As gene therapy refers to the insertion of nucleic acids such as DNA or RNA in the body cells of a subject to treat a disease for example. Classically, an intact gene should be inserted into the genome of the target cell in order to replace a defective gene that is the cause of the disease. In humans, gene therapies have been and are partially successful z. B. carried out in the context of clinical studies. Gendicine ( rAD-p53 ) was introduced in China in 2003 as the world's first finished medicinal product .
Within Europe, gene therapeutics belong to the group of advanced therapy drugs (ATMPs). An overview of the gene therapeutics approved in the USA can be found on the website of the Food and Drug Administration (FDA) .
Usually some cells are removed from the body in order to insert the corresponding nucleic acids in the laboratory ( ex vivo ) . The cells can then be multiplied, for example, and then reintroduced into the body. Gene therapy can also take place directly in the body ( in vivo ). Depending on the type of gene therapy and the technology used, the nucleic acid can be integrated into the cell genome or only remain in the cell temporarily. Accordingly, the therapeutic effect can be permanent or temporary.
A distinction must be made between the following mechanisms:
- Gene replacement therapy: Typical areas of application are recessive diseases. Affected patients have two defective copies of a certain gene, which leads to the outbreak of disease. In gene replacement therapy, the therapeutic nucleic acid codes for that very gene, so that treated cells can have and use an intact copy of this gene after therapy.
- Gene editing, e.g. E.g. using Crispr-Cas9 , also known as genome surgery: The aim of this approach is to correct defects in the genome of a cell. This approach can potentially also be used to treat dominant diseases.
- Prosthetic gene therapy: While the two aforementioned methods rely on largely structurally intact target cells, prosthetic gene therapy is intended to enable other cells to take over the function of cells that have died, similar to a prosthesis. An example of this is the "vision restoration" approach to gene therapy.
There are various methods of transferring a therapeutic nucleic acid into a cell:
- Transduction : This is the most widely used method, when a viral vector (a modified virus ) brings the therapeutic sequence into the cell.
- Transfection (chemical): The nucleic acid and an electrically charged compound (e.g. calcium phosphate) are added to the cells. The electrically charged compound binds to the cell membrane and is endocytosed , allowing the vector to enter the cytosol after the endosomal membrane has been perforated .
- Transfection (physical): During electroporation , a current surge makes the cell membrane temporarily permeable so that the vector can penetrate the cell.
- Transfection (physical): The microinjection offers high chances for a successful integration of the gene (approx. 1: 5), but each cell has to be treated individually.
- Sperm-mediated gene transfer in egg cells
Limitations and Risks
The replacement and permanent insertion of an intact gene in the form of DNA has a chance of success only in so-called monogenic diseases. Diseases that are triggered by more complex genetic damage, such as cancer , cannot be treated causally with gene therapy. In Germany and some other countries, gene therapy may only be carried out in the somatic (not affecting the germline ) cells so that the new genetic information cannot be passed on to the children of the person being treated. This legal restriction is based on ethical and safety aspects (see also germ line therapy ). The greatest possible risk of somatic gene therapy is an undirected integration of the donor DNA at an inappropriate location within the genome of the host cell. Since the point of integration cannot yet be foreseen, other previously intact genes can be disturbed in their function. In the worst case, the therapeutic benefit of the new gene could be nullified by a new, possibly more serious disease caused by the disruption of a previously intact gene.
In practice, gene therapy approaches are currently limited to two different cell types : accessible stem cells and long-lived, differentiated, postmitotic cells. Depending on the cell type, different methods of gene therapy are used.
Somatic cells that can be used as vectors for gene therapy with retroviruses must meet certain requirements:
- They have to be tough enough to survive the "infection", but especially the removal from and re-implantation in the body
- They must be easily removable and reusable
- They should be long-lived so that they can produce the new protein for a long time
The following cell types have proven to be suitable:
- Skin cells: fibroblasts from the dermis (out of date)
- Liver cells
- T cells: T lymphocytes (circulating white blood cells) are responsible for the cellular immune response. The lack of the gene for adenosine deaminase (ADA), which leads to a “ severe combined immunodeficiency ” (SCID), is treated by treating these cells accordingly. Another possible therapy is a defect in the common chain of some interleukin receptors, X-SCID .
- Bone marrow stem cells: They produce the red and white blood cells. Genetic diseases of the blood and the immune system can be treated by gene therapy of the rare stem cells. So z. For example, the beta-thalassemia (a lack of β-globin leads to anemia ) by incorporating an "enhancer sequence" treat stem cells (s. U .: Zynteglo).
Applications on the patient
The Gene Therapy Clinical Trials Worldwide database provided by The Journal of Gene Medicine lists over 1500 clinical studies that have been approved to date (as of 2010).
Purification and molecular characterization of cytokines
The purification and molecular characterization of cytokines was researched by Roland Mertelsmann's team . Both interleukin-2 and G-CSF were displayed homogeneously, first translational and clinical studies on cytokines followed. Since experiments in murine models demonstrated that the local secretion of immunity-stimulating cytokines such as interleukin-2 led to the strong activation of the immune system with therapeutic effectiveness, this approach was also followed in humans. These investigations provided one of the foundations for the later, clinically successful gene therapy strategies.
Therapy of SCID
On September 14, 1990, doctors from the US Federal Institute of Health performed the world's first gene therapy treatment on a four-year-old girl. Ashanti DeSilva suffered from severe combined immunodeficiency (SCID), a very rare disease ( incidence 1: 100,000) caused by a severe defect in both the T and B lymphocyte systems . In patients affected by this defect, the function of the immune system is considerably or completely impaired, i. E. In other words, there is little or no immune response - even a cold can kill children. The gene therapy, which has to be repeated several times a year due to the limited lifespan of the leukocytes , enables patients to live without strict quarantine . The gene therapy at Ashanti DeSilva was preceded by a three-year approval process.
The disease X-SCID , which is identical in terms of symptoms and occurs due to mutations in the common chain of some interleukin receptors (γc, CD132 ), was also treated with a gene therapy approach by Alain Fischer in Paris. After the treatment was initially largely successful, leukemia developed in some patients after a while (for details see X-SCID).
Jesse Gelsinger case
In 1999 gene therapy research suffered a setback. Serious complications arose in a series of experiments conducted by the University of Pennsylvania and directed by James M. Wilson.
18-year-old Jesse Gelsinger suffered from a congenital ornithine transcarbamylase deficit . He took part in the last of six test stages as a test subject. The dose of the adenovirus used as a carrier injected into him on September 13 was 38 trillion particles. That is significantly more than is transmitted in natural infections. His condition deteriorated rapidly, so that he died of multiple organ failure on September 17th . At that time, Jesse Gelsinger was the sixth officially reported death worldwide from an artificial adenovirus infection used in gene therapy experiments. In the six cases, according to the director of the experiment, the underlying disease was the cause of death.
The US health authorities then prohibited senior physician James M. Wilson from carrying out any research on humans, among other things because he deliberately violated predetermined requirements. Gelsinger's state of health was stable before the experiment, but his liver values exceeded the maximum limit set by the authorities.
Therapy of HIV-1 infection
By partially removing the co-receptor CCR5 from the genome of CD4-positive T cells using adoptive cell transfer and genome editing , the decrease in the concentration of CD4-positive T cells in the event of an HIV infection can be slowed down.
The end of Glybera
In October 2012, Glybera ( Alipogentiparvovec ) was the first gene therapeutic agent in the western world to receive approval for the treatment of the rare condition of familial lipoprotein lipase deficiency (LPLD) in adults. In November 2015, the National Association of Statutory Health Insurance Funds and Chiesi GmbH, as the licensee of the Dutch company uniQure, agreed on a reimbursement amount for the medicine. In the disease, which is usually diagnosed in childhood, the body does not produce the enzyme lipoprotein lipase. Because fat particles build up in the blood, it looks white. Patients have to abstain from alcohol and sugar for their entire life and suffer from pain caused by inflammation of the pancreas. In April 2017, uniQure announced that it would not extend the approval in the EU. The approval ended on October 25, 2017.
Glybera had been unsuccessfully applied for in the USA . In order to help patients nonetheless, attempts by individual independent biologists began to make the therapy available for around 7,000 instead of 1,000,000 US dollars.
Talimogen laherparepvec (trade name: Imlygic , manufacturer: Amgen ) is used for the oncolytic therapy of malignant melanoma. It is a genetically modified herpes simplex virus type 1 (replication competent). It was approved in the USA in October 2015 and in the EU in December 2015.
Strimvelis (trade name: Strimvelis , manufacturer: GSK ) is an ex vivo gene therapy for ADA-SCID (severe combined immunodeficiency). Autologous (derived from the patient himself), CD34 + -enriched blood stem cells are transduced with a retroviral vector which codes for the human ADA cDNA sequence. The cells, which henceforth express a working version of adenosine deaminase (ADA), are re-injected (transplanted) into the patient. The therapy costs around 600,000 euros per patient, which on the other hand only corresponds to enzyme replacement therapy in around 2 years. It was approved in the EU in May 2016.
Tisagenlecleucel (CTL019) (trade name: Kymriah ; manufacturer Novartis ) is the first CAR-T-cell therapy agent to be approved in the USA for adoptive immunotherapy, specifically against acute lymphoblastic leukemia (ALL). Since this is the first representative of a completely new therapy, it is called first in class . It is the first gene therapy approved in the USA. Kymriah was approved in the EU on August 27, 2018, and subsequently also in Switzerland on October 22, 2018.
On April 22, 2020, the American health authority FDA granted Kymriah the special status of “Regenerative Medicine Advanced Therapy” (RMAT) for drugs that can be used against previously untreatable diseases in the approval process for the treatment of recurrent or therapy-resistant follicular lymphoma.
Novartis set the treatment price at $ 475,000. The Federal Office of Public Health is responsible for setting prices in Switzerland . In March 2019, Novartis and GWQ ServicePlus agreed on a new reimbursement model: Novartis will reimburse part of the drug costs for Kymriah to GWQ if the therapy result "survival" is not achieved within a defined period of time. This " Pay for Outcome " reimbursement is already being used in other indications. However, the patents on Kymriah are controversial; After two NGOs objected, the manufacturer Novartis withdrew a patent.
Voretigen neparvovec (trade name: Luxturna , manufacturer: Spark Therapeutics ) received a unanimous approval recommendation for a hereditary retinal disease for the USA in October 2017 . Luxturna was approved in the United States in December 2017.
It has also been approved in the EU since November 2018. Novartis acquired the therapy from Spark Therapeutics in January 2018 through a license agreement. Novartis is authorized to distribute Luxturna® in all countries outside the United States.
The cost of the Luxturna treatment is estimated at $ 850,000.
Onasemnogene abeparvovec-xioi (trade name: Zolgensma , manufacturer: AveXis , a subsidiary of Novartis ) is an adeno-associated virus vector-based gene therapy that is used for the treatment of pediatric patients up to two years of age with spinal muscular atrophy (SMA) type 1 , with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene. Zolgensma received FDA approval in May 2019. The high-priced gene therapeutic agent was approved in the EU at the end of May 2020. In March 2020, the European Medicines Agency issued a positive opinion (ie a recommendation for approval) for the EU.
In August 2019, the US health authority accused Novartis of having withheld test results in the approval process. In January 2020, Novartis announced that it would be giving away 100 treatments. "There are no reasons to contradict the compassionate use program ," the Paul Ehrlich Institute is quoted as saying on SPON , although Zolgensma was not yet approved in Europe at the time.
Comparative studies with the approved therapy with Nusinersen (trade name: Spinraza, Biogen ) regarding effectiveness and safety do not exist. In Spinraza it is not a gene therapy. Therefore - in contrast to Zolgensma - it has to be given quarterly. Gene therapy sees the one-time treatment; H. Healing before. In May 2020 the authors of the Süddeutsche Zeitung Astrid Viciano and Michele Catanzaro dealt with the pricing of Zolgensma .
Axicabtagene Ciloleucel (trade name: Yescarta ; manufacturer Kite Pharma , a subsidiary of Gilead Sciences ) is the second CAR-T-cell therapy agent that is used for treatment in both the US (October 2017) and the EU (August 2018) of B-cell lymphomas . In March 2020, the pharmaceutical company Bristol-Myers Squibb (as legal successor to Juno Therapeutics ) was awarded a claim for damages in the amount of 1.2 billion US dollars due to patent infringements . Gilead announced that it would object to this.
Since January 2020, it has been possible to treat a form of the rare hereditary disease transfusion-dependent β-thalassemia (TDT) with the gene therapy Zynteglo (autologous CD34 + cells that code for the β A-T87Q -globin gene). The manufacturer is the US pharmaceutical company bluebird bio . Germany is the first country where this treatment is available.
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- Hemophilia : In an audio interview in the NEJM : “Most will agree that therapies that only have to be administered once are preferable to repeated medication. Therefore, the expectation is that the long-term benefits of these one-off therapies will justify the high costs. ”The interview partners also cite haemophilia as an example: the standard treatment“ can cost US $ 400,000 and more per year and patient. ” BioMarin launched one at the end of 2019 Approval for their gene therapy ( valoctocogene roxaparvovec ) requested from the FDA. According to the Wallstreet Journal , BioMarin is aiming for a price of between USD 2 and 3 million for Valrox on the grounds that this cure eliminates future therapy costs.
- Novartis acquired AveXis in 2018 for $ 8.7 billion.
- The Philadelphia- based US company Spark Therapeutics was acquired by Roche for $ 4.8 billion in 2019 . The takeover required the approval of the US antitrust authority FTC ; thus the purchase dragged on for around ten months.
- In November 2019, Ferring founded a new company, FerGene, to develop and commercialize Nadofaragene firadenovec , which is still under development , intended for the treatment of bladder cancer patients who are non-responders to Bacillus Calmette-Guérin . The FDA has accepted the Biologics License Application / BLA and granted priority review for Nadofaragene firadenovec.
- In November 2019, the Japanese pharmaceutical company Astellas announced that it would take over gene therapy company Audentes for $ 3 billion.
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