And the meaning?
Antisense therapy treats incurable hereditary diseases
Sergey Kolenov, Hi-tech+
The idea, first expressed more than 40 years ago, finally became the basis for mass therapy. A few years after the appearance of the first antisense drug, about a hundred more are at different stages of development. Some of them are able to treat diseases that only one person on the planet suffers from.
More than 40 years ago, researchers proposed using antisense oligonucleotides – short fragments of RNA - to treat hereditary diseases. For example, they can be used to influence the matrix RNA, which serves as an instruction for protein synthesis. According to the scientists' idea, the antisense sequence should attach to a certain section of RNA in order to stop or stimulate the production of a particular protein.
Unfortunately, a number of problems arose on the way to the realization of this idea – for example, toxicity and difficulties with the delivery of antisense oligonucleotides. As a result, many specialists gave up and refused further developments in this direction. However, there were also those who continued to believe in the prospects of antisense therapy, Scientific American notes.
Among the latter were biochemist and molecular geneticist from the Cold Spring Harbor Laboratory Adrian Krainer and his colleague from Ionis Pharmaceuticals Frank Bennett.
Since 2004, they have been trying to create antisense therapy for spinal muscular atrophy (SMA).
Under this name, a number of genetic diseases are combined that lead to the degradation of motor neurons of the anterior horns of the spinal cord and deprive children of the ability to walk, talk and, in the worst case, breathe.
Krainer and Bennett knew that SMA is associated with a mutation in the SMN1 gene and a lack of SMN protein. To make up for its shortage, the researchers decided to target antisense oligonucleotides to the neighboring SMN1 gene and force it to produce the necessary protein in sufficient quantities. To do this, it was necessary to neutralize the RNA fragment that limited the synthesis of SMN.
A few years later, their development was crowned with success – the creation of a drug called nusinersen. It is injected into the cerebrospinal fluid and allows cells to generate the SMN protein necessary for normal development. Although the drug cannot repair damaged neurons, it stops the death of the remaining ones and improves motor functions. And if you apply it shortly after birth, the losses will be minimal.
Nusinersen's testing proved to be very successful, and in 2016 it became the first drug approved for the treatment of SMA. Today, it is hosted by 8,400 people in 40 countries under the name Spinraza. He literally saved many children's lives.
Nusinersen is the first antisense drug that began to be widely used in clinical practice. Following him, seven more were approved. Their success gives hope that similar therapies will be developed for other hereditary diseases. For example, antisense drugs against Huntington's chorea and amyotrophic lateral sclerosis are currently in the final stages of testing. More than 100 more drugs are under development.
Moreover, antisense therapy can become the basis for the treatment of disorders that only one person in the world suffers from. This is no longer science fiction, but reality. A few years ago, neurologist Timothy Yu from Boston Children's Hospital has created a drug for a girl with Batten's disease in less than a year.
Like SMA, Batten's disease is an umbrella diagnosis that covers several ultra–rare hereditary diseases associated with the accumulation of proteins and lipids in cells. Children with this diagnosis rarely live to adolescence.
Yu identified two unique mutations that caused the young patient's illness and led the work on the creation of an antisense drug capable of correcting their consequences. The resulting medicine was named Milasen – in honor of a girl named Mila, the only person for whom it was intended.
Mila received her first dose in January 2018. By this time, she had lost the ability to see and was experiencing seizures 20-30 times a day. Milasen was unable to repair the damage done to her body, but allowed her to ease the cramps and regain mobility.
Of course, the creation of drugs for one patient raises questions from regulators, who usually require mass clinical trials. In addition, the price of their development is very high – for example, about $ 3 million had to be invested in the creation of Milasen. However, perhaps the future of therapy for hereditary diseases will look exactly like this.
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