Every year, genetic modifications are applied this or that way in new areas. Technologies that were thought to be innovative several ago are becoming common tools used in the clinical practice.

There are many people who highly hope for genetic technologies, truly believe they can cope with incurable diseases (in some cases even prior to birth) and delay aging. 

According to the FDA, gene therapy is a technique modifying a person’s genes in order to cure or treat a disease. Mechanisms for making such modifications can include changes both in vivo (inside the body) and ex vivo (outside the body). 

There are a lot of gene modification methods: medics and scientists use alter genomes of specific cell types, edit damaged genes, and vector gene delivery. It is possible to say with a high degree of certainty that the above technologies are no longer used in research labs only and are successfully applied to improve real patients’ lives. At the same time it is impossible to consider them as a panacea, because their potential remains limited.

Ex vivo modification

One of the first quite successful cases when gene therapy was used for patient treatment happened in 1990. A four-year-old Ashanti de Sylva suffering from severe combined immunodeficiency found gene therapy as an alternative to hematopoietic cell transplantation, a method with low efficiency and severe adverse effects. When treated, the patient’s lymphocytes were taken, modified ex vivo by applying a retroviral vector, and brought back to her body.

A lot of ex vivo modifications were applied in the clinical practice in order to help against various disorders, where CAR-T therapy was one of the most promising methods. In 2017, Novartis became the first pharmaceutical company that had obtained FDA approval to use CAR-T cells for treating acute lymphoblastic leukemia patients from 3 to 25 years old. They named the new product as Kymriah.

Genetic modification of patients’ T cells is the basis of the therapy. It makes chimeric antigen receptors on the cell surfaces binding with the protein that expresses tumor cells. When the clinical trials were conducted, 83% of patients have achieved entire or partial remission three months after the CAR-T therapy started. The twelve months survival rate reached 79%, and the survival rate of patients suffering from acute lymphoblastic leukemia and undergoing the standard chemotherapy did not exceed 30%.

When Novartis was given, approval was given to CAR-T therapies by other pharmaceutical companies, e.g., Yescarta, Tecartus by Gilead Sciences and Abecma by BMS. The list of such companies can be prolonged. Moreover, the scientific community is sure that it will expand with time.

Such products are getting more and more popular, although when today’s gene therapy has significant limits. CAR-T technologies are now used only if the standard first-, second-, and even third-line treatment does not give any results, and the treatment may cause numerous severe adverse effects. More than that, therapy that involves genetically modified lymphocytes is very much expensive.

Another significant drawback of this method is a high level of uncertainty over its potential long-term influence, side effects, and relapses (some of them can even be fatal).

Initially CAR-T medicines were developed to treat oncohematology disorders. Although their scope of use happened to be broader than it was expected. According to the re 

In vivo modifications

Glybera approved for using in Europe and the USA in 2012 was successfully discussed. This is the medicine aiming to help patients who suffer from the lipoprotein lipase (the enzyme breaking down complex fats) deficiency. This enzyme low level is the cause of accumulating subcutaneous and visceral lipoprotein complexes and leads to serious health problems like diabetes, pain, infertility, and liver disorders.

Glybera is based on an adeno-associated virus that carries the lipoprotein lipase gene. The enzyme deficiency is compensated by intramuscular injections, i.e., the latter actually cure the patient. When released, this medicine was one of the most expensive ones on the market. The interjections series (while a patient required about 60 doses) initially cost USD 1.5 mln; however, eventually, the price decreased down to 1 mln.

In 2018, as many as 31 patients could afford this expensive medicine. As a result, the high price and the disease rarity made the production of Glybera entirely unprofitable. That is why uniQure made the decision not to continue its marketing authorization and instead concentrate on gene therapy for hemophilia B that is a much more common congenital disease.

As a whole, similar therapies still remain costly. Researchers hesitate whether to introduce medicines based on adeno-associated vectors to clinical practice to treat rare diseases, because high expenses during their production make them completely unprofitable for the relevant industry.

Still, there is a certain progress. Pfizer and Spark Therapeutics are doing their best to defeat hemophilia B, gene therapy happened to be efficient against hemophilia A, and the patient suffering from sickle cell anemia is displaying recovery signs. 

The most expensive medicine that is nowadays used for in vivo gene therapy is Zolgensma. It is manufactured by Novartis, the pharmaceutical giant. The cost of one Zolgensma injection for spinal muscular atrophy is USD 2.1 mln.

This rare neurodegenerative disorder is caused by SMN1 gene mutation. It affects 1 patient out of 10,000. The symptoms of this disease develop in early childhood and make a larger progress with age when children consistently lose their ability to eat, move, and swallow without someone’s assistance. If the disease if not treated, it causes a fatal outcome. Once used, Zolgensma has a normalizing effect for SMN1 functioning and does not let the disease progress. Researchers have proved that it increases patients’ survival rate; in some cases body functions are regained and a patient starts eating and walking without anyone’s assistance.

Although, the medicine is so much expensive that no patients can afford it. As a rule, it is purchased either by the state or charity funds. Its high price is not the only disadvantage of Zolgensma. What is worse, this medicine is not going to become cheaper in the near future.

In fact, Zolgensma was a true breakthrough. At the same time, more and more data is required to evaluate its long-term effect, because the period of monitoring patients who had got the relevant injection has not exceed five years. Moreover, the therapy has severe side effects. According to the observations, there is even one known lethal case. However, researchers are not quite sure that the death was caused by taking this particular medicine. 

The above examples are only a few gene therapies used in the clinical practice for in vivo treatment. It seems that these techniques and methods are highly promising. On the other hand, there is not enough data that confirms their long-lasting effect.

CRISPR gene editing

In 2015 Nature published the article about the CRISPR/Cas9 technology where it was called as a “game-changer”. In the article this technology development was compared to the introduction of PCR to laboratory practice. “Molecular scissors” have offered promising and quite vast clinical opportunities to edit genes having utmost precision, “cutting off” genes with defects, and replacing them with those that function normally. 

CRISPR is relatively successfully used when treating sickle cell anemia, β-thalassemia, and Duchenne muscular dystrophy. Although, it is not fully used in the systemic clinical practice.

One more promising area of applying “molecular scissors” is the cancer therapy. According to the results of the research made by Chinese scientists, CRISPR was used for editing the genes of those patients who suffered from non-small-cell lung carcinoma and disrupting a gene encoding the PD1 protein. The researchers made the conclusion that the technology was safe for clinical practice. At the same time, according to further studies, the researchers expressed concerns over the long-term health effects resulting from genome editing.

As a whole, doubts about the accuracy of CRISPR make up the principle obstacle to making it an ordinary clinical practice. Researchers are still not 100% sure that “scissors” will do the cutting as it is intended, which causes questions about the potential outcomes of such editing. 

In 2015, Chinese geneticists carried out an experiment largely discussed in the scientific community. They made an attempt to modify human embryos and edit the gene causing β-thalassemia. They had fixed the defect, but the success rate was estimated only on the level of 5-10%. Moreover, the alteration was not perfect at all: in addition to the intended changes, researchers also fixed several unexpected mutations.

However, one more experiment conducted by Chinese scientists caused more serious discussions. In autumn 2018 He Jiankui, a biophysics researcher, stated the birth of two genetically modified twin girls, and their genome CRISPR had been edited before they were born. Their father was HIV-positive, and the aim of the experiment was to create embryos immune to the virus. 

Besides, in the experiment several other couples took part. As a result of this experiment, at least three genetically edited children were born. The statement of Jiankui became a real scientific sensation. However, it still caused controversy over ethical issues.

The technology of CRISPR is not perfect at all. A lot of long-term results of editing children’s genomes are still unknown. It is not quite clear what unintended mutations exactly can be caused by it and what health effects can appear in the future. 

As for potential consequences, they include quite high risks of cancer and other diseases because of genetic mosaicism (this is a condition when a single organism includes cells that have several genomes). The research lab of Jiankui is going to monitor the health condition of the girls until they are 21 years old and make regular reports.

In general, the vast majority of scientists agree that there is no matter how tempting and promising the idea of prenatal genome alteration may look, the technique of editing a genome is still too inaccurate in order to achieve the set goals.

About the Author

Rustam Gilfanov is an IT entrepreneur and a venture partner of the LongeVC Fund.