Beyond 2020: Looking into the Crystal Ball for Gene Therapy

Gene therapies have come a very long way since the first clinical trials back in the early 2000s. Viral vectors and adeno-associated viruses (AAVs) have been studied for over 50 years, and their biology is far better understood than in the early days of gene therapy. As a result, gene therapy products with enhanced safety profiles have been approved, and initial long-term efficacy data has been collected. These first successes are driving more development and significant investment in the field. In fact, over 1,000 clinical trials are currently ongoing in the gene therapy space, which has become one of the most heavily funded biotech sectors. The urgency, uniqueness, and uncertainty surrounding gene therapy manufacturing creates many challenges. Let us take a look into the crystal ball of gene therapy to address unanswered questions and plan for uncertainity beyond 2020.

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Concerns and Limitations Remain

Questions about safety, limited manufacturing capacity, and cost are three significant issues facing gene therapy developers. One of the recent concerns is the occurrence of adverse events attributable to the high doses administered to patients. This has raised questions regarding whether viral vectors are safe enough to remain the delivery vehicle of choice for delivering the genetic payload, particularly at high doses. The safety profiles have improved tremendously, although continued long-term efficacy data should be collected.


Gene therapies have primarily targeted rare diseases, and, despite safety fears, the demand for approved products and clinical candidates combined is higher than the capacity available to manufacture them. Production of viral vectors requires specialized facilities and expertise, and not all companies and contract manufacturing organizations (CMOs) have these advanced capabilities. Costs per dose in the millions of dollars brings up questions concerning sustainability and access; even though these are potentially one-time, curative treatments, and innovations that can reduce costs and ultimately prices (whether those involve process optimization or operational innovations) are needed to practically commercialize these therapies.

Finally, the ethical controversy around manipulating the genetic code cannot be disregarded. Patients receiving these gene therapies typically have no other treatment options, which is a key driver for the development of these novel modalities, minimizing barriers to adoption, but the ethics of this approach remains an area of concern for some, particularly as the industry looks to target more common diseases using these modalities in the future. 

Potential of Non-viral Delivery Systems and CRISPR

While non-viral delivery of genetic material eliminates the safety issues associated with the use of viral vectors via physical methods, such as electroporation, sonoporation, or needles or chemical carriers, such as lipids, polymers, or peptides, there are reasons why they have not yet become mainstream even though R&D spending has increased significantly. Delivery efficiency is by far the biggest hurdle for almost all non-viral vector-based therapies with a need to increase the transfection efficiency to achieve comparable in vivo and in vitro results .

Interest in the application of CRISPR-based techniques for gene therapy development is also very high. To date, CRISPR and other gene editing tools have been used mainly for research purposes, but they have potential for profound therapeutic impact. Just like conventional gene therapies, the safety and long-term efficacy of CRISPR-based treatments must be extensively evaluated, and their ethical use must be considered as well. Government regulations around the applicability of gene editing technologies can be very strict, and there are manufacturing challenges as well, particularly with respect to practical implementation at scale.

Multi-Dosing Possibilities

Gene therapies have conventionally been viewed as one-shot solutions. The possibility of multiple dosing cannot be overlooked, due to the relative infancy of the field. For certain treatments, decline in the long-term production of the protein of interest has been observed. The U.S. FDA recently rejected an application for a gene therapy program owing to lack of long-term data. In such scenarios, the redosing strategy may be appropriate and necessary. This will increase demand projections, creating more complexity for manufacturing solutions.

Rush to Market

There is a real sense of urgency to commercialize gene therapies. Although there is a consensus on the need to develop platform/templated manufacturing processes, programs are often so rushed — in many cases leveraging accelerated approval designations and strategies — typically resulting in developers opting for individual solutions. The nature of viral vectors and lentiviruses also engenders customized approaches; for instance, depending on the target indication, AAV loads can differ as much as 10,000-fold.

That rush to market has also resulted in the acceptance of less efficient processes, particularly the use of adherent cell culture in plasticware. The industry is gradually moving toward suspension cell culture in bioreactors, which is much more scalable, but transfection using plasmid DNA continues to be problematic during scale-up. The use of producer cell lines would eliminate some of these challenges, but much work still remains to be done in this area.

Rapid commercialization has also led to the use of equipment and processes designed for monoclonal antibody (mAb) production. Viral vector processes involve much smaller volumes — in some cases, hundreds of milliliters compared with many liters for conventional biologics. Current expression systems like HEK293 often produce a very high percentage (over 90%) of empty capsids. Empty capsids are currently removed during downstream purification, but, ideally, improved upstream transfection ratios would remove this particular downstream bottleneck.

Overall, there is a need to move from fit-for-purpose tools to purpose-built tools for viral vector manufacturing and, as importantly, analytics, including high-throughput screening and process analytical technologies (PAT). Fortunately, vendors such as MilliporeSigma have been working with gene therapies for years, both through internal R&D efforts and in partnership with customers, to develop new, purpose-built products. Leveraging this expertise is definitely going to be crucial in addressing the challenges presented by the urgency and uniqueness of gene therapies.

An Evolving Regulatory Environment

Uncertainty regarding the regulatory environment presents another challenge to gene therapy developers. Regulatory requirements are evolving as the field matures and more knowledge about the science of gene therapies and experience with gene therapy manufacturing is garnered. Key questions today include (to name a few): Do plasmids need to be fully GMP compliant? What should be the percentage of full capsids in AAV drug product? What is the strategy for viral clearance?

Plasmids are (expensive) raw materials used in the upstream manufacture of viral vectors. Regulatory agencies, such as the FDA and EMA, require that plasmids are manufactured under GMP conditions. Plasmid suppliers provide a list of critical quality attributes (CQAs) related to purity and homogeneity.

There is no clear threshold for the ideal percentage of full capsids in AAV drug product. The goal is obviously to reduce the empty impurities to the best extent, resulting in nearly all full capsids. The results from clinical trials could determine what the percent purity and dosing should be for a given gene therapy product although there is a constant push to maximize the full-to-empty capsid ratio.

Inadequate clearance of adventitious viruses from the manufacturing process is a clear risk that requires a mitigation strategy. In the rush to get initial gene therapy approvals, virus filtration techniques and process log reduction values (LRVs) used for mAbs are generally considered acceptable. With more approvals and the better process understanding and additional data they have brought, virus filtration is likely a “must have” in Section A2 of regulatory filings, such as IND/BLA. To address this specific situation, virus-retentive filters have been developed by vendors such as MilliporeSigma that enable selective removal of adventitious viruses with the desired log of clearance. 

Need for Talent 

Another ongoing challenge for gene therapy developers is the limited availability of human talent with the experience and expertise necessary in viral vector development and manufacturing. Demand for skilled personnel in the biopharmaceutical industry as a whole has been growing for some time.

The practical solution is to provide on-the-job training to employees. It is the best way for beginners to learn; hands-on experience trumps all other modes of training. As the gene therapy field evolves, relevant courses will also likely become available within academic curricula. Industry groups currently offer basic-level educational experiences as part of conferences and workshops.

In addition, vendors like MilliporeSigma that have extensive expertise are sharing their knowledge and resources with customers. We serve as technical consultants to our customers, providing value by leveraging our experience in viral vector bioprocessing. We have literature and resources dedicated to gene therapy that provide additional tools for workforce development. We are playing a role in advancing gene therapy by creating coursework specific to gene therapy manufacturing. 

Reimbursement Issues

Manufacturing developments will lead to improvements in yield and quality, and thus increased productivity. Improvements in downstream processing methods could eliminate the need for expensive raw materials, such as plasmids and affinity resins. Purpose-built tools will facilitate optimization of both upstream and downstream unit operations. All of these advances will ultimately be translated into lower costs for gene therapies, making them more accessible and sustainable.

In the meantime, the issue of reimbursement remains challenging for treatments with price tags in the millions of dollars. Repayment strategies are already being developed by insurance providers. An installment approach, with payments made over a period of time, appears to be most common. Some of these financial milestones are performance-based, with payments made over time only if the efficacy of the treatment is confirmed.

As greater numbers of gene therapies are approved, we can expect reimbursement strategies to evolve accordingly. The ultimate goal of all this significant investment of time and resources is to provide lifesaving therapies to patients in dire need of medical treatment.

The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada.

Ratish Krishnan

Ratish Krishnan is an Associate Director for Cell & Gene Therapy BioProcessing for the Americas at MilliporeSigma. He is a process development scientist by background and has a decade of experience in vaccine, monoclonal antibodies, and viral vector modalities from preclinical to late-stage process characterization, validation, and commercialization activities, such as BLA authoring. He is passionate about providing solutions to bring treatments to market. He has presented scientific lectures at conferences and webinars and has made key contributions in peer-reviewed journals, articles, and white papers.

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