Therapies aimed at a single patient: between hope and tragedy

Just a year ago, the case of a baby, K.J. Muldon, who suffered from a rare genetic metabolic disease –which can cause irreversible and fatal neurodegeneration– and was cured thanks to personalized gene therapy. A pioneering example of so-called n=1 therapy, that is, a therapy specifically created to treat a specific mutation present in only one patient. This success story was considered one of the great scientific achievements of 2025, and filled many parents with hope for their children affected by very serious rare diseases without treatment.

Even now, the great feat of genetically diagnosing a patient within the first 48 hours of life and managing to cure the baby in less than 6 months, thanks to the "editing" of a specific mutation to correct it, seems almost unbelievable. Consider that different cell and mouse models were generated to present the exact same mutation as the baby; vectors in the form of liposomes (fat vesicles) were developed to deliver the molecules responsible for gene editing to liver cells; furthermore, its safety was checked, for example in monkeys, to assess that it did not cause an exacerbated immune reaction. This research, which would normally take years of effort, was executed in months thanks to several biotechnology companies that considered it their priority R&D objective.

The case of K.J. Muldon was not the first patient treated with n=1 therapy, but it was the first complete cure. The first case was the development of a molecule called Milasen, in honor of the first patient, a girl named Mila, who suffered from Batten disease. She was treated with a therapy specifically developed for her, thanks to the persistence of her parents, who managed through crowdfunding to raise the million dollars needed to pay for the research necessary to develop an innovative therapy and test it in cell and animal models before administering it to Mila. Unfortunately, Batten disease has a rapid and devastating progression from the onset of the first symptoms, and Mila died without being cured. They weren't in time.

Malpractice: the death of a 6-year-old Chinese girl

Bioethical regulation requires that, to apply a therapy, it must first be checked that it is safe, then effective, and finally, its unwanted side effects must be checked. For this reason, clinical trials have several phases to evaluate these objectives. On the other hand, for therapies for rare diseases, with so few patients, the results obtained in preclinical models (normally in mice and monkeys, and now also in organoids derived from patients) are absolutely crucial, particularly in n=1 therapies, where it is necessary to specifically generate humanized models with the patient's mutations and demonstrate their efficacy and safety at the same time. There is no room for error, therefore, scientifically and bioethically they must be, or should be, impeccable.

This is not what happened in the n=1 therapy case which, unfortunately, hit the press recently surprising scientists and discouraging society. A case that was supposed to be the first cure of a genetic disease by direct gene editing in the brain, has ended up being a case of "scientific malpractice and bioethics, which ended with the death of Mei, a 6-year-old girl affected by a very rare neurodevelopmental disease. This case occurred in China, within a research group led by an internationally renowned scientist, who has quickly sought success and global recognition. You can find its story in an article published in ARA, but here I would like to emphasize the facts that force us to rethink how these personalized therapies are designed and applied.

In this case, Mei's parents funded the research for this therapy. The preclinical mouse model showed very promising results, and that's why it was moved to the monkey model which, unfortunately, did not show the same success. On the contrary, the animals showed symptoms of an unwanted and potentially lethal immunological reaction. Disregarding these results that called for caution, the scientists obtained permission (in China, the bioethical requirements for this type of therapy are not as strict) to treat the girl, who developed a massive immune response that caused her death in 5 days. The most serious part is that the scientific article only publishes the positive results, completely omitting the negative ones and, obviously, silencing the girl's death and the parents' funding.

Bioethically inadmissible

Bioethically, this case violates all classical principles of medical bioethics: 1) the principle of non-maleficence and 2) beneficence (since the monkeys' results indicated reactions that could compromise life, therefore, it was not a death due to misfortune or ignorance, but rather due to malpractice and lack of precaution); 3) the principle of autonomy (the parents were not adequately informed and were convinced that the risk to their daughter's health was minimal); and 4) the principle of justice, in which Chinese institutions wanted to silence them, without admitting any kind of error or recognizing their contribution to research. Total lack of transparency.

To what extent do these unacceptable situations according to our bioethical principles not increase society's distrust in scientific advances in personalized therapies, which will be so important in the 21st century?