There is much to be gained: Opportunities and challenges in gene and cell therapies

Nearly all science fiction series have ideas about what medicine might be like in the future: Patients simply being scanned, doctors using artificial intelligence to make a diagnosis in the shortest possible time and developing customized medicines. Too good to be true? In fact, cell and gene therapies have a great deal of potential as particularly effective, personalized therapies, especially for diseases that are currently difficult, if not impossible, to treat.

The crucial starting point is the human genome – the blueprint of human life. Every cell nucleus contains our DNA, which consists of around 3.2 billion base pairs. This is an enormous amount of data! How does this translate into the specific characteristics of an organism? The information of certain DNA segments, the genes, is first transcribed into RNA. The RNA is exported from the nucleus and serves as a template for protein synthesis. These proteins are the actual building blocks and active molecules of cells and their quantity and composition determine all processes of life.

We have known for a long time that many diseases originate from genetic mutations. And it is a compelling idea to simply correct defective genes – like spelling mistakes in a highly complex word processing program. However, it is taking longer than originally expected to develop these kinds of therapies. Although the exact sequence of human DNA was decoded in 2003, the interplay of the various genes is extremely complex. It's a bit like learning a completely new language: we already know the letters and individual words; however, it will take decades to understand all the linguistic subtleties. Not least, advances in artificial intelligence and computing power are helping us along this path – after all, we're talking about analyzing vast quantities of data.

Thanks in part to bioinformatics, there have been important breakthroughs in the development of new therapies in recent years. This is particularly true for rare diseases caused by the mutation of a single gene. Until now, treating the symptoms, rather than curing the disease, has frequently been the only option. Thanks to gene therapies, we can now actually address the causes of inherited diseases. A single treatment can be effective for a long time – ideally for a lifetime.

Take hemophilia, for example: In one gene therapy study, patients with genetically impaired blood clotting were shown to live for years without additional treatment following gene therapy to repair the defunct gene. Another example is a therapy approved in the United States for a hereditary form of retinal degeneration that can prevent otherwise inevitable loss of sight.

Gene and cell therapies also offer fascinating possibilities for the treatment of cancer. Cancer cells bypass the body's immune system by mimicking signals of healthy cells. In the laboratory, immune system T-cells can be reprogrammed into so-called CAR-T-cells that recognize and attack cancer cells.

In 2012, the development of gene and cell therapies was boosted by the discovery of the CRISPR/Cas9 technology, commonly known as "genetic scissors". It is based on naturally occurring mechanisms that bacteria use to defend themselves against invading viruses. Thanks to this technology, it is possible to precisely target and cut the DNA at a very specific region in the enormously long gene strand. This makes genetic research much faster and cheaper. In addition, the CRISPR technology enables relatively targeted repair of defective genes. The first clinical studies on this have already been carried out for the treatment of the blood disease beta-thalassemia, for example.

Another exciting field of research is RNA-based therapies. These can be used to suppress the synthesis of disease-causing proteins, for example. The production of RNA is comparatively simple. In contrast to DNA-based methods, the risks from unintentional alterations are also significantly lower because the RNA is rapidly degraded. In addition, researchers are working on ways to regulate RNA-based treatments and, if necessary, stop the process in the event of undesirable side effects. Beyond gene and cell therapies, the Covid-19 vaccines are the first RNA-based agents to benefit the broader community. They were developed more quickly than traditional vaccines and are proving highly effective.

How are we progressing in the development and application of gene and cell therapies?

One important aspect is the manufacture of therapies. Since they are generally tailored to a specific patient, production is extremely laborious. Many steps are still carried out by hand. Efforts to automate and scale up to larger quantities are still in their infancy. This applies not least to the mechanisms that transport the genetic information into the cells. These mechanisms are necessary because the molecules involved are very large compared with traditional drugs. Lipid nanoparticles and viral vectors can be used as vehicles.

Using a virus to transport genetic material? At first, this idea may take some getting used to. However, viral vectors are extremely effective at transferring genetic material into cells. For therapeutic use, the natural genetic material of the virus is removed so that it can no longer cause disease. The therapeutic gene is then inserted. This sounds complicated – and it is. In fact, viral vectors are among the most complex therapeutic modalities we can produce today. This currently makes them a limiting factor in the production of gene and cell therapies. At Merck, we are working hard to expand our capacities in this area.

Another sticking point is the testing and approval of gene-based therapies. Since they are often used for rare diseases, clinical trials on the usual scale are not possible. In addition, these kinds of therapies cannot be tested on a healthy control group. All this poses particular challenges for companies and regulatory authorities, e.g. due to the fact that the efficacy and safety of the treatment must be verified over many years of follow-on studies.

The pricing of these therapies also requires special consideration. The high complexity of their development and manufacture makes them very expensive. However, if a gene or cell therapy can replace a lifetime of treatments, it is often the cheaper option in the long term.

Last but not least, new treatment methods also raise new ethical questions. There is broad consensus in the medical research community that alterations to the human germline are not justifiable. However, this does not answer all the relevant questions: Where is the line between fighting a disease and optimizing humans? What risks are acceptable in order to cure a deadly disease? Questions such as these require social discussions beyond the medical field. At Merck, we thus already convened an interdisciplinary, international advisory committee ten years ago to advise us on ethical issues.

The bottom line is that the challenges surrounding gene and cell therapies remain immense but so are the opportunities. That is why we should not just leave this field to others. Currently, by far the largest proportion of clinical trials in this field are taking place in the United States and China. Yet Europe has excellent research, pioneering companies and well-trained specialists. We should strengthen and expand this innovation ecosystem. There is much to be gained.