2021 Current Status and Market Outlook of Cell and Gene Therapy
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2021 Current Status and Market Outlook of Cell and Gene Therapy
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2021 Current Status and Market Outlook of Cell and Gene Therapy.
Cell therapy refers to the transplantation or transfusion of normal or bioengineered human cells into the patient’s body.
The newly transfused cells can replace damaged cells or have a stronger immune killing function, so as to achieve the purpose of treating diseases.
Generally speaking, cell therapy mainly includes tumor cell immunotherapy and stem cell therapy.
Cell therapy has broad prospects in the treatment of cancer, blood diseases, cardiovascular diseases, diabetes, and Alzheimer’s disease.
- Tumor cell immunotherapy refers to the acquisition of immune cells from the patient’s body, and then culture and expansion in vitro, and then return to the patient’s body to stimulate and enhance the body’s autoimmune function to treat tumors, mainly including:
- adoptive cellular immunotherapy,
- tumors Vaccines,
- non-specific immune stimulation and immune checkpoint blocking therapy,
- adoptive cell immunotherapy includes:
- tumor infiltrating lymphocyte (TIL) therapy,
- TCR-T cell therapy, CAR-T cell therapy,
- lymphokine activated killer cell (LAK) therapy ,
- Cytokine-induced killer cell (CIK) therapy,
- dendritic cell therapy
- natural killer cell (NK) therapy.
- Stem cell therapy uses the self-renewal ability and differentiation potential of stem cells to treat blood system diseases, nervous system diseases, cardiovascular diseases, liver diseases, endocrine diseases and other diseases.
Scanning electron micrograph of human T cells from the immune system of a healthy donor. The picture is from NIAID.
Gene therapy refers to the transfer of foreign normal genes to target cells to correct or compensate for diseases caused by defective and abnormal genes to achieve the purpose of treatment.
The target gene transfer methods used in gene therapy so far can be divided into two categories: viral methods and non-viral methods.
In the viral method of gene transfer, both RNA and DNA viruses can be used as vectors for gene transfer, and retroviral vectors and adenovirus vectors are commonly used.
The basic process of transfer is to recombine the target gene into the viral genome, and then infect the host cell with the recombinant virus so that the target gene can be integrated into the host genome.
Non-viral methods include calcium phosphate precipitation, liposome transfection, and microinjection.
In 2021, scientists have made significant progress in the field of gene therapy and cell therapy. Let us take a look at the important progress made in this field in this year.
1. New progress in cell therapy
(1) Reveal the rare side effects of CAR-T cell therapy.
In December 2021, Oliver Van Oekelen and others reported for the first time that they have completed a course of CAR-T cell therapy (BCMA CAR-T) targeting BCMA More than three months later, a patient with multiple myeloma began to experience progressive neurological symptoms similar to Parkinson’s disease, including tremors and changes in handwriting and gait.
Evidence of the presence of BCMA protein was found in the basal ganglia of the patient, and scars were found in this area, indicating that BCMA CAR-T cells can cross the blood-brain barrier in at least some patients, causing progressive neurocognition And movement disorders.
Therefore, although CAR-T cell therapy is effective for multiple myeloma, its neurotoxicity needs to be closely monitored [1].
(2) Exploring the causes of T cell failure
CAR-T cells are not as effective for cancers that form solid tumors as they are for treating blood cancers. This is because when T cells are exposed to their target antigens for too long (about a few weeks), they will trigger failure. , They usually do in the case of solid tumors. In December 2021, Charly R.
Good and others designed CAR-T cells that target a cell marker called mesothelin and exposed these T cells to pancreatic tumor cells that express mesothelin. 4 weeks. After 4 weeks, CAR-T cells showed typical signs of failure, and signs of T cells turning into natural killer cells (NK cells) were found in CAR-T cells from cancer patients in a state of failure.
They observed that CAR-T cell failure was accompanied by a surge in the levels of two proteins ID3 and SOX4, which act as master switches for a large number of genes in immune cells.
Silencing these two obvious T cell failure switches allows CAR-T cells in a depleted state to maintain most of the tumor killing power even after long-term exposure to tumor cells [2].
Electron micrograph of human lymphocytes. Picture from Dr. Triche/National Cancer Institute.
CAR-T cells may also experience T cell failure when treating blood cancers. In November 2021, Caitlin Zebley and others performed a longitudinal genome-wide DNA methylation analysis of CD8+ CAR-T cells targeting CD19 that were infused to patients with acute lymphoblastic leukemia (ALL).
They report that CAR-T cells undergo rapid and extensive reprogramming of inhibitory DNA methylation on effector-related genes.
The changes of CAR-T cells after infusion are further manifested in the suppression of genes related to memory potential (such as TCF7 and LEF1), and genes related to DNA methylation characteristics (such as demethylation of CX3CR1, BATF and TOX) ) Is inhibited, which marks the transition to exhaustion-progenitor T cells.
Therefore, CAR-T cells have undergone DNA methylation procedures related to exhaustion, so preventing this process may be an attractive method to improve the efficacy of CAR-T cells [3].
In November 2021, Brooke Prinzing and others determined how an epigenetic program drives T cell failure.
By evaluating human CAR-T cells that target a range of tumor antigens in different solid tumor models, they found that indeed knocking out the DNMT3A gene generally retains their ability to attack cancer cells, no matter which tumor type or antigen they target.
This highlights the central role of DNMT3A in controlling the function of human CAR-T cells. These findings lay the foundation for early-stage clinical testing in the future [4].
(3) Improve the curative effect of
CAR-T cells CAR-T cells usually target antigens on the surface of cancer cells, and cannot target antigens in cancer cells.
In October 2021, Mark Yarmarkovich and others developed a new cancer treatment method that targets proteins in tumor cells that are essential for tumor growth and survival in response to this.
Using the power of large data sets and advanced computing methods, they can identify peptides present on the surface of tumor cells, and can use peptide-centric chimeric antigen receptors. Antigen receptor, PC-CAR) T cells (PC-CAR T cells) target them.
PC-CAR T cells are a new type of genetically modified T cells that can stimulate immune responses and eliminate tumors.
This discovery opens the door to the treatment of a wider range of cancers with immunotherapy and the application of each therapy in a larger proportion of the population [5].
T cell, the picture comes from CC0 Public Domain.
In October 2021, Edikan A. Ogunnaike and others used a high concentration of human fibrinogen, converted it into fibrin with enzymes, and developed a porous fibrin gel using the fibrin produced , And then let this porous fibrin gel mixed with CAR-T cells and placed in the brain area after surgery.
This gel forms a net-like fibrin scaffold in the brain. In this fibrin scaffold, CAR-T cells evenly wrap themselves in the pores of the scaffold. Of the 14 postoperative mice with glioblastoma that were given this gel and CAR-T cells, 9 (64%) had no tumors after 94 days of treatment, and only CAR-T cells were given.
This is true for 2 out of 10 post-operative mice (20%) with glioblastoma [6].
In September 2021, Koichi Hirabayashi and others discovered a newly developed CAR-T cell immunotherapy that uses genetically modified T cells to target and attack two antigens on cancer cells.
The mice are very effective. This dual targeting limits the re-growth of tumors and prevents neuroblastoma cells from evading these aggressive T cells [7].
In August 2021, Lexus R. Johnson and others found that RN7SL1 can improve the function of CAR-T cells themselves. CAR-T cells expressing RN7SL1 have additional advantages, that is, longer duration, better tumor infiltration, less functional failure, and greater anti-tumor function [8].
At the same time, Yun Qu et al. genetically modified CAR-T cells to release more adenosine deaminase (ADA), which disrupted the tumor’s immunosuppressive microenvironment.
This effectively reduces T cell exhaustion, thereby helping these cells maintain their cancer-killing ability [9].
The genetically modified Pmel-1 T cells enhance adoptive cell therapy in a high tumor burden environment. Picture from Nature Biomedical Engineering, 2021, doi:10.1038/s41551-021-00781-2.
In August 2021, Ian C. Miller and others added a gene switch to CAR-T cells and developed a remote control system to accurately deliver these genetically modified T cells into immunosuppressive tumors in mice In the microenvironment, where they kill tumors and prevent recurrence.
Laser pulses were irradiated to the location of the tumor from outside the body of these mice. The gold nanorods delivered to the tumor convert light waves into local mild heat, raising the temperature to 40-42 degrees Celsius, which is just enough to activate this gene switch of CAR-T cells, but it will not be so hot that it damages healthy tissues and these passing genes.
Transformed T cells. Once turned on, CAR-T cells begin to kill tumors and prevent cancer recurrence [10].
At the same time, Yiqian Wu et al. injected the redesigned CAR-T cells that express the CAR protein only when heated to the tumor of the mouse, and then placed a small ultrasound transducer on the skin area above the tumor. To activate CAR-T cells.
This ultrasound transducer uses a so-called focused ultrasound beam to focus or concentrate short pulses of ultrasound energy on the tumor.
This causes the tumor to warm up to 43 degrees Celsius moderately without affecting the surrounding tissues. This new experimental therapy significantly slowed the growth of solid cancer tumors in mice [11].
In March 2021, Yue Liu and others designed a synthetic T cell receptor (Synthetic T cell receptor) and an antigen receptor (Antigen Receptor).
After genetic modification, T cells expressing these two receptors (ie STAR-T cell) combines the characteristics of CAR-T cells, but adds an internal signal transduction mechanism to simulate natural T cells.
In a variety of mouse models, compared with CAR-T cells, STAR-T cells can better control a variety of solid tumor types without failing [12].
Schematic diagram of the structure of TCR, CAR and STAR receptors. The picture is from Science Translational Medicine, 2021, doi:10.1126/scitranslmed.abb5191.
In February 2021, Rogelio A. Hernandez-Lopez and others were inspired by the natural hypersensitivity reaction circuit and designed a two-step positive feedback loop that allows CAR-T cells to distinguish target antigens based on the antigen density threshold.
In this loop, the low-affinity synthetic Notch receptor of HER2 controls the expression of the high-affinity CAR of HER2.
Therefore, increasing the density of HER2 has a synergistic effect on CAR-T cells, that is, increasing CAR expression and activation.
This method allows CAR-T cells to distinguish the expression level of the same target protein in different cells, so that they only kill cancer cells, and spare healthy cells with the same protein markers as cancer cells [13].
In January 2021, Max Jan and others used the commonly used anticancer drug lenalidomide to construct an “ON” switch and an “OFF” switch for CAR-T cells to regulate the activity of these cells.
They found that administering the commonly used anticancer drug lenalidomide can control the effector functions of CAR-T cells with “ON” switches and CAR-T cells with “OFF” switches.
In the future, people are expected to use this new switchable cell therapy to treat diseases while reducing toxic side effects [14].
2. New advances in gene therapy
(1) Gene therapy is expected to treat a series of diseases.
In December 2021, two studies published in the international journal NEJM reported that a gene therapy called LentiGlobin can enable patients undergoing one-time surgical treatment.
The blood function of patients with sickle cell disease has returned to normal. These patients are now able to produce a stable number of normal red blood cells containing healthy hemoglobin.
In addition, these patients have not suffered from the severe pain episodes caused by sickle cell disease.
Although these two studies have revealed the potential and therapeutic effect of LentiGlobin therapy in the treatment of sickle cell disease, it is also necessary to clarify the potential risks it may bring [15] [16].
In November 2021, a new phase 1/2 clinical study reported a new gene therapy for the treatment of hemophilia A (hemophilia A, also known as factor VIII deficiency)—injection of SPK-8011 (one A new type of recombinant AAV vector, which is modified to produce FVIII in the host’s liver cells)—causing the continuous expression of coagulation factors lacking in patients with this disease in the body, thereby reducing—in some cases completely Eliminated—painful and potentially life-threatening bleeding events.
This is the first time that patients with hemophilia A have maintained stable factor VIII levels after receiving gene therapy [17].
The coagulation factor Ⅷ activity of 18 participants after SPK-8011 input, the picture is from NEJM, 2021, doi:10.1056/NEJMoa2104205.
In November 2021, Patricia González-Rodríguez and others found that mitochondria in dopamine-releasing neurons suffered damage-the loss of functional mitochondrial complex I (mitochondrial complex I, MCI)-was enough to cause Parkinson’s disease, and Gene therapy targeting the substantia nigra effectively improves the efficacy of levodopa in relieving symptoms [18].
In July 2021, Xinzheng Guo et al. used CaMKII active antibody markers and found that whenever retinal ganglion cells are exposed to toxins or the optic nerve is traumatized by crush injury, the CaMKII pathway signal will be damaged, which indicates that CaMKII activity and There is a correlation between the survival of retinal ganglion cells.
When looking for a method of intervention, they found that activating the CaMKII pathway with gene therapy proved to have a protective effect on retinal ganglion cells.
Gene therapy on mice before toxic stimulation (causing rapid damage to these cells) and after suffering from optic nerve crush (causing slower damage) increased the activity of CaMKII and strongly protected retinal ganglion cells[ 19].
In February 2021, Aneal Khan et al. used autologous lentivirus-mediated CD34+ in a single-arm pilot study (NCT02800070) in 5 adult male patients with type 1 (classical) Fabry disease.
Gene therapy of hematopoietic stem/progenitor cells, these cells can be modified to express α-galA.
The results showed that there were no serious adverse events (AE) caused by the experimental drug. The α-galA produced by all patients within a week was close to the normal level.
The study revealed that gene therapy may be an effective treatment option for patients with Fabry disease, but more studies are needed to verify [20].
Schematic diagram of nodulin and cTuberin protein. The picture is from Science Advances, 2021, doi:10.1126/sciadv.abb1703.
In January 2021, Pike-See Cheah and others developed a form of gene therapy in a mouse tuberous sclerosis model: using a condensed form of tuberin (cTuberin). DNA adeno-associated virus vector (AAV).
The average survival time of these mice receiving this gene therapy was extended to 462 days, and their brains showed signs of reduced damage [21].
(2) New delivery platform
In September 2021, Mohammadsharif Tabebordbar and others developed a new adeno-associated virus (AAV) family, which improved the targeting of muscle tissue, which may be safer and more secure for patients with muscle diseases. efficient.
This group of viral vectors (which they call MyoAAV) reaches muscles more than 10 times more efficiently than viral vectors currently used in clinical trials, and avoids the liver to a large extent.
They found that due to this increase in efficiency, MyoAAV can be used to deliver therapeutic genes at a dose that is about 100 to 250 times lower than viral vectors used in other studies and clinical trials, potentially reducing the risk of liver damage and other serious side effects [ twenty two].
The fully assembled SEND protective capsule is released from the cells and can be used for gene therapy after collection. The picture comes from McGovern Institute.
In August 2021, Michael Segel and others developed a platform for delivering molecular drugs to cells. The platform is called SEND, which can be programmed to package and deliver different RNA cargoes.
SEND uses natural proteins in the body to form virus-like particles and bind RNA, and it may cause fewer immune responses than other delivery methods. Using this platform, people are expected to develop better gene therapies to treat diseases [23].
(3) Use gene editing to develop gene therapy.
In April 2021, F. Chemello and others successfully adopted a new type of gene therapy to treat Duchenne muscular dystrophy (Duchenne muscular dystrophy, DMD, also translated as Du Xing’s Muscular dystrophy) mice, using CRISPR-Cas9-based tools to restore a large portion of the dystrophin protein that is missing in many DMD patients.
This method may develop a method for the treatment of DMD and provide a reference for the treatment of other genetic diseases [24].
In January 2021, Luke W. Koblan and others used an adeno-associated virus (AAV)-based vector to deliver enzymes encoding base editing to mice with progeria, and the treated mice could Avoid the occurrence of this disease.
With the help of this technology, people are finally expected to correct a series of human genetic diseases, including progeria [25].
TwinPE mediates sequence replacement of CCR5. The picture is from Nature Biotechnology, 2021, doi:10.1038/s41587-021-01133-w.
In December 2021, Andrew V. Anzalone and others developed a new version of lead editing: twin prime editing (twin prime editing, twinPE), which can integrate or replace gene-sized DNA sequences.
They used twinPE technology to perform two adjacent lead edits, introducing a larger DNA sequence at a specific location in the genome, and at the same time rarely produced unwanted by-products.
With further development, this technology may be used as a new gene therapy to insert therapeutic genes in a safe and highly targeted manner to replace mutated or missing genes [26].
(4) Control the expression level of therapeutic genes
In July 2021, Alex Mas Monteys and others developed a “dimmer switch” system (“dimmer switch” system) based on an alternative RNA using small molecules of oral drugs Splicing technology can control the level of protein expressed by gene therapy vectors;
it can make the RNA in gene therapy vectors inactive, and the addition of small drug molecules can promote the splicing of the carried RNA to form its active form [27 ].
3. Gene therapy and cell therapy market outlook
Globally, cell therapy and gene therapy have and are changing the way humans treat a series of diseases. By the end of 2019, more than 27 cell therapy/gene therapy products have been launched globally, and nearly 1,000 companies are engaged in the R&D and commercialization of this area.
The global cell therapy/gene therapy is expected to reach US$20 billion in 2021.
According to Evaluate Pharma’s forecast, the global market for cell therapy, gene therapy, and nucleic acid therapy will grow from US$1 billion in 2017 to US$44 billion in 2024, with a compound annual growth rate of up to 65%.
With such a market value estimate, in the past few years, gene therapy and gene therapy have become and will continue to be one of the most concerned pharmaceutical fields [28].
The market size trend chart of cell therapy, gene therapy and nucleic acid therapy products, data source: BioPharmaDealmakers[28]; EvaluatePharma, March 2019.
In cell therapy, CAR-T cell therapy, TCR-T cell therapy and stem cell therapy have great development prospects and market potential.
As far as CAR-T cell therapy is concerned, 6 CAR-T cell therapies have been launched globally. They are Novartis’ Kymriah, Gilead’s Yescarta and Tecartus, BMS’s Breyanzi and Abecma, and China Fosun Kate’s CAR-T cell therapy product Yiqililunsai injection (also known as Akilunsai injection, trade name: Yikaida).
Among them, the first four cell therapies all target CD19 and are used to treat diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and mantle cell lymphoma; Abecma, which was launched in March 2021, targets BCMA for Treat multiple myeloma.
For the treatment of adult patients with relapsed or refractory large B-cell lymphoma after second-line or above systemic treatment. Yikaida, launched in June 2021, is used to treat adult patients with relapsed or refractory large B-cell lymphoma after second-line or above systemic treatment.
With the development of gene therapy, the safety and effectiveness of vectors used in gene therapy products have gradually improved.
As of the end of 2019, there have been more than 20 gene therapy products on the market worldwide.
Gene therapy products approved by the U.S. FDA include Vitravene, Macugen, Rexin-G, Kynamro, Imlygic, Exondys51, Spinraza, Defibrotide, Luxturna, Patisiran, Zolgensma, Kymriah and Yescarta; gene therapy products approved by the European Union include Vitravene, Glybera, Spinraza, Defibrotide, Luxturna, Patisiran, Strimvelis and Zalmoxis; gene therapy products approved for marketing in China include Gendicine and Oncorine; gene therapy products approved for marketing in Russia include Neovasculgen; gene therapy products approved for marketing in South Korea include Invossa[29].
In the future, with new breakthroughs in different fields such as molecular biology, gene, protein and omics, scientists will develop more and more cell therapy products and gene therapy products to treat HIV infection, cancer, and blood system. A series of diseases such as diseases, neurological diseases and genetic diseases.
references:
1.Oliver Van Oekelen et al. Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy. Nature Medicine, 2021, doi:10.1038/s41591-021-01564-7.
2. Charly R. Good et al. An NK-like CAR T cell transition in CAR T cell dysfunction. Cell, 2021, doi:10.1016/j.cell.2021.11.016.
3.Caitlin C. Zebley et al. CD19-CAR T cells undergo exhaustion DNA methylation programming in patients with acute lymphoblastic leukemia. Cell Reports, 202, doi:10.1016/j.celrep.2021.110079.
4.Brooke Prinzing et al. Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity. Science Translational Medicine, 2021, doi:10.1126/scitranslmed.abh0272.
5. Mark Yarmarkovich et al. Cross-HLA targeting of intracellular oncoproteins with peptide-centric CARs. Nature, 2021, doi:10.1038/s41586-021-04061-6.
6. Edikan A. Ogunnaike et al. Fibrin gel enhances the antitumor effects of chimeric antigen receptor T cells in glioblastoma. Science Advances, 2021, doi:10.1126/sciadv.abg5841.
7. Koichi Hirabayashi et al. Dual-targeting CAR-T cells with optimal co-stimulation and metabolic fitness enhance antitumor activity and prevent escape in solid tumors. Nature Cancer, 2021, doi:10.1038/s43018-021-00244-2.
8. Lexus R. Johnson et al. The immunostimulatory RNA RN7SL1 enables CAR-T cells to enhance autonomous and endogenous immune function. Cell, 2021, doi:10.1016/j.cell.2021.08.004.
9. Yun Qu et al. Adenosine Deaminase 1 Overexpression Enhances the Antitumor Efficacy of Chimeric Antigen Receptor-Engineered T Cells. Human Gene Therapy, 2021, doi:10.1089/hum.2021.050.
10. Ian C. Miller et al. Enhanced intratumoural activity of CAR T cells engineered to produce immunomodulators under photothermal control. Nature Biomedical Engineering, 2021, doi:10.1038/s41551-021-00781-2.
11. Yiqian Wu et al. Control of the activity of CAR-T cells within tumours via focused ultrasound. Nature Biomedical Engineering, 2021, doi:10.1038/s41551-021-00779-w.
12. Yue Liu et al. Chimeric STAR receptors using TCR machinery mediate robust responses against solid tumors. Science Translational Medicine, 2021, doi:10.1126/scitranslmed.abb5191.
13. Rogelio A. Hernandez-Lopez et al. T cell circuits that sense antigen density with an ultrasensitive threshold. Science, 2021, doi:10.1126/science.abc1855.
14. Max Jan et al. Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide. Science Translational Medicine, 2021, doi:10.1126/scitranslmed.abb6295.
15. Sunita Goyal et al. Acute Myeloid Leukemia Case after Gene Therapy for Sickle Cell Disease. New England Journal of Medicine, 2021, doi:10.1056/NEJMoa2109167.
16.Julie Kanter et al. Biologic and Clinical Efficacy of LentiGlobin for Sickle Cell Disease. New England Journal of Medicine, 2021, doi:10.1056/NEJMoa2117175.
17. Lindsey A. George et al. Multiyear Factor VIII Expression After AAV Gene Transfer for Hemophilia A. NEJM, 2021, doi:10.1056/NEJMoa2104205.
18. Patricia González-Rodríguez et al. Disruption of mitochondrial complex I induces progressive parkinsonism. Nature, 2021, doi:10.1038/s41586-021-04059-0.
19. Xinzheng Guo et al. Xinzheng Guo et al. Preservation of vision after CaMKII-mediated protection of retinal ganglion cells. Cell, 2021, doi:10.1016/j.cell.2021.06.031.
20. Aneal Khan et al. Lentivirus-mediated gene therapy for Fabry disease. Nature Communications, 2021, doi:10.1038/s41467-021-21371-5.
21. Pike-See Cheah et al. Gene therapy for tuberous sclerosis complex type 2 in a mouse model by delivery of AAV9 encoding a condensed form of tuberin. Science Advances, 2021, doi:10.1126/sciadv.abb1703.
22. Mohammadsharif Tabebordbar et al. Directed evolution of a family of AAV capsid variants enabling potent muscle-directed gene delivery across species. Cell, 2021, doi:10.1016/j.cell.2021.08.028.
23. Michael Segel et al. Mammalian retrovirus-like protein PEG10 packages its own mRNA and can be pseudotyped for mRNA delivery. Science, 2021, doi:10.1126/science.abg6155.
24. F. Chemello et al. Precise correction of Duchenne muscular dystrophy exon deletion mutations by base and prime editing. Science Advances, 2021, doi:10.1126/sciadv.abg4910.
25. Luke W. Koblan et al. In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice. Nature, 2021, doi:10.1038/s41586-020-03086-7.
26. Andrew V. Anzalone et al. Programmable deletion, replacement, integration and inversion of large DNA sequences with twin prime editing. Nature Biotechnology, 2021, doi:10.1038/s41587-021-01133-w.
27. Alex Mas Monteys et al. Regulated control of gene therapies by drug-induced splicing. Nature, 2021, doi:10.1038/s41586-021-03770-2.
28.Next-generation therapeutics: cell and gene therapy gathers pace
https://www.nature.com/articles/d43747-020-00715-y
29.Gene Therapy Arrives
https://www.nature.com/articles/d41586-019-03716-9
2021 Current Status and Market Outlook of Cell and Gene Therapy
(source:internet, reference only)
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