The news in November that a Chinese scientist may have edited the genes of embryos, resulting in the birth of two baby girls, reminds us that gene editing is still an exciting — and often controversial — field.
At the recently concluded J.P. Morgan Healthcare Conference in San Francisco, the sense of foreboding about the future of this industry had dissipated. As I spoke with my colleagues in the field and executives from other companies, I got a sense that we were confident that gene editing is poised on the edge of great success, with therapies already approved by the U.S. Food and Drug Administration and the European Medicines Agency. Those attending a satellite session sponsored by the Alliance for Regenerative Medicine, of which I am a member, expressed hope that we’re on the verge of advancing cures for both orphan and non-orphan diseases.
Perhaps some of this bonhomie was due to the fact that the gene-editing industry is young enough that good news for any single company is good news for all. There is a shared sense of scientific exploration in the emerging gene-editing sector. All of us are focused on helping patients, despite the sometimes intense legal wrangling over CRISPR patents and other competitive aspects of our nascent business. And we’re confident that with the right stakeholders engaged, we’ll be able to develop solid guidelines to conduct clinical trials in an ethical fashion that protects participants and does the most good for patients.
At the same time, companies working with CRISPR-Cas9 and other approaches to gene editing are trying to overcome similar obstacles: delivering therapies to the right cells in the body and figuring out how to manufacture these therapies for both clinical trials and eventual commercialization. Regardless of how well we are able to engineer gene-editing therapies to make them as safe and effective as possible, the issues of delivery and manufacturing will be crucial to success.
There are two key challenges in delivering a CRISPR-Cas9 therapy so it is effective in the body: It must be delivered to a specific tissue, and it must also be delivered to the cells within that tissue. Many companies, including mine, are looking at two leading methods of delivering CRISPR-Cas9 treatments to cells: viral vectors and lipid nanoparticles.
Viral vectors. The sole purpose of a virus is to deliver genetic modifications to the cells it infects, altering them to produce more copies of the virus. In gene editing, we use the methodology of viruses by making specific ones that include the CRISPR-Cas9 machinery, and then use these viruses to deliver gene modifications to target cells.
It sounds great, and can work well. Viral vectors are particularly good at targeting cells of the retina, so this methodology is the delivery system of choice for gene-editing approaches to inherited retinal diseases. But in practice, viral vectors are difficult to manufacture and hard to scale up for commercial production. We need more science to make them a practical delivery vehicle.
Lipid nanoparticles. These tiny synthetic particles are made up of fatty acids, sterols like cholesterol, and other materials that are effective at transporting proteins across cell membranes. Lipid nanoparticles work by mimicking one of the body’s natural carrier particles, called chylomicrons, that are composed of proteins, lipoproteins and triglycerides. Chylomicrons carry dietary fats and other lipids throughout the body.
Lipid nanoparticles are the system of choice for delivering CRISPR-Cas9 therapies to the liver because the liver is designed to filter particles that enter the bloodstream. In practice, the liver takes up lipid nanoparticles and delivers their CRISPR-Cas9 components to the nuclei of liver cells, where the payload does its work. More research is needed to find lipid nanoparticles that can target different tissues in the body while delivering their payloads safely and effectively into cells.
When it comes to manufacturing, gene-editing companies face a unique set of challenges. One is whether to rely on a contract manufacturing organization (CMO) to supply what is needed for the near and long term. Preclinical companies are all working to figure out how to make these complex molecules, with different delivery mechanisms. So everyone, including the contract manufacturing organizations, is on the same learning curve.
Companies that advance to clinical trials will require a much larger quantity of experimental drugs. Two manufacturing questions face these companies: If we started our manufacturing program in house, should we continue down that road and build our own manufacturing facility? If we started with a contract manufacturing organization, should we continue working with it or bring manufacturing in-house and build our own facility?
The right answer is tricky enough to qualify as a business school case study. Building manufacturing capacity is frighteningly expensive. And it won’t be ready for three to five years after you’ve made the decision to green light the project. So making the right decision requires an extraordinary amount of capital, foresight, and luck.
At the moment, some companies are hedging their bets. They are working with contract manufacturing organizations to reserve chunks of their manufacturing capacity. If the gene-editing company is ultimately in a position to use that capacity, great. If it isn’t ready when the contract with the CMO starts, the contract serves to tie up the CMO’s capacity, slowing down others on the road to commercialization. Other companies are planning to build in-house manufacturing capacity and hoping it comes online just as it is needed.
All eyes on ethics
As the Second International Summit on Human Genome Editing showed, there are other challenges facing gene-editing companies. The media spotlight is now focused on the ethics underpinning the gene-editing approach to improving human health.
At my company, Casebia Therapeutics, our guidelines are straightforward: We do not support the editing of human germline cells. We agree with the recommendations of the International Society for Stem Cell Research and the U.S. Academy of Sciences, which have called for a moratorium on such editing until we have a full understanding of the safety and potential long-term risks of germline genome modification.
As the gene-editing community focuses on the extraordinary promise of editing somatic cells to address profound unmet medical needs and its potential for alleviating human suffering, we also need to solve the more prosaic problems of delivery and manufacturing.