2019, a group of researchers at Hanyang University in Seoul silenced a gene, FABP4, known to be involved in obesity and associated diseases, such as type 2 diabetes. The authors were able to show that following CRISPR intervention, mice which had been fed a high-fat diet lost 20 % of their body weight, as well as displaying a reduction in inflammatory responses and insulin resistance. Whilst it may be a number of years before CRISPR, or related technologies, are approved for use in humans, these studies demonstrate the potential of such genetic editing techniques and highlight the revolutionary possibilities of this kind of technology for curing previously intractable disease.

It is evident that gene therapy represents a new paradigm of ‘curative’ medicine, potentially suitable for a variety of diseases, ranging from cancer to neurological disorders to infectious disease. The rapid development, significant commercial interest and investment in such therapies, coupled with the significant costs and time required to get such therapies to market, mean having an effective IP strategy is essential for innovation in this field.

Patent rights have been hotly disputed in the genesis of this technology, as shown in the ongoing patent ownership dispute between the Broad Institute (Cambridge, MT) and the University of California, Berkeley (UCB), reported in detail previously.

Although the focus has been on the dispute between the Broad Institute and UCB, many other CRISPR related patent applications have been filed by various institutes and companies hoping to get a piece of the action. With over 7400 CRISPR-related patents being filed in 2018, with various breadth of claim scope, in addition to the patent applications directed to alternative gene editing technologies, such as zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALENs) and engineered meganucleases derived from mobile genetic elements of microbial origin, the result is a complex third party patent landscape that innovators must carefully navigate to avoid legal disputes.

As with the patenting of other more conventional therapies, when seeking to patent gene and cell therapies, careful attention must be taken in the patent application drafting stage to avoid the various, and divergent, subject matter exclusions in Europe, the US, and beyond. Depending on the details of the invention it may also be necessary to make biological deposits under the Budapest Treaty. Further, as with many exciting new technologies, gene therapies are often borne out of collaborative ventures, which have the potential to introduce great complexity when drafting and filing patent applications, which must be navigated carefully.

Gene therapy is rapidly gaining a foothold in the fast-growing biotechnology sector and very significant investment is required to bring such treatments to market. To support such investment a strong and commercially driven IP strategy is crucial. At GJE, our highly experienced patent attorneys in our biotechnology group will help you to develop an effective IP strategy to support you in successfully taking your discovery from the lab bench, through development, to market and beyond.

To discuss your biotechnology intellectual property strategy, get in touch with Ross Cummings via ross.cummings@gje.com.

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