Xendo was exhibiting at the yearly conference of the European Society
THEN AND NOW
In the early days, gene therapy was mainly investigated in academic research centers. Currently, the number of marketed ATMPs (including gene therapies) is still limited, but as there are over 900 ongoing ATMP trials you can expect that gene and cell therapies are well on their way to become an important treatment modality with a high potential to deliver new and improved treatments to patients. Currently, most development is still seen in indications where there is an unmet medical need but its expected that ’the focus on common diseases will also increase.
Since the inception of the European Society
Besides academic institutions, biotech startups are now also contributing significantly to gene therapy development. The approval of Glybera (uniQure) in 2012 was a major milestone for the entire field and may have initiated major biopharmaceutical companies to increase their involvement in Gene Therapy. The approval of Strimvelis (GSK) in 2016 was an example of a collaboration between start-up and big pharma and surely there are more to come as we know some multinationals are partnering with pioneers in the field.
At the conference, impressive progression was reported throughout the major fields within Gene Therapy:
- Ocular and central nervous systems Gene Therapy;
- Cancer Gene Therapy;
- Muscle and pulmonary Gene Therapy;
- Metabolic and lysosomal storage diseases;
- Blood Disorders.
In these fields, scientists presented their progress and companies their pipelines, both addressing the technical and scientific advances in gene therapy. Significant effort is being put into research and early development to overcome the many challenges that still lie ahead.
To be able to apply different treatments, new strategies are under development. Though gene replacement is still prominent in the field, technical advances are made to allow for a switch towards gene repair; with CRISPR/Cas9 as a well-known example. Nevertheless, it will remain challenging to assure the absence of off-target effects using this technology. In addition, RNA inhibition strategies add another
For some the sky may be the limit, still, there are serious challenges that need to be resolved before any major breakthrough of Gene Therapy in medicinal practice can be achieved. In general, these challenges show a high similarity between different fields and vectors.
Firstly, one should be able to provide a sufficient therapeutic dose to the target tissue and cells. This may be solved by increasing the manufacturing capabilities, allowing the manufacture of highly concentrated vector doses. However, when doses become too high this may also impact the safety profile of the vector and its use. In general, improving manufacturing platforms may not be the easy solution for this challenge. A different challenge is to improve delivery of a vector to the appropriate tissues and cells. A great deal of research is currently going on to improve vector platforms but also work on new vector types was presented. However, if you’re able to efficiently target the right tissues and cells at an appropriate dose, the transgenes would need to be expressed at a suitable expression level, which means not too low but definitely not too high.
Another technical challenge is how to achieve a long-term effect which is especially relevant in areas where the mechanism of action relies on gene replacement or repair strategies. As is the case when a mutated gene is the underlying cause of a disease and needs to be replaced by a functional gene, which would (of course) need to be present throughout a patients entire life. Though only a marginal subfield within the gene therapy community, long-term effects of epigenetic modifications could definitely put a new perspective on things and will surely raise the regulators’ attention given the potential impact of epigenetic inheritance.
Prevention or intervention
The question whether you need to intervene in the development of a disease was argued both ways. In some cases, disease progression may be too far along in order to be able to effectively cure patients with gene therapy and early screening of patients may become more relevant in order to intervene in early stages of disease development. An issue here might be to demonstrate the efficacy of a treatment because the onset of disease symptoms in a non-treated patient may also take a significant time. Following this strategy you would need extensive follow-up, prolonging development and approval timelines.
The transition from a relative small lab-table to the larger industrial environment is one of the most commonly underestimated pitfalls. During the transition phase, a product and its manufacturing processes should be defined and controlled after which internal and external requirements are integrated and guide further development. Ideally, these changes and lot-to-lot variations of a product shouldn’t hamper pre-clinical and clinical studies. Many iterations and a creative problem-solving attitude are therefore required to build in sufficient robustness. Since quality cannot be tested into the product but only verified, the quality should be built into the process from the start.
Given the numerous technical challenges, it’s paramount to integrate a solid regulatory strategy into your technical and clinical development strategies. If gene therapy development is conducted by SMEs and academics, it is often seen that these parties struggle with the regulatory path also because of lacking resources and an undervalued importance of implementing regulatory strategies in product development.
At the conference, a recurring topic during our conversations was related to the application and need of a product development mindset, which differs significantly from the academic mindset that is still dominating. Product development requires a multidisciplinary approach to achieve the required synergy between research, product and process development, regulatory, quality, analytics, non-clinical and clinical experts. A rule of thumb is that successful product development would need a backward strategy. In other words, start with the end in mind, define your stage gates and milestones and develop a strategy that bridges science with development and manufacturing and
blog by: Harm Hermsen and Christian Maasch