Individual therapy
Personalized medicine helped a girl with a rare neurodegenerative disease
Polina Loseva, N+1
American doctors have created a new genetic drug in order to cure eight-year-old Mila Makovets from Batten's disease, a rare form of neurodegeneration. Doctors discovered a unique mutation in Mila that led to the development of the disease, and developed an antisense oligonucleotide that helped reduce the severity of the symptoms of the disease. This is a rare case of a superpersonalized drug that will not be able to help anyone else – at least, doctors have not yet found other patients with the same mutation. The report is published in The New England Journal of Medicine (Kim et al., Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease).
Personalized medicine usually refers to the choice of medicine taking into account the characteristics of the patient. For example, instead of being guided by prescribing standards, it is possible to sequence the patient's genome and select a drug depending on a specific mutation. Or you can take a tissue sample from him (for example, a tumor), cultivate it in the laboratory and check on it which of the existing means will cope with the disease best. Finally, it is possible to create a drug for the patient from his own cells: this is what they do now, for example, with gene therapy – cells are taken, genetically modified, multiplied and injected back. Such a medicine, of course, will be unique – as well as the cells of each person – but in each of these cases, doctors act according to a single protocol.
American doctors have demonstrated an example of superpersonalized medicine, in which not only the drug, but also the method of its creation and the principle of operation is developed for a specific patient. A group of doctors from different clinics, led by Dr. Timothy Yu, worked with a girl named Mila Makovets (her story is told in detail by the STAT portal).
In the first years of her life, Mila developed on the same level with her peers, only after three years her mother began to notice alarming symptoms. First – the twisted position of the leg, then clumsy movements, then the girl's vision began to fall, convulsions appeared. By the age of 6, she saw practically nothing, could not swallow on her own, and began to react worse to external stimuli.
Neurologists diagnosed Mila with Batten's disease, a rare neurodegenerative disease. This disease is caused by a recessive mutation in the MFSD8 gene, that is, in the girl, both alleles of this gene should have carried it. However, genetic diagnostics showed that the girl, like her mother, is a heterozygote for this mutation, the second allele of the gene looked healthy.
Doctors who undertook to understand the genome of Mila found strange changes in one of the non-coding parts of the second, "healthy" MFSD8 gene. In most of our genes there are "semantic" sections – exons that carry information about the structure of the protein, and "meaningless" gaps – introns, which the cell then removes from the RNA by splicing, stitching the edges of the exons together. Scientists have found out that a retrotransposon is embedded in one of the introns in Mila's genome – one of the mobile elements that travel through DNA. And at this point an abnormal splicing site appeared: cellular machinery stitched the previous exon not with the next one, but with the edge of this retrotransposon. As a result, an abnormal protein was formed that did not work. Thus, none of the MFSD8 allele in Mila's genome was complete.
There is still no cure for Batten's disease, as for most neurodegenerative diseases. And moreover, there is no ready-made way to cope with the unique insertion of a retrotransposon. Dr. Yu decided to develop a medicine from scratch. To do this, he and his colleagues focused on the drug nusinersen approved several years ago. This is an antisense oligonucleotide – that is, an RNA sequence that is complementary and can stick to a specific RNA site in the cell. Nusinersen is used to correct splicing defects in spinal muscular atrophy. In fact, it blocks the "fake" point of splicing and prevents the cell from making a break in the wrong place.
Scientists used the same principle to create a cure for Mila. They sequenced its genome and RNA, determined the exact place where the incorrect splicing occurs, and created a set of oligonucleotides that could contact this place. Scientists tested all candidates for the role of medicine on Mila's cell culture. It turned out that one of the oligonucleotides works more efficiently than the others and increases the ratio of normal protein to mutant in cells by three times. Based on it, a drug was created and named "Milasen" – in honor of the only patient who will be treated with it.
The researchers managed to conduct a short experiment on rats: they were injected with Milasen in different concentrations and evaluated the side effects. No serious complications were found in the animals. At the same time, Mila's condition was deteriorating, and there was very little time left for checks. Usually, patients with Batten syndrome are not predicted to live more than 11 years, so scientists have switched to treatment. At first Mila received injections every two weeks, gradually the dose was increased and switched to injections every three months. The drug was injected intrathecally, that is, into the spinal canal, so that it reaches the nervous tissue faster.
Mila has been undergoing treatment for more than a year and a half now. Despite the fact that it was not possible to completely stop neurodegeneration, and the volume of her brain continues to decrease, her general condition has improved. She has learned to swallow on her own, and she no longer needs a feeding tube. It reacts to external stimuli. The number of convulsive seizures has also decreased: if earlier there were up to 30 per day and they lasted a few minutes, now there are rarely more than 10 of them, and they have become shorter.
The researchers note that they managed to create a drug so quickly – the development took about a year – only thanks to a favorable combination of circumstances. A similar drug has recently entered the market, and it was already known that it was effective and non-toxic, and Mila's mother organized a fundraiser to support her, which allowed her to pay not only for treatment, but also for development. Nevertheless, we should hardly expect a repeat of this story soon: there are many patients with unique mutations in the world for whom it is not so easy to choose a therapy, there are no analogues to focus on, and there is no money for development. And Milasen itself is unlikely to help anyone else: doctors have not yet found more patients with the exact same mutation.
Antisense therapy is also being tried on animal models of a variety of diseases. The first results are already available for the treatment of amyotrophic lateral sclerosis, prion diseases and Huntington's chorea.
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