A biological GPS to treat hereditary diseases

More than 300 million people in the world suffer from genetic diseases. In 1988, the first clinical trial of gene therapy, approved for Gaucher disease, began, which opened the way to a new and hopeful era for the treatment of these ailments.

30 years later, the journey continues. More than 2,000 gene therapy clinical trials have been carried out and there are 36 drugs approved for commercialization in the world.

Along the way, science has encountered obstacles such as the toxicity of drugs, the difficulty of producing them on a large scale and, especially, the challenge of taking them to the affected tissue and inside the cell.

Recently, the design of a kind of gps synthetic in protein form could open a new door in the treatment of these diseases.

The challenges of gene therapy

Genetic disorders occur as a result of mutations in the sequence of genes. If these alterations affect the DNA of the cells that originate the ovules and sperm, they will be transmitted to the offspring.

To replace or repair the mutated gene, gene therapy uses short pieces of DNA or RNA as a “patch.” These have also been used to block the expression of pathological genes and proteins.

Although there are many trials underway, few of them work in patients. Currently, as noted above, there are only 36 drugs approved by drug agencies in the world.

The main impediments are reaching the target tissue, crossing the membrane that surrounds the cell and penetrating it. At the moment, one of the best tools scientists have to overcome these obstacles are the so-called cell-penetrating peptides (CPPs).

On board the PCCs

PCCs consist of short chains of less than 30 amino acids that can cross the cell membrane. Some of them, such as TAT ​​and penetratin, are found in organisms such as viruses or flies of the genus Drosophila. Others are of synthetic origin.

They can also function as vehicles, transporting drugs, DNA, proteins, and viruses across the membrane into cells.

Within the body, most of these CPPs have a positive charge, which facilitates their attachment to the membrane, like a magnet. The entry mechanisms and the type of target cell depend on each CPP, but they do not alter the cell membrane, so they are not usually toxic.

There are a growing number of clinical trials underway with these peptides, although none have yet been approved.

The case of Duchenne muscular dystrophy

Among the diseases caused by genetic mutations, and from which new therapies could benefit, are muscular dystrophies. There are 30 types, and Duchenne muscular dystrophy stands out among them, the most common and severe form in children. It affects 7.1 of every 100,000 live born male babies, representing 20,000 new cases each year in the world. The life expectancy of patients is around 22 years.

The first symptoms, difficulties in walking or moving, appear between the ages of 3 and 5 and progress rapidly. Children need a wheelchair from the age of 12-15, and as the disease progresses, a respirator becomes necessary as well.

The origin is in the mutation of the gene that allows the production of the dystrophin protein, essential for muscle cells. The abnormality prevents the production of dystrophin or causes it to be rapidly removed. Due to this deficiency, the muscle is damaged and replaced by scars and fat with each contraction.

Although in most cases the mutation is inherited, approximately 30% occur spontaneously during fetal development.

Duchenne muscular dystrophy occurs mainly in males because the dystrophin gene is on the X chromosome. Females can carry the mutation, but because they have two X chromosomes they rarely have symptoms.

Shutterstock / Dan76

looking for a cure

The cure for the disease would happen to replace the gene, correct the mutation or avoid that part of the gene so that the cell recovers the production of the protein. For this, short DNA and RNA fragments have been designed, called oligonucleotides, capable of specifically binding to the area containing the mutation.

Oligonucleotide treatment has been approved by the US Food and Drug Administration (FDA) in patients with Duchenne muscular dystrophy. However, the effectiveness is limited, especially due to the difficulty of getting these molecules to all the muscles; especially to the heart and the diaphragm, very affected by the dystrophy.

Recently, a group of researchers from the University of Oxford and Cambridge has proposed a possible solution to this problem. They have fused these oligonucleotides with a new family of CPPs, specially designed – as if they incorporated a GPS – to reach the muscle and cross the cell membrane.

The results show great efficacy and safety in tests with animal models. This has facilitated the approval of the first clinical trial in humans with these hybrid molecules, which is currently underway.

If the positive results in patients with muscular dystrophy were repeated, hope would open up for them and their families. And what’s more: by using different peptides and DNA fragments for the mutated gene, other genetic diseases could benefit from this treatment in the near future.

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