MilliporeSigma

Benjamin Borgo

Gene therapies have long held immense promise for the correction of genetic mutations that induce disease states, as well as for the expression of proteins or RNAs that hold therapeutic value inside diseased cells. The most recently discovered tools for genome editing, more specifically the CRISPR technologies, have come to the forefront of clinical efforts at developing newer, better therapeutics.

Between 2014 and 2018, NIH funding for CRISPR related research has increased by almost 100 times, to over $1 billion[1], and, according to information available on PubMed, the percentage of CRISPR-focused publications focused on therapeutic applications has catapulted from around 3 percent in 2015 to over 16 percent in 2019. In addition, a review of clinical trial data available on clinicaltrials.gov show that the first clinical trials for CRISPR have demonstrated tangible patient benefits, with four CRISPR programs in Phase II trials in the U.S. alone.

As academic research continuously advances toward clinical development and to the patients, both the challenge and potential for advancement of manufacturing processes related to these new therapies are growing. CRISPR-based therapeutics can be delivered to patients in a number of ways. Some, using viral vectors, have well developed manufacturing processes that undergo constant optimization by companies like MilliporeSigma. Other therapies, specifically the direct delivery of ribonucleoprote in complexes into either cells for ex vivo therapies, or patients for in vivo therapies, will require substantial optimization to economically deliver to patients at scale.

Challenge 1: Integrated manufacturing of gene therapy APIs

To date, most non-viral gene therapy components are manufactured piecewise (RNA, protein, delivery vehicle, etc.) and assembled by the facility administering the therapy. Scaling this sort of a quasi-manufacturing process to cost-effectively reach consumers is nearly impossible. Instead, the manufacturers and contract development and manufacturing organizations (CDMOs) will have to expand their validation processes to include more diverse range of components and molecules than they have in the past. The companies supplying these types of modalities will have to learn to think about drug products more holistically. While majority of manufacturers of these types of materials currently focus on only a fraction of the necessary drug substance; rapid, scalable production will require integrated, end-to-end systems incorporating a wider range of manufacturing expertise than with more traditional molecules.

As with any new treatment, the regulatory landscape is fraught with uncertainty. Cutting-edge medical centers are seeing extraordinary success with engineered cell therapies modified by CRISPR achieving “cure” rates unimaginable just a few years ago; these therapies are, however, too expensive to scale. To effectively reduce the cost and broaden access to these treatments, manufacturers and drug developers must partner to define clear quality and regulator metrics to allow faster, safer production of the required substances that is scalable to the necessary level to meet patient demand. This need will become even more pronounced as cell and gene therapies shift from rare diseases to more common ones, such as oncology.

Challenge 2: Mapping innovation in research to success in therapeutics

drug development pipeline, researchers are closer than ever to the clinical relevance of their work. A robust, and ideally rapid, pipeline for translating innovation in new CRISPR tools, such as single base editing proteins, assures that the most suitable system is always being used rather than simply the most established one. These tools also rapidly expand the applicability of gene therapies that previously relied on DNA cleavage almost exclusively. Moving from the research bench to the clinic, however, presents a number of hurdles. Safely removing as many of these hurdles as possible will require suppliers, manufacturers and CDMOs that can more closely partner with, and provide materials to, scientists across the research-clinic spectrum.

Solution: A focus on new modalities, from bench to bedside

Clearly, the need for CRISPR-based therapies requires substantial scientific discovery and validation as it becomes more mainstream, shedding its label of ‘new’ for a label of ‘proven’. Importantly, it will also require suppliers and manufacturers that can support the challenge of novelty and discovery, providing new tools quickly to researchers, as well as the challenge of manufacturing ready materials, including GMP-grade versions of the aforementioned tools that are appropriate for research through clinical development and validation. The ultimate success of gene therapies, and the patients they cure, will depend on the ability of both early discovery scientists and process manufacturing innovators to develop not just new technologies, but a new mindset for delivering these critical medicines to patients.