“Sometimes they are liquid, sometimes solid—encased in pills or fixed onto patches. In short, medicines are usually simple substances—uncomplicated compounds. Ideally, they are effective, yet inherently passive. However, medications can function quite differently: they can become active and operate (or react) autonomously; they can receive instructions and multiply at the appropriate site within the body. In such cases, they are far more than mere effective compounds—they become "living therapies."
This term has become increasingly common since medicine rediscovered the potential of the cell itself as a therapeutic agent—a development that dates back several decades. Today, patients worldwide are treated using their own cells or, when necessary, cells from other donors—as is the case with stem cell transplantation. Yet the concept of living therapies extends far beyond the simple replacement of defective or missing cells. Cells possess an invaluable advantage: they are highly programmable. This can be achieved by introducing or replacing DNA—and thus genes—or by delivering therapeutically relevant information (perhaps piggybacking on RNA molecules) to a specific location in the body, where it flips a crucial genetic switch to "on" or "off." Finally, it is even conceivable to use constructs containing living, engineered bacterial cells to create a sort of internal bioreactor, supplying the patient with programmed therapeutic agents as needed.
Scientists at Harvard University have just presented one such construct—notable for its exceptional longevity—in the journal *Science*. It can apparently survive in the body for up to six months, acting as an autonomous drug depot. Genetically programmed *E. coli* bacteria are embedded in a soft hydrogel cushion within a container enclosed by a biocompatible polyvinyl alcohol mesh. Their task is to release therapeutic agents following infection by the hospital pathogen *Pseudomonas aeruginosa*. The implant is activated only when it is needed. Only when the chemical signal originating from the life-threatening pathogen reaches the bacteria within the implant do they release the antibacterial agent.
For the team led by David Mooney, the true feat of bioengineering lay in creating an environment within this implantable bioreactor dense enough to keep the bacteria intact for many months while simultaneously preventing them from proliferating uncontrollably. They succeeded in doing this with mice. However, whether and how such a construct might clear regulatory hurdles remains as uncertain as the question of how readily such programmed microbial implants would be accepted.
The situation is quite different regarding living therapies based on human body cells. Cancer research has already firmly established the principle of living "designer therapeutics" through CAR-T cells. In principle, the first generation is still treated like conventional medication: the active cells are introduced into the body from the outside. Essentially, these are genetically reprogrammed immune cells (T cells) that, once transferred into the bloodstream, target and neutralize—as precisely as possible—only the malignant cells they were genetically engineered to recognize. The key component is the "chimeric antigen receptor," which strips away the camouflage tumor cells use to evade the immune system, allowing the CAR-T cells to render the cancer harmless.
Cells programmed in this way can now—in many cases—keep not only leukemias and lymphomas (i.e., malignant B cells in the blood) in check; CAR-T cells are also capable of attacking solid tumor masses, provided the cells exhibit specific surface markers. Hundreds of clinical trials investigating this are currently underway worldwide. Yet, to date, fewer than one-fifth of cancer patients who would be eligible for such immunotherapies actually receive this treatment. The reason: Producing CAR-T cells is complex, often too time-consuming, and invariably very expensive. The average price is cited as 350,000 euros.
One-quarter of patients die while waiting for the therapy.
It is not uncommon for the treatment attempt to fail after the blood cells have been collected because problems arise during the production process.
Nevertheless, progress is rapid. New advances are reported every week. This also applies to the CAR-T cell therapies that many experts consider the next major step in living therapies: in vivo CAR-T cells. Instead of the complex process of collection, reinfusion, and preparation in—often transporting them to and from the laboratory or production facility—the aim is to generate the T-cells directly within the patient's body. The vehicles required for genetic programming—viruses or nanocapsules—are now available. For instance, US hematologists led by Justin Eyquem at the University of California demonstrated in the journal *Nature* how they could specifically target these therapeutic cells using gene-delivery vehicles and effectively reprogram them. A year ago, Germany’s Paul-Ehrlich-Institut paved the way for European research by approving the first clinical trial—conducted by the company Interius Bio Therapeutics—using such an *in vivo* approach in patients with hard-to-treat blood cell cancers.
Programmable immune cells acting as living therapeutics are now being used to treat conditions beyond just cancer. At the University Hospital Erlangen-Nuremberg, CAR-T cells are being successfully used to eliminate rogue B-cells from the blood; in affected patients, these cells produce autoantibodies that trigger autoimmune disorders such as ulcerative colitis. The remarkable thing is that these living medicines appear to work in chronically ill patients after just a single dose of CAR-T cells. The pioneering work of the Erlangen-based group led by Fabian Müller has attracted worldwide attention.
Gene therapists like Alessandro Aiuti from Milan are achieving similar success, albeit with a completely different patient population. A pediatrician and hematologist specializing in rare genetic diseases, he played a pivotal role in the first successful gene therapies performed on children—dozens of whom have since been completely cured. Just a few days ago, he took stock of the situation at the international "For-Tra Workshop" organized by the Else Kröner-Fresenius Foundation in Frankfurt, highlighting what can be expected next from living therapies. One example among many is lysosomal storage diseases (LSDs); around seventy such conditions are currently known. Affected children usually die at an early age or—as seen in metachromatic leukodystrophy—suffer from an enzyme deficiency that causes the breakdown of the brain's white matter. The therapeutic approach does not necessarily involve correcting the specific genetic defect itself—as these defects are often complex in congenital disorders and difficult to access within the body. Instead, Aiuti and his colleagues have devised a way to remedy the enzyme deficiency using programmed blood cells. Precursor immune cells in the blood are genetically engineered to migrate into the brain as microglia—the brain's defense cells—and produce the necessary enzymes there. Through this and similar methods, Aiuti has already enabled many children to lead healthy lives; some have remained symptom-free for up to twelve years.
"What we have learned is that the chances of a cure are greater the earlier the therapeutic agents are administered," said Aiuti. This makes it crucial to deploy "such medicines for novel therapies"—or ATMPs—as early as possible and to minimize the hurdles standing in their way.
Many such obstacles were discussed at the workshop in Frankfurt: high costs for market authorization, a lack of harmonized approval processes, and the absence of reimbursement models. For Manel Juan of the Hospital Clinic Barcelona, "the system is failing," even though the success of CAR-T cell therapy has clearly demonstrated its immense potential. As for the high costs? "They would drop radically if these therapies became routine and were used as a first-line treatment option," Aiuti noted. Thomas Voit of University College London therefore urged: "We must investigate the long-term benefits and thereby demonstrate the cost savings, because a cure ultimately saves a great deal of money." [1]
1. Bioreaktor in der Blutbahn: Arzneien sind längst nicht mehr nur dröge Stoffe. Viele leben und agieren als zelluläre Agenten im Körper, nachdem sie trickreich programmiert wurden. Allerdings ist die Einführung der neuen Medizin noch hindernisreich. Frankfurter Allgemeine Zeitung; Frankfurt. 27 May 2026: N1. JOACHIM MÜLLER-JUNG
Komentarų nėra:
Rašyti komentarą