Bringing the Gene Therapy Conversation to You – Virtually

Meghan Hosely
June 11th, 2020

On June 3, members of the research community came together virtually for Advarra’s first Virtual Symposium: Gene Therapy Research in the Age of COVID-19. The discussion included updates on hot topics and emerging issues in gene therapy and in particular genetically modified COVID-19 vaccines. Advarra’s Director of Biosafety Services, Daniel Eisenman, was accompanied by Meagan Vaughn of Translate Bio, Andrew Stober of Encoded Therapeutics, and Kaitlin Morrison of UNC Lineberger Comprehensive Cancer Center. Each presenter explored the unique challenges gene therapy research poses for research sites, sponsors, CROs, and study participants. Below are some key takeaways from each panelist’s presentation during the Symposium.

Defining Gene Therapy Research

According to the National Institutes of Health (NIH), gene therapy is “an experimental technique that uses genes to treat or prevent disease.” The genetic material is primarily recombinant or synthetic nucleic acid molecules, and the Food & Drug Administration (FDA) has issued approvals for gene therapies since 2015. Since then, gene therapy has gained traction – as of June 3, there are 315 Phase III trials listed on clinicaltrials.gov. Gene therapy research has played an especially big role during the COVID-19 pandemic: currently, the most prominent vaccine candidates contain engineered genetic material.

Additionally, gene therapy research is also pivotal in oncology – roughly two-thirds of current gene therapy studies are in oncology. Studies include reprogrammed immune cells, cancer vaccines, and oncolytics (reprogramming viruses to kill cancer).

Genetically Engineered COVID-19 Vaccines

Messenger ribonucleic acid (mRNA) is also prevalent in gene therapy studies and has two different types of applications. While mRNA vaccines are used to combat infectious disease and oncology, mRNA therapies are used to combat protein deficiency as well as cancers. Therapies and vaccines are seen at work in infectious diseases such as COVID-19 and influenza, oncology studies in areas such as lung cancer or breast cancer, and protein replacement for indications such as cystic fibrosis.

Similar to many other therapeutics, there are benefits and challenges to mRNA vaccines and therapies. Advantages include a flexible and adaptable platform for participants; dosage adjustment is possible; the vaccines and therapies are easy to synthesize; and mRNA uses the body’s cellular machinery to produce protein. Challenges include the stability, delivery, translation efficiency, and immunogenicity of the therapies.

Among pharmaceutical companies developing COVID-19 vaccines, mRNA-based vaccines are a popular approach due to their rapid development capacity. These vaccines are made quickly and are relatively inexpensive to manufacture, which is especially critical during the current outbreak. Since it’s made quickly and fairly low-cost, the product can be made in high volume to meet public demand in a timely manner.

Manufacturing Challenges

Despite the recent meteoric rise of gene therapy research, there are still challenges when manufacturing the supply of gene therapies. About 80-90% of gene therapy manufacturing mirrors biotech manufacturing, and because of that, it’s easy to apply the same manufacturing strategies – but the reality is, it’s not a clear transfer.

While there are similarities between gene therapy and biotech manufacturing – including cell culture backbone, purification techniques, and drug product presentation – there are many critical differences. Gene therapy manufacturing output per batch is relatively low given the need for highly concentrated doses. The specialized manufacturing techniques are still fairly new, and the manufacturing approaches are still being optimized. Manufacturing capabilities need to be developed to match demand.

Additionally, there are differences in the supply of gene therapies. The timeline from production to supply is considered to be much shorter, which ultimately leaves little room for process development, optimization, and supplier qualification. The supplies are also usually shipped in low inventory, and distribution depots typically operate with higher volumes of inventory.

FDA and Local Regulatory Considerations

Once the investigational therapy makes it to the research site and participants, it’s important to focus on protocol development, informed consent form (ICF) development, and regulatory reviews. All of these considerations require extra time and attention to ensure a study proceeds smoothly.

Gene therapy research involves additional considerations which ultimately affect how the study is carried out. The FDA requires a long-term follow-up plan for research involving integrating vectors that deliver genetic material into the DNA of research participants, which is recommended to be up to 15 years. Plans to account for that follow-up, where it will occur, or even the stages of follow-up should be in place before the protocol is ever set into motion. Furthermore, many gene therapies are either infectious in nature or utilize infectious agents in the manufacturing process, and because of that, added training and safety precautions may be necessary for the research staff as well as the research participants.

As with any other clinical trial, participants must understand the risks and benefits of participating, and what to expect when participating in research. Writing the ICF at the recommended eighth grade level can be still challenging for participants to understand the anticipated and unique side effects gene therapy has to offer. Consider an extra piece of education for the participants, giving them a different lens through which to learn about and understand the study.

As always, when crafting a gene therapy protocol, it’s important to know the guidelines of the FDA, institutional biosafety committee (IBC), and institutional review board (IRB). Gene therapy is still a relatively new field, so be patient and be willing to clarify any questions anyone has. Providing the FDA, IBC, and IRB with education up front will save institutions time in the end, ultimately moving the research timeline forward. The earlier sites can get participants on the protocol, the faster the drug can move to market, advancing medicine for all.