Over the last decade, there has been robust growth of gene therapies entering the clinic to treat a wide array of diseases, from lymphoma to spinal muscular atrophy and many more. However, the early days of gene therapy were plagued with challenges due to the lack of tools available to accurately characterize the biochemical properties of these drugs and how they interacted with the human genome. Today, there have been significant technological advances in the field, and stakeholders are pushing the boundaries to develop these treatments not only for orphan indications but for broader disease categories as well. To advance the next generation of safer, more efficacious, and cost-effective gene therapies, innovators need to consider that the pathway to commercialization includes candidate characterization and bioanalytical evaluation.
The evolution of gene therapy
The need to improve gene therapy characterization stems from the challenges witnessed during the early days.
While the concept of gene therapies first began in the 1970s, it wasn't until the 1990s that it began to show promise on two fronts. The first was plasmid DNA delivery, where genetically driven diseases were corrected using DNA editing of the genome. The second was viral gene therapies, including retrovirus, adenovirus, and lentivirus delivery systems. These two modalities led to the first phases of clinical adoption of gene therapies, and companies soon emerged hoping to be the first to market.
However, in 2000, the FDA put a hold on all gene therapy clinical trials due to a treatment-related death that occurred after a viral gene therapy. The agency began to scrutinize all gene therapy biopharma companies, which ultimately led many of them to close down. As a result, for many years little was done to bring gene therapies to commercialization.
During this lull, academic researchers were advancing assay development and beginning to characterize gene therapy properties, specifically off-site targeting that led to serious adverse effects. As these breakthroughs started to shine a positive light on gene therapies, companies began to come back online with the hope of bringing safer and more effective gene therapies to patients.
The stigma of treating patients with gene-altering therapeutics has dissipated. Today, more than 20 gene and cell therapies are approved by the FDA, indicating that stakeholders—from investors to regulators to clinicians—are pushing for the field to grow.
Most recently, the field has seen the adoption of RNA-based genetic modification making significant progress due to higher efficiency at altering genetic expression than DNA-based systems. As demonstrated by the innovation during the COVID-19 pandemic, RNA can now be used to deliver vaccines and a variety of other therapeutics.
Moving the pipeline forward
The gene therapy field is rapidly advancing, with safer and more effective drugs entering the market. However, to move candidates through the pipeline and into the clinic, gene therapy researchers need to understand characterization and bioanalytical processes critically and use these resources efficiently. In particular, innovators need to dig deeper to characterize the molecule of interest with assays that are acceptable to regulatory agencies.
Fortunately, regulators' requirements for characterizing these products are becoming similar to other modalities, such as small molecules and antibody biologics. Companies can now work closely with research organizations to help develop accepted state-of-the-art assays and reagents to demonstrate safety and reproducibility.
For example, mRNA gene therapies have a complex delivery system, composed of up to five lipids and other excipients. Through bioanalytical assays, each therapy component can be characterized for size, charge, and how it disassembles within the patient. Ultimately, each particle needs to be analyzed individually before and after administration into the patient.
Driving down gene therapy costs
Gene therapy is still primarily focused on treating orphan indications, primarily because these diseases have the path of least regulatory resistance. However, leaders in the field are thinking on a larger scale about using gene therapies, specifically RNA-based, for broader and more common indications such as high cholesterol and cancer.
As the number of potential indications increases and safety and efficacy are further validated, biopharma teams are working closely with other stakeholders to reduce costs. For example, some gene therapies can cost $350,000 per dose in smaller disease indications, and it is these specialized situations where you can get insurance companies to help cover payment. However, insurance companies are unlikely to do this for larger patient populations.
To help reduce costs, gene therapy infrastructure is being repurposed; manufacturing and bioanalytical facilities no longer need to be built from the ground up. Numerous contract research organizations can make lipid nanoparticle RNA products, as seen with the billions of vaccine doses created for COVID-19. In a couple of years, when the SARS-CoV-2 virus is not as prevalent, that state-of-the-art infrastructure can be used to develop the next generation of gene therapies.
Cross-disciplinary collaboration
Gene therapy products are uniquely complex because their development constitutes different fields of life sciences coming together. From standard chemistry to viral biology, it is essential to assess the molecule's intricate physicochemical and biophysical characteristics, including thermal and chemical stability, lipid nanoparticle composition, and encapsulation efficiency.
To that end, as companies bring their programs forward, they need to work with a diverse team of virologists, biochemists, and formulation scientists. This is critical during the early stages of candidate characterization to ensure that resources are used efficiently for cost-effectiveness and assays are done under regulatory standards for building the next generation of safer and effective gene therapies.
Frank Tagliaferri is Vice President, Pharmaceutical Development at Pace Analytical Life Sciences