Reducing barriers to mainstream gene therapy

By Jane Byrne contact

- Last updated on GMT

© GettyImages/chaluk
© GettyImages/chaluk

Related tags: Gene therapy, congestive heart failure, production costs, adeno-associated virus, Dna

AskBio, which develops adeno-associated virus (AAV) gene therapies for genetic disorders, has won an R&D grant valued at £2m (around US$2.7m) from Scottish Enterprise.

The company is to invest £3.4m (around US$4.5m) alongside the grant.

The funds will support research into the manufacturing challenges associated with scaling gene therapies for widespread patient access, to further develop technologies to improve the safety and efficacy of current therapies, and to enable the treatment of genetic diseases with more complicated disease pathways the industry is not yet able to address.

Along with the creation of 11 new jobs in Edinburgh, the developer said it will further enhance its Pro10 platform, an AAV manufacturing process that can be scaled and applied throughout the group.

The grant will also advance development of the tool kit of inducible, repressible, tunable and responsive expression cassettes to be adopted in the current clinical pipeline and new disease targets.

Gene therapy has the potential to treat a wide range of diseases including certain forms of muscular dystrophy, congestive heart failure and some diseases of the central nervous system but, at present, only two market-approved therapies are available. 

David Venables, president, AskBio Europe, commented: “The grant awarded by Scottish Enterprise supports AskBio in working towards developing even safer and more effective gene therapies through improved development and manufacturing techniques. Science and innovation keep progressing, and that makes this an exciting time to develop this type of therapeutic agent.”

AskBio’s technology is inside both currently approved AAV gene therapies, which include Luxturna, developed by Spark Therapeutics, for the treatment of patients with inherited retinal disease, and Zolgensma, developed by AveXis,  for the treatment of patients with spinal muscular atrophy (SMA).

AveXis licenses AskBio’s self-complementary DNA technology for Zolgensma.

While the promise of such therapies is being shown, significant barriers remain before gene therapies can become more broadly impactful, according to AskBio.

With global headquarters in Research Triangle Park, North Carolina, and European headquarters in Edinburgh, UK, AskBio has generated hundreds of proprietary third generation AAV capsids and promoters, several of which have entered clinical testing.

BioPharma-Reporter (BPR)​ spoke to Ken Macnamara, (KM​), PhD, chief operating officer, AskBio Europe, to get the AAV developer’s take on the factors preventing gene therapy going mainstream.

BPR: What criteria did AskBio have to fulfill to be awarded this grant?

KM:​ The research must be highly novel with significant risk from which a successful outcome will accelerate business growth within Scotland and globally.

BPR: What are the current manufacturing challenges associated with scaling gene therapies for widespread patient access? 

Ken Macnamara AskBio
Ken Macnamara, chief operating officer, AskBio Europe

KM:​ As we see growing evidence that gene therapy is a viable, transformational medicine, along with an acceleration in the number of AAV therapeutics moving towards regulatory approval, the ability to manufacture these therapies for diseases with large patient populations does not exist today and costs are extremely high.

Many companies can manufacture small batches of therapeutics for clinical applications, but as they approach commercialization, the challenges of production costs and timelines remain an issue. We recognized this more than a decade ago and focused on creating robust, scalable manufacturing capabilities.

Today, the challenges for manufacturing gene therapy are being met by simply adding large amounts of capacity, which is not the long-term answer. There is a significant amount of innovation taking place that will no doubt shape the future of manufacturing AAV gene therapeutics. This work continues today in our Edinburgh and US facilities to further improve the technology. 

BPR: What are some of the typical safety and efficacy issues linked to current therapies?

KM:​ Currently approved gene therapies have provided effective therapy by targeting tissues in the body with an administered gene that produces a new, effective protein. This new gene replaces the defective or missing gene causing the patient’s underlying disease.

Because the techniques are relatively new, some of the risks may be unpredictable; however, medical researchers, institutions, and regulatory agencies are working to ensure that gene therapy research is as safe as possible.

AAV is not known to cause human disease, and it cannot make more of itself without outside help, so it will not replicate in the body like normal viruses do. AAV is engineered to carry therapeutic genes by removing some of its genetic cargo and replacing it with human gene sequences. This results in an AAV vector, a therapeutic genetic medicine.

Risks associated with AAV gene therapy vector administration include unwanted immune system reactions. The body's immune system may see the newly introduced AAV vectors as intruders and attack them, which may cause inflammation and, in severe cases could be local and mild or throughout a greater area of the body and be more serious. AAV vectors can also target tissues other than the intended tissue. Thus, it's possible that AAV vectors may affect additional cells, not just the targeted cells containing mutated genes. These are called off-target effects. If this happens, healthy cells may be damaged.

BPR: Can you indicate the other significant barriers that remain before gene therapies can become more broadly impactful?

KM:​ Therapies need to express the gene in the right tissue, at the right level, for the right amount of time. There is a great deal of research happening throughout the gene therapy field to identify the best means of delivering and controlling activation of the genetic material. Furthermore, the response of the patient’s immune system also needs to be considered based on the therapy. Additional funding, like that from Scottish Enterprise, can help speed up the development process of promising therapies.

BPR: How does AskBio envisage exploring the treatment of genetic diseases with more complicated disease pathways that the industry is not yet able to address?

KM:​ One of the most exciting advances in modern medicine has been the discovery of how AAV vectors can be used as an effective delivery system for therapeutic genetic material into living tissue. AAV gene therapy has broad therapeutic implications for a vast array of diseases.

Some genetic diseases are caused by mutations in a single gene, while others are a result of mutations in multiple genes, for example, cancer. Additionally, environmental factors, such as smoking and diet, can play a role in diseases. The complexity of these disease characteristics creates variables in developing and testing potential treatments. Currently the gene and cell therapy options that exist today are limited to treating diseases caused by a single gene mutation.

AskBio’s Edinburgh team leads the gene therapy field in the design and development of synthetic gene expression cassettes. The technology is essential for controlling the expression of AAV therapeutics, thereby improving their safety and efficacy. This R&D project will enable AAV therapeutics to be turned on and off and dialed up or down depending on the amount of drug needed at any given time. This technology provides a desired safety switch and level of variable dosing that previously did not exist. Before this breakthrough, AAV therapeutics could only express at one constant level and could not be turned off, which limited the type of therapeutics for which AAV could be used and may hold the key to treating pathway diseases where multiple genes are affected.

BPR: On the job creation front, is the talent already hired or are you starting a recruitment drive?

KM:​ The grant allows us to make some positions permanent and bring in new talent.

Ken Macnamara joined AskBio in 2019 with a wealth of R&D, business operations, financial planning, intellectual property and quality/compliance experience gained from start-up to multinational firms. He most recently was COO at Synpromics.

Dr Macnamara began his career at the University of Edinburgh, where he earned a PhD in chemistry before helping to start Lab901 (Scottish SME). There, he was a product development manager responsible for developing the TapeStation and ScreenTape technologies from concept to market success. Lab901 was acquired by Agilent Technologies in 2011. Dr Macnamara then served as R&D director for the Microfluidics business at Agilent.

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