Laura A. Kerepesi, PhD, associate director – Preclinical Manufacturing, Andelyn Biosciences shares insight on the key learnings from 2022 within the C> sector, as well as upcoming 2023 trends around gene therapy.
What are the key learnings from 2022?
In the last year, the gene therapy space has continued to mature, with the number of gene therapies in the development pipeline rising steadily to a total of 2,031 and two new drug approvals globally. Our expanding understanding of genetics and advances in molecular engineering techniques has enabled gene therapies to branch out from the treatment of rare diseases into the more common indications, including various cancers and heart diseases.
The success of many approved gene therapies has relied on viral vectors, including adeno-associated virus (AAV) and lentivirus (LV). As tools for the delivery of genetic material, viral vectors can introduce functional genes to patient cells to overcome underlying genetic defects. With advancements and improvements in viral vector design, development, and manufacturing, the efficacy and safety of gene therapies have and will continue to improve.
Innovative engineering of AAV serotypes has enabled more precise tissue specificity and helped to minimise possible side effects or off-target tissue expression. These novel serotypes often require additional downstream process optimisation to achieve higher recoveries, which incurs additional upfront development costs and time. But they also can reduce the dose required to attain the desired therapeutic effect, meaning one batch can serve more patients.
Vector designs removing unnecessary or risky plasmid sequences such as affinity or detection tags, ampicillin resistance genes, or unnecessary phage promoters, improve viral vector safety. Deliberate and thoughtful cassette design is required for product safety and has significantly reduced delays when moving to clinical manufacturing.
As well as efficacy and safety improvements, innovations in vector design have enhanced manufacturability. We are now seeing upstream processes capable of achieving higher packaging efficiencies while reducing off-target packaging such as the vector plasmid backbone. Vector production capacity has improved as a result. Developers also have improved vector design leading to better control of expression levels of viral vector genes in patients, with more fine-tuned transgene expression.
Considering the improvements that careful design can facilitate in the overall safety, efficacy, and manufacturability of viral vectors, a key lesson moving into 2023 will be to continue to embrace the innovations and technologies helping to advance gene therapies.
What trends and innovations does the pharma industry expect in 2023?
Offering the ability to deliver functional genes to patients to correct underlying genetic defects, gene therapies have long been considered a revolutionary treatment option for rare and orphan diseases. As genetic engineering techniques advance, we’re now entering an era where gene therapies in the development pipeline are not only targeting rare and ultra-rare diseases but more common indications, including cancers and heart disease.
Many of these gene therapies – both in vivo and ex vivo – rely on viral vectors such as adeno-associated virus (AAV) and lentivirus (LV) for the delivery of genetic material. In fact, the majority of the 22 gene therapies approved globally as of 2022 use viral vectors to introduce genes to patient cells.
As these revolutionary therapies branch into wider therapeutic areas and further demonstrate their utility, production demand can be expected to rise. To meet growing viral vector needs, developers and manufacturers must optimise production platforms - particularly upstream processes - to reduce the number of batches required while reducing the cost of goods for manufacturing.
Moving forward, viral vector developers and manufacturers must consider how current processes can be further refined. Incorporating new-generation reagents into transfection steps can help to improve productivity and the use of customised media with carefully selected additives can increase vector harvest yield. Processes also should be adapted to create cleaner initial feed streams and increase initial full to empty capsid ratios.
One key trend that can be expected in the coming year to support the increasing demand for viral vector production is the adoption of stable producer cell lines. Although there is often extensive up-front development time, the overall benefits of stable producer cell lines, in the long run, are advantageous. Offering reduced manufacturing variability, improved scaling, lower cost of goods, and removed the need for plasmid manufacturing, it is no surprise growing numbers of developers are considering this alternative to transient transfection methods.
It truly is an exciting time in the gene therapy area and with the adoption of increasingly innovative and advanced technologies and methodologies, we can anticipate continued demand for these progressive therapies for many years to come.