Abstract
Gene therapy has shown great potential for the treatment of diseases that previously were either untreatable or treatable but not curable with conventional schemes. Recent progress in clinical gene therapy trials has emerged in various severe diseases, including primary immunodeficiencies, leukodystrophies, Leber’s congenital amaurosis, haemophilia, as well as retinal dystrophy. The clinical transformation and industrialization of gene therapy in Asia have been remarkable and continue making steady progress. A total of six gene therapy-based products have been approved worldwide, including two drugs from Asia. This review aims to highlight recent progress in gene therapy clinical trials and discuss the prospects for the future in China and wider Asia.
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Introduction
Gene therapy may be defined as a treatment in which genetic material is introduced into a cell, to enhance the effect of functional genes or modify malfunctioning genes. Gene therapy was originally conceived as a strategy to treat monogenic diseases, but it has expanded its application spectrum to many other conditions including cancer1, 2 and infectious diseases,3, 4 well beyond the primary immunodeficiencies.5, 6 Both ex vivo and in vivo strategies have been used in clinical trials (Figure 1). In 1990, the first gene therapy clinical trial, targeting adenosine deaminase deficiency-severe combined immune deficiency disorder (ADA-SCID), was approved by the US Federal Drug Administration. Unfortunately, in 1999, an 18-year-old man died from a severe immune response to the Ad5 vector used in a subsequent clinical trial.7 Fischer et al.10 reported the treatment of SCID-X1 with a Moloney murine leukaemia virus vector in 2003 and, although successful, 3 of 11 patients developed leukaemia.8, 9, 10 These setbacks caused concern and skepticism in gene therapy clinical trials but attitudes are changing gradually. The past two decades have witnessed rapid progress in this field and gene therapy is poised to become a promising approach through its potential to treat a disease at its genetic roots. It was encouraging that gene therapy was selected as one of the runners up to ‘Breakthrough of the year’in 2009 by Science magazine.11 Cancer immunotherapy for eradication of blood cancers using chimeric antigen receptor (CAR)-modified T cells finally achieved ‘Breakthrough of the year’ in 2013.12 These achievements not only depend on the development of gene therapy vector systems but also on the accumulation of clinical experience.
Many gene therapy technologies have been applied in clinical trials. Up to April 2017 (http://www.abedia.com/wiley/), 2463 gene therapy clinical trials had been completed, were ongoing or had been approved worldwide (Figure 2). The United States (64.4%) has conducted most of the trials, followed by Europe (23.7%) and Asia (6.1%). Most gene therapy trials target cancer (64.6%), followed by monogenetic diseases (10.5%), infectious diseases (7.4%) and cardiovascular diseases (7.2%). To date, six gene therapy-based products13, 14, 15, 16, 17, 18 have been approved around the world to target cancer, peripheral arterial disease, lipoprotein lipase deficiency, ADA-SCID, as well as spinal muscular atrophy (Table 1). It is worth mentioning that the approval of Spinraza, a 2′O-methoxyethyl phosphorothioate-modified antisense drug for treatment of patients with spinal muscular atrophy, by the US Federal Drug Administration was an important milestone in gene-based product development.18, 19
The United States has been at the forefront of the gene therapy research and accounts for 62.9% of the world with 1550 clinical trials. The United Kingdom and Germany undertook 8.9% and 3.7% of the total, respectively (Figure 3). China, similar to other countries, has also attached great important to gene therapy and approved the first gene therapy-based product for clinical use in 2003.13 Besides, Chinese scientists were the first to use cells modified using the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 gene-editing technique in a clinical trial.20 These inspiring results suggest that China is becoming a leader in this field, particularly in the industrialization of gene therapy. This review aims to highlight recent progress in gene therapy clinical trials as well as the gene delivery vectors in China and wider Asia.
Number and phase of gene therapy clinical trial in Asia
Up to April 2017, 150 gene therapy clinical trials had been undertaken in Asia (Figure 4), which account for 6.1% of world trials (http://www.abedia.com/wiley/). China undertook the most (70 trials, 68 in mainland China and 2 in Taiwan), closely followed by Japan (42 trials) and South Korea (20 trials). More than two-thirds of gene therapy clinical trials performed in Asia are phase I or I/II. Phase II trials account for 20.6% of the total and phase II/III and III make up only 3.3% of all trials. Two phase IV clinical trials are ongoing at Sichuan University’s West China Hospital in Chengdu for the treatment of thyroid, and oral and maxillofacial malignant tumours, respectively. The two phase IV clinical trials are ‘Open-Label, Multi-Center, Randomized, Active-Controlled, Phase 4 Study of rAd-p53 Gene Mono-Therapy, With Concurrent Radioactive Iodine, or Combination With Surgery in Subjects With Advanced Malignant Thyroid Tumors’ and ‘Open-Label, Multi-Center, Randomized, Active-Controlled, Phase 4 Study of rAd-p53 Gene Mono-Therapy, With Concurrent Chemotherapy, or Combination With Surgery in Subjects With Advanced Oral and Maxillofacial Malignant Tumors.’
Vectors used for gene therapy in Asia
Vector performance has a critical role in gene therapy clinical trials. Effective strategies for clinical gene therapy are largely depending on the vectors, which are responsible for delivering functional genes to target cells or tissues (in vivo) or into autologous cells (ex vivo). In general, there are two approaches to deliver genes into a cell, that is, viral and non-viral. The most popular approach among the many vector systems used in Asia are adenovirus vectors (32%), followed by retrovirus (11.3%) and naked/plasmid DNA vectors (9.3%). Adeno-associated virus vectors make up only 4.7% of total vector systems, but they have demonstrated great clinical application value for in vivo gene delivery.21 It is worth noting that seven trials based on CRISPR-cas9 have been started in Asia from 2017, all of them conducted in China. Advances in vector manufacturing and characterization will improve the safety and efficiency of vector systems in clinical trials.
Diseases targeted by gene therapy in Asia
The majority of gene therapy clinical trials in Asia have addressed cancer (64.7%), cardiovascular diseases and inherited monogenic diseases (Figure 5). In addition, other gene therapy clinical trials have focused on infectious diseases, neurological diseases, as well as ocular diseases.
Cancer
Cancer gene therapy is one of the most active fields, with various cancers having been targeted to date, including haematological, lung, hepatocellular, nasopharyngeal, as well as head and neck cancers.22 The p53 gene is the most commonly mutated gene in human cancer and the most intensively studied tumour suppressor protein in cancer gene therapy.23 The world’s first gene therapy-based product (marketed as Gendicine) is a recombinant adenovirus vector encoding human p53 tumour suppressor gene (rAd-p53).13 It was approved by the State Food and Drug Administration of China in 2003 to treat head and neck squamous cell carcinoma and has been used for the treatment of solid tumours.24 Another gene therapy based product, Oncorine, which is the marketed name of H101 and aims at late-stage refractory nasopharyngeal cancer was approved by State Food and Drug Administration of China 2 years later,14 becoming the first oncolytic virus drug approved in the world. Initially, Oncorine was conceived as an oncolytic virus that would selectively replicate in p53-defective tumour cells. However, subsequent study demonstrated that loss of E1B-55K-mediated late viral RNA export, rather than p53, restricts Oncorine replication in primary cells.25, 26 H101, H102 and H103 make up the H100 series of recombinant oncolytic adenoviruses, and H102 and H103 are also ongoing clinical or preclinical trials in China.
Another gene commonly used in cancer gene therapy experiments is the herpesvirus thymidine kinase gene, which is often termed a suicide gene. Herpes simplex virus thymidine kinase has been used to convert the nontoxic pro-drug ganciclovir into the cytotoxic triphosphate ganciclovir.27, 28 Several clinical trials using adenovirus vectors (ADV-TK) have been completed or are ongoing in Asia. The results demonstrated that ADV-TK can be administered safely to cancer patients and showed therapeutic potential towards malignant tumours, including glioma, hepatocellular carcinoma and head and neck cancer.29, 30, 31
KH901 is a conditionally replicating oncolytic adenovirus, which reportedly selectively replicates in and lyses telomerase-positive tumour cells and expresses granulocyte macrophage colony-stimulating factor.32, 33 A phase I study investigated the therapeutic effect of KH901 in patients with recurrent head and neck cancer and showed that intratumoral administration of KH901 was feasible and well tolerated.34 OrienX010 is a recombinant human granulocyte macrophage colony-stimulating factor herpes simplex virus injection to treat solid tumours such as melanoma, liver cancer and lung cancer. A phase I trial evaluated the safety of the application of OrienX010 and follow-up clinical studies of this product are being planned.35
Endostatin is a broad-spectrum angiogenesis inhibitor and has been used for the treatment of tumours in gene therapy. EDS01 is a recombinant human endostatin adenovirus injection36 that has shown tumour suppressor effect in phase I clinical trials. This product is being tested in a phase II clinical trial at West China Hospital in Chengdu. Another antiangiogenic product is E10A (a recombinant human endostatin adenovirus), for which a phase II clinical trial has demonstrated safety and efficacy in patients with advanced head and neck squamous cell carcinoma or nasopharyngeal carcinoma.37 In addition, heat shock protein 70 (HSP70), Dickkopf-3 (Dkk-3/REIC) and NK4 genes have also been used in cancer gene therapy in Asia.
CARs represent a promising cancer immunotherapy, based on genetic modification of autologous T cells targeting tumour-specific surface antigens.38, 39 It is highly effective at eradicating B-cell leukaemias and lymphomas that are resistant to standard therapies. In contrast, due to the hostile immunosuppressive microenvironment, CAR-T cells show limited therapeutic efficacy in solid tumours. The main challenges of CAR-T therapy for solid tumours are (1) poor infiltration of T lymphocytes into solid tumours, (2) the identification of proper tumour-associated antigens and (3) immunosuppressive environment within solid tumour.40, 41 June and colleagues1 reported a successful clinical trial treating chronic lymphoid leukaemia with a lentiviral vector expressing a CAR with specificity for the B-cell antigen CD19, coupled with CD137 and CD3-zeta signalling domains. Han and collegues42 conducted a clinical trial to assess the efficacy of CD33-directed CAR modified T cells (CART-33) for the treatment of refractory acute myeloid leukaemia. Although the patient died 13 weeks after the CART-33 infusion, the trial provided beneficial experience for further research. Recently, in a phase I clinical trial, Han and collegues43 reported the treatment of relapsed or refractory Hodgkin lymphoma with autologous T Cells expressing CD30 CARs. Of 18 patients, 7 achieved partial remission and 6 achieved stable disease. These results guarantee a large-scale patient recruitment for further research.44 Besides, they investigated CART cocktail immunotherapy targeting epidermal growth factor receptor and CD133 in a patient with advanced cholangiocarcinoma. The results suggested that CART cocktail immunotherapy may be feasible for the treatment of cholangiocarcinoma as well as other solid malignancies.45 Recently, Qian and colleagues46 investigated a CAR-T therapy targeting carcino-embryonic antigen-positive colorectal cancer patients with metastases and they observed efficacy in most patients.
Advances in gene-editing technologies also help expand the spectrum of diseases that can be targeted by gene therapy. Particularly worth mentioning is the development and application of CRISPR-Cas9 in preclinical and clinical trials.47, 48 Testing the CRISPR-Cas9 gene-editing technique in patients with lung cancer has received ethical approval at West China Hospital. Thus, Chinese scientists have been the first to inject people with cells modified using CRISPR-Cas9.
Cardiovascular diseases
Cardiovascular diseases such as critical limb ischaemia, ischaemic heart disease and intermittent claudication, always have poor prognosis and adversely influence patients’ quality of life. A large proportion of cardiovascular gene therapy trials have been designed to increase blood flow to ischaemic regions. The fibroblast growth factor, vascular endothelial growth factor and hepatocyte growth factor (HGF) have been most widely applied in Asia. A Phase I/IIa open-label clinical trial reported the potential therapeutic efficacy of DVC1-0101 in critical limb ischaemia patients.49 DVC1-0101 is a non-transmissible recombinant Sendai virus vector expressing human fibroblast growth factor-2. DVC1-0101-based gene therapy was effective and could significantly improve limb function as well as patients’ quality of life over a 6-month period.50 In addition, studies in animal models and a phase I clinical trial have demonstrated the safety and effectiveness of adenovirus-HGF in inducing angiogenesis.51, 52, 53, 54 A phase II clinical trial has been conducted in China to investigate the safety and efficiency of adenovirus-HGF for the treatment of ischaemic heart disease. Several other gene therapy-based products tested in clinical trials such as NL003/VM202RY (a DNA plasmid that contains human HGF coding sequence) and VMDA-3601 (a DNA plasmid that contains human vascular endothelial growth factor coding sequence) also showed promising results.
Monogenic diseases
Following US Federal Drug Administration approval of the first gene therapy trial to treat ADA-SCID in 1990, genetically modified autologous T lymphocytes transduced with the human ADA cDNA were successfully transferred in Japan in 1997.55 The patient’s immune function improved after periodic infusions. Given the risk of development of T-cell leukaemia due to insertional mutagenesis caused by the retroviral vector, autologous CD34+ cells were used to increase safety in a phase I trial. Haemophilia is another monogenetic disease, caused by dysfunction of the coagulation proteins factor VIII (haemophilia A) or factor IX (haemophilia B). As early as 1996, Chinese scientists reported the treatment of haemophilia B with autologous skin fibroblasts transduced with a human clotting factor IX cDNA.56 Other gene therapy trials aimed at monogenetic diseases such as granular corneal dystrophy, retinitis pigmentosa, familial lecithin–cholesterol acyltransferase deficiency, as well as chronic granulomatous disease are ongoing in Asia.
Neurological diseases
Metachromatic leukodystrophy is an autosomal recessive disease caused by a deficiency in the enzyme arylsulfatase A, whereby the enzyme activity in leukocytes is less than 10% of normal cells.57 Adrenoleukodystrophy is a disease linked to the X chromosome caused by a deficiency in adrenoleukodystrophy protein.58 Targeting of the haematopoietic compartment has shown promising results in the treatment of metachromatic leukodystrophy and adrenoleukodystrophy. In China, a phase I/II clinical trial using haematopoietic stem cells (HSCs) genetically modified with a lentivirus vector has been approved for the treatment of metachromatic leukodystrophy and adrenoleukodystrophy.
Parkinson’s disease is a common neurodegenerative disorder that mainly affects the motor system. Aminoacid decarboxylase is an important enzyme in the biosynthesis of dopamine, which functions as a neurotransmitter.59, 60 Children with defects in the aminoacid decarboxylase gene show compromised development, particularly in motor function.61 Tyrosine hydroxylase and cyclohydrolase 1 are also important enzymes in the synthesis of dopamine. Increasing the expression of dopamine-synthesizing enzymes is a promising strategy in gene therapy. ProSavin is a lentiviral vector encoding the dopamine biosynthetic enzymes tyrosine hydroxylase, aminoacid decarboxylase and cyclohydrolase 1. A phase I/II clinical trial has reported the safety of ProSavin and improvement in motor behaviour was observed in patients.62 In Asia, Wu and colleagues63 have reported the treatment of four children 4 to 6 years of age with Adeno-associated virus vector encoding human aminoacid decarboxylase gene, and all of the patients showed increased dopamine level and improvements in motor behaviour.
Infectious diseases
Various gene therapy approaches are being used for the treatment of infectious diseases in Asia, including HIV and hepatitis B. A phase I clinical trial using a prime-boost vaccine strategy to induce both humoral and cell-mediated immunity in HIV-infected patients is ongoing at Beijng Ditan Hospital of Capital Medical University Beijing in China. This vaccine is based on naked/plasmid DNA combined with modified vaccinia virus Ankara and is expected to increase the level of HIV-specific immune responses. In South Korea, a phase I clinical trial investigated the safety and efficacy of GX-12, a genetic vaccine including naked DNA with HIV-1 antigen genes and human interleukin-12 mutant as immune adjuvant in HIV-infected patients with highly active antiretroviral therapy. However, to date, with the exception of the Berlin patient case, no gene therapy approach has fully cured HIV-infected patients.64
HB-110 is a therapeutic DNA vaccine against chronic hepatitis B, including the HBV envelope proteins, core protein, polymerase and human interleukin-12.65 Its safety and immunogenicity have been evaluated in a phase I clinical study in South Korea. HB-110 was safe and well tolerated in chronic hepatitis B patients, but it induced weaker HBV-specific T-cell responses in Korean patients than in Caucasian patients, which may due to the higher level of immune tolerance in Asian patients.66
Challenges and future prospects
China started conducting gene therapy clinical trials in 1987, making up ~46.7% of the total trials in Asia, followed closely by Japan. China approved the first two gene therapy-based products, Gendicine and Oncorine, for clinical use in 2003 and 2005. However, since then, gene therapy seemed to reach a plateau in China, as well as wider Asia. The limited clinical benefits caused concern and skepticism regarding the further development and application of these gene therapy strategies. However, these attitudes are rapidly changing with the emergence of novel genetic technologies, particularly advances in gene-editing and the CAR-T field. However, major challenges must still be addressed to revitalize and promote the development of gene therapy. Lentiviral and Adeno-associated virus vectors should be further optimized to enable cell-type-specific uptake. Advances in vector design could also help to mitigate the risk of insertional mutagenesis in clinical trials. In addition, all vector types likely induce an immune response67 and further advances could also help vectors to circumvent the innate and adaptive immune system.
Gene therapy trials often address rare diseases, but better understanding of disease pathogenesis and the accumulation of clinical experience will help to promote the emergence of novel gene therapy strategies for common diseases. In addition, larger number of patients and longer follow-up periods will be required to validate existing clinical data.
Gene-editing technologies have provided powerful impetus in the further development of gene therapy strategies.68 Zinc finger nucleases were used to disrupt the gene that encodes CCR5 for the treatment of HIV-infected patients.3 The CRISPR-Cas9 system has been tested in animal disease models such as Duchenne muscular dystrophy and haemophilia B.69, 70,71,72 Recently, testing CRISPR-Cas9 in patients with lung cancer has received ethical approval at Sichuan University’s West China Hospital. The recent report entitled ‘Human Genome Editing: Science, Ethics, and Governance’, has provided a first set of guidelines for the application of genome editing in humans.73 Clinical studies of genome editing-based gene therapy will be performed in near future, and ethical and safety issues must be strictly evaluated.
The regenerative potential of stem cells such as HSCs can be critical for improved gene therapy strategies.74 Gene-modified HSCs can function as a long-term source of their gene-corrected progeny in patients. HSC gene therapy can avoid the risk of morbidity due to mismatched human leukocyte antigen between donors and recipients, particularly when no matched HSC donor is available in severe immunodeficiencies such as SCID-X1,75 ADA-SCID76 and Wiskott–Aldrich syndrome.5, 77
Conclusions
Gene therapy research in Asia is on the increase, however, much importance should be attached to narrowing the gap with the United States and Europe. In China, gene therapy-based products are considered as new drugs and the application and management of these products is conducted by State Food and Drug Administration of China. The approval process of phase I gene therapy clinical trials is very strict in China and could be optimized. Gene therapy is widely expected to provide treatments for previously intractable diseases. Although not exempt of setbacks, effective and informative results are being increasingly reported from gene therapy trials. The clinical transformation and industrialization of gene therapy in Asia are considerable and will progress further towards gene-editing tools as well as HSC-based strategies, which will increase precision and efficiency in gene therapy approaches.
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We acknowledge National Natural Science Foundation of China for funding through project number 81472195.
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Deng, HX., Wang, Y., Ding, Qr. et al. Gene therapy research in Asia. Gene Ther 24, 572–577 (2017). https://doi.org/10.1038/gt.2017.62
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DOI: https://doi.org/10.1038/gt.2017.62