Clinical case

Gene therapy for cancer treatment approved for the first time

Yuri Deigin, Forbes, 31.08.2017

In the future, gene therapy can save people from many diseases. In practice, the first important step has been taken: for the first time this method has been approved for use in oncology.

The gene therapy market has every chance of becoming the fastest growing market in the world in the next 10 years. The prospects that genetic manipulation opens up motivate representatives of Big Pharma not only to conduct their own research, but also to actively buy up the most promising companies.

The pharmaceutical giant Novartis, apparently, can initiate the widespread introduction of gene therapy into global clinical practice: the Food and Drug Administration (FDA) approved the use of gene therapy for patients aged 3 to 25 years suffering from acute lymphoblastic leukemia.

Treatment helps to achieve remission, and in some cases even defeat the disease. The media has rightly dubbed this event the "new era of medicine" – humanity is gradually coping with previously incurable diseases with the help of genetic manipulation.

Let's remember what led to the beginning of the "new era" and see where one of the most promising markets is heading.  

How it all started

About 15 years ago, scientists managed to "read" the genome and finally get access to the "source code" of the human body, which stores all the necessary data about it, and most importantly, controls its life and death. It took several more years to comprehend the acquired knowledge and gradually begin to translate it into the field of practical application: first into diagnostic, and then into clinical practice.

Over the past 100 years, science has learned to cope with pathogens of various diseases, such as viruses and bacteria, quite well – thanks to vaccines and antibiotics – but ailments caused by mutations in genes have long been considered incurable. Therefore, the decoding of more than 3 billion pairs of nucleotides has opened up truly unlimited prospects for the development of "medicine of the future" – primarily preventive genetic therapy, and, ideally, fully personalized medicine.

Market experts predict rapid growth in these areas: the cancer gene therapy market is projected to reach $4 billion by 2024, the gene therapy market as a whole – $11 billion by 2025, and forecasts for the entire personalized medicine are even more optimistic: from $149 billion in 2020 to $2.5 trillion by 2022.

The first fruits of decoding the human genome were the improvement of the diagnosis of congenital diseases or predisposition to them (many will recall the case of the BRCA1 gene and Angelina Jolie). Against this background, the market of so–called "consumer genetics" began to develop rapidly - it is expected that by 2020 it will grow to $ 12 billion.

Genetic tests give the patient the opportunity to analyze and find "bad genes" in his body or, conversely, rejoice at their absence. Initially, a rather expensive pleasure ($999-2500) became more and more affordable as the cost of sequencing decreased. For example, the price of a comprehensive study, which is offered today by one of the world market leaders, the company 23andMe, is $ 199. In Russia, prices are slightly higher: from 20,000 to 30,000 rubles.

In addition, targeted therapy is becoming a reality, which is especially important not only for hereditary diseases, but also for cardiovascular and infectious diseases, as well as oncology - the leading causes of death worldwide. Genetic manipulation allows the patient to introduce "good" genes to compensate for the problems caused by the hack work of the "bad" genes – for example, as in the case of hemophilia, and in the future will allow the "repair" or completely remove harmful genes – for example, those that cause neurodegenerative Huntington's disease. So far, gene therapy occupies a very modest place in the pharmaceutical market, but its share is bound to grow steadily.

Of course, there are still many problems that need to be solved: this includes a high risk of immune reactions, the high cost of therapy and, perhaps, even ethical issues related to making changes to the human body at the genetic level. However, such manipulations are a chance for patients whose diseases are either recognized as incurable or cannot be effectively treated with existing drugs, as well as a new weapon in the fight against aging, giving humanity hope for healthy longevity on a completely different level, and the market – new, much more promising ways for development.

First victories

The development of Novartis specialists mentioned at the very beginning is a real breakthrough of recent times. The company was the first on the market to demonstrate effective therapy for one of the varieties of acute lymphoblastic leukemia – B-cell type, which is the most common form of cancer that develops in childhood and adolescence.

The therapy created is based on the technology of chimeric antigen receptors CAR–T (chimeric antigen receptor, CAR). Transgenic T-limofcites, "equipped" with these receptors, are able to recognize malignant cells, and then destroy them – a specially designed receptor, "trained" on the patient's cancer cells, helps them in this. It is he who activates the T-limoficit in contact with the desired cell. Thus, CAR-T therapy allows us to use the effective anticancer mechanism already available to all of us – the immune system – to combat oncological processes.

Clinical trials have shown impressive results: 83% of patients who were not helped by chemotherapy were able to achieve partial or complete remission three months after the start of treatment with CAR-T therapy. A year later, 79% of the patients were alive. Previously, only 16% to 30% of patients with this form of cancer had a chance of salvation.

The cost of the first gene therapy in the USA is almost $475,000. FDA approval is of great importance not only for Novartis, but also for other companies working in the same field, for example, Kite Pharma Inc, Juno Therapeutics Inc and Bluebird Bio Inc, which develop drugs with a similar principle of action. Experts note that FDA approval almost always means an influx of investment: this will naturally entail improving treatment methods and reducing their cost, which makes the victory over cancer more and more real.

Even before the success of Novartis, impressive breakthroughs in the "war" against genes were achieved in the field of hereditary diseases.

A few years ago, a real event in the pharmaceutical market was the appearance of Glybera, the world's most expensive gene therapy drug aimed at the extremely rare deficiency of lipoprotein lipase, which leads to death due to the fact that blood vessels are clogged with fat. However, the rarity of this disease, coupled with the high cost of therapy ($ 1 million), led to the fact that the manufacturing company refused to renew its registration certificate - since 2012, only one patient has been treated; fortunately, successfully. And, despite the fact that Glybera failed from a commercial point of view, the first blow to genetic diseases was dealt.

Hemophilia is also affected. Not so long ago, American scientists reported on the results of tests of a new drug SPK-FIX for the treatment of hemophilia B-type – they have become the most successful in the history of the fight against this disease. This was the result of a partnership between Pfizer and Spark Therapeutics, which began in 2014, when the pharmaceutical giant began to expand its presence in the gene therapy market. Of course, the clinical application requires more extensive additional research, but it is unlikely that any obstacles will arise for this, especially since Pfizer intends to actively continue its expansion.

In May of this year, the company announced the beginning of cooperation with Sangamo Therapeutics, which aims to create a gene therapy for hemophilia A–type. Pfizer will spend over $500 million for these purposes: the pharmaceutical giant will pay Sangamo $70 million in advance, and is ready to invest another $300 million in research, commercialization and production of the key drug Sangamo SB-525, as well as $175 million in the development of other drugs against hemophilia A, if any.

A year earlier, Pfizer acquired Bamboo Therapeutics startup for $700 million, which specialized in creating gene therapy for diseases associated with damage to the neuromuscular central nervous system - including Duchenne muscular dystrophy (MDD).

It is diagnosed mainly in boys aged 3-5 years: at first it manifests itself in difficult movements, by the age of 10 the patient can no longer walk, and by the age of 20-22 he dies.

The culprit is a mutation of the dystrophin gene, which is located on the X chromosome. In the "pre-genomic" era, therapy could only slightly alleviate the patient's suffering, but gene therapy opens up new prospects for a full, healthy life for people suffering from this congenital disease.

Perhaps the main blow to MDD and other hereditary diseases is being prepared to be inflicted by CRISPR/Cas9, which has already helped to completely rid mice of this ailment.

Molecular Scissors

CRISPR/Cas9 technology has been talked about for years – this inexpensive, convenient and effective tool for DNA editing has every chance for widespread introduction into clinical practice. Potentially, it can help in the fight against almost any diseases from hereditary to those that are still incurable (cancer, HIV, Alzheimer's disease): roughly speaking, "molecular scissors" can cut out "bad" genes or replace them with the right ones.

This is how the Washington University team used CRISPR/Cas9 against Duchenne muscular dystrophy: a special RNA molecule indicated to the Cas9 protein "scissors" which part of the gene they needed to correct and how, which they did. The aim of the specialists was the 53rd exon (the protein-coding region of the gene) out of 79 exons of the DMD gene, carrying the so-called nonsense mutation. With such a mutation, a section of the sequence is formed in the gene, which prematurely stops protein synthesis. This exon is located in the "focus of mutations" – the part of the gene in which the greatest number of defects (approximately 60%) occur, leading to the development of Duchenne disease.

Another CRISPR victory became known in mid–August - "scissors" were used to correct "genetic errors" that lead to the development of Huntington's disease and amyotrophic lateral sclerosis (it was to attract public attention to the latter that a wave of ice water dousing swept over the Internet a few years ago).

It is also worth noting the successful use of CRISPR for editing human embryos – in early August, Mitalipov's groups from the University of Oregon and Belmonte from the Salk Institute published an article describing the process of correcting mutations in human embryos.

The prospects of CRISPR/Cas9 were quickly noted by investors: even Bill Gates invested in one of the CRISPR startups. We are talking about the company Editas Medicine, which raised $ 120 million, and in February 2016 successfully entered the IPO, selling shares worth $ 94 million. Its competitors are also quite successful: in May, the startup Intellia Therapeutics raised over $100 million during the IPO, and CRISPR Therapeutics received $56 million. The capitalization of each company exceeds $ 500 million and, apparently, will only grow.

No wonder CRISPR inspires specialists around the world so much. The famous Harvard geneticist George Church, for example, plans to use it to recreate a mammoth, as well as come close to solving the aging processes of the body. According to the scientist, genetic manipulation will allow us to crack the aging program embedded in our genes and finally make the ancient dream of humanity about eternal youth a reality.

Genes vs Youth

Church is not alone in his intentions to defeat aging. Gerontologists around the world are generally convinced of the need for such a struggle. Aging is considered as a pathological process and the root cause of age-dependent diseases, including, in addition to cancer and cardiovascular diseases, also, for example, Alzheimer's disease – an incurable epidemic of the near future today. The victory over aging seems to be the next, and increasingly real step in the development of gene therapy.

Most experts explain this process by the gradual deterioration of the body, the accumulation of various "breakdowns" with age due to its imperfection. Basically, the struggle on this "front" is symptomatic – specialists are trying to eliminate individual signs of aging.

For example, Maria Blasco from the Spanish National Cancer Research Center (Centro Nacional de Investigaciones Oncologicas, CNIO) tried to "rejuvenate" mice by "completing" short telomeres (areas at the ends of chromosomes). She managed to extend both the average and maximum life expectancy, and in two groups at once ("adult" and "old"): one received telomerase gene injections (TERT, TERT therapy) at the age of 420 days (an increase in median survival by 24% and an increase in maximum life expectancy by 13%), and the other – at the age of 720 days (an increase in median survival by 20% and an increase in maximum life expectancy by 13%).

However, this has not yet developed into larger–scale clinical trials - investors doubt the commercial success of such an approach. However, this did not stop the American Elizabeth Perrish, CEO of BioViva biotech company, who decided to try telomerase therapy on herself, without waiting for the completion of the necessary tests for this. In Colombia, she was injected with the hTERT telomerase gene and the follistatin FS gene (designed to inhibit myostatin and prevent muscle loss with age). It is too early to talk about the results of this bold experiment, but as far as we can judge, he has not yet received confidence in the market – investors reacted to him very skeptically.

This is also evidenced by the failures of Michael Fossel, a professor of clinical medicine at the University of Michigan and CEO of Telocyte, who unsuccessfully tries to attract investment to test the same "telomerase approach" to the treatment of Alzheimer's disease. He was one of the first to talk about the fact that, perhaps, not beta-amyloid or tau protein, but aging is the root cause of the disease.

The history of the struggle with Alzheimer's disease speaks in favor of this assumption. Pharmaceutical giants are repeatedly defeated, and in the period from 2002 to 2012, only one of the 244 candidates for a drug for Alzheimer's disease received FDA approval and joined the ranks of acetylcholinesterase inhibitors – safe, but ineffective.

CRISPR could probably help here, too. The fact is that one copy of the E4 allele of the apolipoprotein E gene increases the risk of developing the disease by 3-4 times, and two – by 8-12! Perhaps genetic manipulations will help to deliver the E2 allele into the body, or even replace one of the copies of the E4 allele with it, since the presence of E2 reduces the risk of Alzheimer's compared to the "wild type" E3 allele. However, Alzheimer's disease threatens those who do not have any genetic prerequisites for this, so so far this approach is not popular.

Hacking the program

Many experts consider aging not as a set of random breakdowns, but as a program encrypted in DNA. In addition to the already mentioned George Church, Academician of the Russian Academy of Sciences Vladimir Skulachev and the head of Gero, Peter Fedichev, adhere to this approach.

This program begins to operate from the moment of puberty and slowly but inexorably leads to death. Moreover, this is a fairly regulated process. Each species has a clear limit of life, which is allowed to it. In a mouse, for example, it is, on average, 2.5 years, in a human – about 80 years. At the same time, there are other rodents that live many times or even an order of magnitude longer than mice – for example, squirrels or the famous naked digger.

The main question is whether aging can be turned off or at least slowed down. Perhaps the revolutionary technology that reverses cellular development, which was discovered by Shinya Yamanaka, professor at the Institute of Advanced Medical Sciences at Kyoto University, will help answer this question: he found that the induction of the joint expression of four transcription factors (Oct4, Sox2, Klf4 and c-Myc, and all together – OSKM, or Yamanaki factors) which are closely related to the main stages of the cell life cycle, turns somatic cells back into pluripotent. Yamanaka received the Nobel Prize in 2012 for this truly revolutionary discovery.

Using Yamanaki's breakthrough, a group of scientists from the Salk Institute led by Juan Carlos Izpisua Belmonte tried to apply this natural mechanism of resetting the biological clock to prolong the life of adult animals. And I was not mistaken. Using Yamanaka factors, they were able to confirm the hypothesis about the possibility of rolling back the "epigenetic clock", that is, cell rejuvenation, and increase the average life expectancy of rapidly aging mice by 33%-50% compared with various control groups.

In mice treated with therapy, there was a decrease in all critical markers of aging: markers of senescent cells p16INK4a and beta-galactosidase, and a marker of double-stranded DNA breaks gamma-H2AX, and metalloproteinases, and interleukin-6, and so on. Moreover, the production of mitochondrial reactive oxygen species decreased in mice and telomeres lengthened. By the way, telomere lengthening was independently confirmed by Maria Blasco's group already mentioned above – she also joined the study of Yamanaki factors and published her results in January 2017.

In fact, all the pieces of the anti–aging puzzle, which are being chased by many existing therapies (senolytics, telomerase, etc.), can be put together with the help of genetic manipulation alone - as it should be with programmed aging.

This discovery did not go unnoticed, including by promising market players. For example, back in December 2016, immediately after the publication of Belmonte, Ned David (Nathaniel David), the head of the famous startup Unity Biotechnology, who develops means to combat atherosclerosis, and in the future, other age-dependent diseases by destroying senescent (or decrepit) cells, personally visited him twice. Not so long ago, the company received $ 116 million for this purpose from investors such as Peter Thiel and Jeff Bezos. And in March 2017, David and Belmonte discussed potential next steps. So, it is quite possible that California investors will very soon see commercial potential in Belmonte's breakthrough.

The prospects

Gene therapy, despite its relative youth, has already proved its effectiveness in the fight against genetic defects. Treatment of previously invincible diseases is, perhaps, only a matter of time, and the fight against aging and, accordingly, radical prolongation of life is the next logical step, which, in light of the achievements of the Belmonte group, seems quite real. So companies that work in this direction can become a very valuable asset for investors.

Unfortunately, no one has been able to offer effective strategies to achieve a significant – at least 15% – extension of human life to date. Starvation did not justify the hopes, metformin and rapamycin, so beloved by gerontologists (on mice or dogs), as well as other "geroprotectors", did not prove to be too effective.

Therefore, if in the near future there is no cardinal turning point in the search for a radical prolongation of life, our loved ones simply will not live to the moment when the mechanisms of aging will be solved, and science will finally be able to stop it. Perhaps gene therapy and, in particular, the path proposed by Belmonte, will become such a turning point. But in order for it to happen in the next 20 years, and not 50, a lot of people need to hurry up – scientists, investors, and politicians. And the task of society is to hurry them up.

Portal "Eternal youth" http://vechnayamolodost.ru  01.09.2017