Nature: Gene therapy brings dawn to incurable brain diseases

Diana Kwon recently published an article in Nature about the research progress of gene therapy.

Huntington's disease (Huntington's disease, HD) is an inherited disease that can cause extensive brain degeneration and disturbances in thinking, behavior, mood and movement.

The gene associated with Huntington's disease is called HTT, which encodes a protein called Huntington.

Although the genetic cause of Huntington’s disease has been well understood since 1993, there is currently no treatment that can prevent or slow the development of the disease.

Antisense oligonucleotides antisense oligonucleotide (Antisense Oligonucleotides, ASOs) (Antisense Oligonucleotides, ASOs) drug hopeful.

FDA

Other ASO researchers are going beyond the disease defined by a single mutation and looking at diseases with a more complex genetic basis.

At the end of last month, a large phase III clinical trial was abruptly suspended because the benefits of the drug did not outweigh the risks.

Because the efficacy of ASOs in many cases is not clear, and they are usually injected through the spinal column, some researchers have long urged caution with ASOs.

Although the results of this experiment are disappointing, we still have reason to be positive and enthusiastic about the effects that this model can achieve.

Spinal muscle atrophy (SMA) is a rare hereditary neurodegenerative disease.

In 2017, the FDA approved an ASO therapy called nusinersen, which is the first disease modification therapy ever to treat SMA.

However, researchers at Ionis Pharmaceuticals (originally called Isis Pharmaceuticals) in Carlsbad, California, made key changes to the chemical backbone of the drug, which improved the efficacy and stability of the drug, so that ASOs could be protected from damage.

nusinersen

Krainer's team focused on the proteins that bind to the RNA strands and cause fragments to be lost, hoping to prevent them from interfering with the process of producing a complete SMN protein.

In 2004, Krainer collaborated with pharmacologist Frank Bennett to find an ASO that can bind to the chain and hide the fragment from interference by proteins that might suppress it, so that functional SMN can be produced .

In 2011, this compound called nusinersen entered clinical trials .

nusinersen nusinersen compounds in clinical trials of compounds in clinical trials in subjects suffering from SMA SMA were infants who carried the body of a baby III III trial early termination of the trial was stopped early : : acceptance of the drug Patients are more likely to achieve exercise targets and survive than patients receiving placebo.

After the success of nusinersen, researchers began to study other diseases related to well-defined gene mutations, such as Huntington's disease.
This led to the production of the drug tominersen , which targets the CAG repeats on the RNA strands produced by normal and defective HTT genes , and marks them, and destroys the marked sequences by the enzyme of RNase H1 .
The results of a phase I/II clinical trial published in 2019 showed that tominersen reduced the concentration of huntingtin mutants in cerebrospinal fluid without causing any serious side effects.

tominersen tominersen by targeting the normal and defective by targeting the normal and defective HTT HTT gene produced by the gene produced by the CAG CAG repeats on the chain of the RNA RNA strand , and mark, by the repeat sequence, and mark, by RNase H1 RNase H1 The enzyme destroys the labeled sequence .
The enzyme destroys the labeled sequence tominersen tominersen reduces the concentration of the huntingtin mutant in the cerebrospinal fluid without causing any serious side effects.
It reduces the concentration of huntingtin mutants in the cerebrospinal fluid without causing any serious side effects.

The success of Huntington’s early trials caught the attention of researchers in neurodegenerative diseases because protein tangles are a key feature of many such diseases.
But an unexpected announcement at the end of March brought a huge blow.
On the recommendation of an independent expert committee, the tominersen phase III trial involving 791 participants from 18 countries was terminated early , and the committee has conducted a planned review of the data.
Roche said in a statement that there are no new safety concerns, but the potential benefits of the drug do not outweigh the risks.

Under the recommendation of an independent expert committee, the tominersen III tominersen phase III trial was terminated early by the participation of 791 791 participants from 18 18 countries under the recommendation of an independent expert committee.
Early termination of the trial

Drugs similar to tominersen's mode of action are still being used to treat other diseases of similar causes.
For example, some cases of ALS are caused by too many mutant proteins, and some ASOs for this type of disease are undergoing clinical trials.
The most advanced is the ASO drug tofersen developed by Ionis for the treatment of hereditary ALS, which is currently in phase III trials.

The long-term effects on related diseases are not yet known, and it is also unclear whether tominersen 's phase 3 trial has this problem.

The long-term effects on related diseases are not yet known, and the long-term effects on related diseases are not yet known.
It is also unclear whether this problem exists in the third phase of tominersen tominersen .
Does this issue exist in the third phase of the trial?

Some ASOs directly target mutant proteins.
Wave Life Sciences in Cambridge, Massachusetts is testing therapies for small mutations, which sometimes accompany CAG repetitions on mutant copies of HTT.
The purpose of this is to keep healthy huntingtin levels relatively intact.
However, the drug only works on a small percentage of Huntington's disease patients who carry these mutations.
This difference can only be identified by a detailed sequencing method, which is not often used in clinical practice.

Recently, researchers have begun testing ASO for more common neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease.
The vast majority of cases have nothing to do with specific genetic mutations, and these diseases are more common than genetic diseases.
The ASO program for Alzheimer's disease aims to reduce the level of tau protein, a protein that forms toxic tangles in the brain.
For Parkinson's disease, the goal is to reduce alpha-synuclein, which aggregates into pathological clumps called Lewy bodies.

Researchers have begun testing Researchers have begun testing ASO ASO for more common neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease.
Used for more common neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease.

But Kevin Talbot, a neuroscientist at Oxford University in the UK, said that for this type of neuroregenerative disease, several genes in a network are likely to be involved.
It is still unclear how changes in one gene in the network will affect other genes.
According to Talbot, another problem is that these drugs currently require repeated lumbar punctures to reach targets in the central nervous system.
Before ASOs can be applied to a wider range of diseases, it is important to find a way to allow these drugs to pass through the blood-brain barrier, thereby reducing their invasiveness.

Research on mice suggests that future ASOs may have a more powerful use in the brain: replacing lost neurons.

Last year, Xiang-Dong Fu, a cell biologist at the University of California, San Diego, and his colleagues demonstrated that it is possible to use ASOs to convert non-neuronal brain cells ( called astrocytes ) into neurons .
The research team injected ASO drugs into the brains of mice that lost neurons in Parkinson's disease.
Once there, the drug activates a network of genes, causing astrocytes to become neurons.
In a mouse model of Parkinson's disease, Fu's research team found that the treated animals improved in certain behaviors.
The transformation of these astrocytes into ASO is still in the early stages.
Before this technology can be used clinically, it needs to be tested on non-human primates, because their brains are closer to human brains than mice.
Currently, researchers are eagerly awaiting the results of the phase III clinical trial of tofersen for the treatment of ALS, and more information about the exact reason why the clinical trial of tominersen for the treatment of Huntington’s disease was stopped.

Use using ASOs ASOs non-neuronal brain cells will be non-neuronal brain cells ( ( called astrocytes called astrocytes ) ) into neurons is possible into neurons is possible

Original source:

Kwon D.
Genetic therapies offer new hope against incurable brain diseases.
  Nature .
2021;592(7853):180-183.
doi:10.
1038/d41586-021-00870-x

Kwon D.
Genetic therapies offer new hope against incurable brain diseases.
  Nature .
2021;592(7853):180-183.
doi:10.
1038/d41586-021-00870-x Kwon D.
Genetic therapies offer new hope against incurable brain diseases.
  Nature

 

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