The frozen "frozen life", see how scientists "thaw" for them

In 2014, the "ice bucket challenge", which was popular all over the world, entered the public's vision, which caused a rare disease of Jelly disease, which caused a lot of social attention.

Today is the 22nd "Frozen People Day" in the world. In this special day, let's pay attention to gradually frozen diseases and pay attention to the frozen life of gradually frozen people.

Figure 1 Ice Brick Challenge Source: From Charles Krupa

What is gradient?

The scientific name of Gradual disease is "muscle atrophy side sclerosis", which is a rare motor neuronal disease. Sports neurons can convey the brain's instructions to muscles and control the body to make various actions.

The person who suffers from frozen disease is manifested as gradually "frozen" by the body and cannot move. What's more cruel is that the patient's cognitive ability is not affected, which means that "gradually frozen people" will watch themselves "frozen" when they are awake - can not breathe.

Figure 2 Clinical manifestations of Grave Advernce: References [1]

What is the current situation of galaxy disease?

At present, frozen disease is almost in a state of "no medicine", and the World Health Organization has identified it as "one of the five major illnesses".

In the long years of developing galaxy therapy drugs, although more than 50 drugs can extend the life of animal models, clinically, there is no treatment method to reverse the development of gradients.

Riluzole and Edaravone are currently only two drugs with the ability to intervene in the disease.

Rurizole mainly plays a neuropapture effect by inhibiting the release of neurotransmitters in the brain, but it is only effective for 6 months before treatment, and it can only extend the survival period for 2 to 3 months. Edala Feng is a free radical clearance agent. By reducing oxidation to stimulate the role of patients, it is good for patients with early onset and rapid progress of the disease, but it is still unclear whether it can extend the survival period.

In the predicament of no special effects, patients with gradual frost disorder had to delay the failure of various functional functions through other means.

For example, patients need to pay special attention to the functions of the respiratory tract and digestive tract, and carry out effective rehabilitation activities to protect the activity and activity of muscles and joints, and try to maintain the status of physical activity.

At the same time, we must pay special attention to the patient's mental health and take timely psychological guidance. These supporting treatment methods play an important role in improving the quality of life of patients, and can even extend the survival of patients.

New therapy on the road on the road

Recently, with the continuous development of biotechnology, cell therapy and gene therapy are bringing hope to the "frozen people".

Cell therapy, also known as cell transplantation, refers to transplanting human cells that have transformed normal or biological engineering into the patient's body, replaced the original damaged cells, or exert biological function by secreting factors to achieve the purpose of treating diseases.

For patients with gradients, their brains are in inflammatory environments, while transplanted stem cells can secrete various neurotic nutrition factors, provide nutritional support for motor neurons, and slow the lesions.

At present, the application of accumulating stem cells and nerve stem cells is the most widely used. For example, in 2017, a clinical trial was carried out in Israel, and the researchers transplanted intercocnical stem cells into patients with galaxy disease through muscle and sheath transplantation.

The results show that the 14 subjects are tolerated well, the deterioration of the deterioration of lungs slows down, and the function score of gradients is slowed down (Figure 3). The course of the 6 months after treatment has improved at least 25 %, showing that cell transplantation is displayed, which shows that cell transplantation is shown The huge potential when treating felmeal.

Figure 3 The treatment effect of germ -free stem cell transplantation for gravity: reference [2]

Emerging gene therapy is also a very potential way of treatment. The main strategies include antonymal oligonucleotide (ASOS), RNA interference (RNAI), gene editing, gonad -related virus (AAV) media delivery.

Both ASOS and RNAIs have mediated their degradation through targeted messenger RNA, thereby reducing the expression of target genes to play a role. These two strategies are mainly aimed at family frozen symptoms. This type of frozen disease has clear mutation genes, such as SOD1 and C9ORF72. In terms of principle, as long as the mutant gene is "eliminated", the symptoms of people will be relieved and even fully recovery.

According to the latest achievements, Biogen (Bo Jian) ​​has developed Tofersen, ASO drugs for SOD1, and clinical I/II tests show that Tofersen can reduce the concentration of SOD1 protein in the cerebrospinal fluid (Figure 4).

On October 17, 2021, the company announced the results of Tofersen's key III clinical trial research. The results show that although the main endpoints have not reached the research, many times and exploration indicators of biological activity and clinical functions have seen the trend that is conducive to TOFERSEN, and the subjects who have started treatment earlier have obtained better treatment Effect.

Figure 4 TOFERSEN can reduce SOD1 protein sources in the cerebrospinal fluid in patients with gradients: reference [3]

In terms of using RNAI strategy to treat gradual frost, in July 2020, "New England Medical Magazine" published a small RNA (RAAVRH10.MI-SOD1) that is targeted by AAV internal injection by AAV to treat gradually frozen frozen frozen frozen frozen Symptoms, research shows that the expression of SOD1 protein in the spinal cord after injection has declined, and 1 of patients with the function score of the gradual freezing disease have remained stable and no deterioration of deterioration (Figure 5), which indicates that the small RNA injection in the sheath can be used as a family gradual gradual gradual family nature. Potential treatment of freezing disease. Figure 5 Raavrh10.mi-SOD1 Treatment of SOD1 mutations and frozen frozen results Source: References [4]

In addition, gene editing cannot be ignored in the process of treatment of gradients. Among them, the discovery of the genes scissors CRISPR-CAS system gives people the ability to edit genomes accurately. It can target specific genome sequences, induce the broken DNA double chain, and then destroy the expression of genes.

In 2017, "Scientific Progress" magazine published the first gene editing research on gradient disease. Researchers delivered the CRISPR-CAS tool targeting SOD1 through vein injection to the new-born gradient model mice and successfully brought SOD1 protein protein. The level is reduced by 2.5 times.

The treated mouse movement neurons were stored, the exercise function was improved, the onset time was delayed by 37%, and the survival rate increased by 25%(Figure 6).

Figure 6 The genetic editing of SOD1 delays the incidence of gradient mice and improves the source of survival rate: reference [5]

In addition to the above -mentioned treatment methods, scientists have also tried to use various vectors, such as AAV or lipid nanoparticles to deliver gods to nutritional factors to provide nutritional support for degenerate neurons.

Although these methods are non -specific and are unlikely to cure gradual frost, it may extend the time of survival of patients with gradients, so it has certain application prospects.

New technologies help gradually freeze people to "speak"

In addition to paying attention to the survivability of patients with jellyflowing disease, scientists are also very concerned about their quality of life. For late frozen people who are difficult to improve, scientists are also working hard to improve their ability to communicate with the outside world.

The famous physicist Hawking realizes communication with others through a voice expression system. The system translate Hawking's ideas into words by capturing the muscle movements of the eyeball and facial.

Nowadays, severe frozen patients have another new choice. Article published on March 22 this year reported a new technology -Brain Computer Interface (BCI), which can Read the brain signal and select a combination of a combination of sentences through the letters on the machine [6].

A 36 -year -old men from Germany successfully expressed their love for his son with BCI. This allows us to see that BCI is helping to regain the ability of the outside world to regain communication with the outside world.

Figure 7 Patients to realize their ideas through the BCI system.

Although frozen symptoms are terrible, scientists are rescued the "frozen people". We look forward to more in -depth and detailed scientific research in the future, the treatment plan for continuous improvement of frozen symptoms, and frozen the life of the "frozen people" as soon as possible.

Produced: Popular Science China

Author: Li Yuhuan (Jilin University)

Producer: China Science Popularization Expo

Edit: Wang Tingting

references

1. Hardiman, O., Et Al., Amyotrophic Lateral Sclerosis. Nat Rev Dis Primers, 2017. 3: P. 17071.

2. Petrou, P., et al., Safety and Clinical Effects of Mesenchymal Stem Cells Secreting Neurotrophic Factor Transplantation in Patients With Amyotrophic Lateral Sclerosis: Results of Phase 1/2 and 2a Clinical Trials. JAMA Neurol, 2016. 73(3) : p. 337-44.

3. Miller, T., Et Al., Phase 1-2 TRIAL of Antisense Oligonucleotide Tofersen for Sod1 ALS. N English, 2020. 383 (2): p. 109-119.

4. Mueller, C., Et Al., SOD1 Suppression with Adeno-Associated Virus and Microrna in Familial ALS. N English, 2020. 383 (2): P. 151-158.5. GAJ, T., et al. ET al., In vivo Genome Edition Improves Motor Function and Extends Survival in a Mouse Model of ALS. Sci ADV, 2017. 3 (12): p. Eaar3952.

6. CHAUDHARY, U., Et Al., Spelling Interface USING Intracortical Signals in A Completely Locked-in Patient enabled via Auditory NEUROEDBAING. Nat Commun, 2022. 13 (1): 13 (1): 13.3.3

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