Innovative Crystallization Technique Revolutionizes Gene Therapy Drug Production

Gene therapies represent some of the most advanced and costly treatments available today, primarily designed to address specific diseases. However, the high expense often restricts access for patients in need. A significant factor contributing to this cost is the manufacturing process, which can produce up to 90% non-active material, leading to a slow and inefficient separation of these unwanted components. In fact, separation processes account for nearly 70% of the total production costs associated with gene therapies. Recent research from the Department of Chemical Engineering and Center for Biomedical Innovation at MIT has unveiled a revolutionary approach to enhance this separation process. The findings, detailed in the journal ACS Nano, have the potential to significantly streamline production and reduce costs. As noted by researcher Vivekananda Bal, since 2017, there have been approximately 10,000 clinical trials focusing on gene therapy drugs, with around 60% utilizing adeno-associated viruses as vectors for the modified genes. These viruses feature protective shell structures known as capsids, but the current manufacturing systems frequently yield large quantities of empty capsids devoid of genetic material. These empty capsids can constitute between 50% to 90% of the total yield and pose a therapeutic challenge, as they can trigger immune responses without providing any therapeutic benefit. Thus, their removal is essential during the manufacturing process. Unfortunately, existing purification techniques are not designed for scalability and involve multiple stages, lengthy processing times, and high product losses. The challenge of differentiating between full and empty capsids arises from their nearly identical physical properties. Bal explains that they share similar structures, protein sequences, molecular weights, and densities, making effective separation difficult. Traditional methods primarily employ chromatography to achieve separation; however, this process is time-consuming and inefficient, resulting in up to 40% product waste. In contrast, the team explored a preferential crystallization method commonly used in small molecule pharmaceuticals but previously untested for protein purification, particularly for capsid-based drugs. This innovative approach offers reduced operating time and product loss while achieving exceptionally high purity due to its selectivity. The purification time using crystallization is approximately four hours, compared to 37-40 hours required by chromatography methods—making it nearly ten times more efficient. By leveraging slight differences in electrical potential between full and empty capsids, this method facilitates effective separation by favoring the crystallization of full capsids while discarding empty ones. The promising results have shown that this method can be scaled for large-scale pharmaceutical production. The research team is currently pursuing patent protection and is in discussions with various pharmaceutical companies to initiate trials of the system. This collaborative effort could pave the way for commercialization within a few years. The research team includes notable contributors from MIT’s Center for Biomedical Innovation and has received support from organizations such as the Massachusetts Life Sciences Center and the U.S. Food and Drug Administration.