Current Gene Therapy

Neurological disorders affecting the central and peripheral nervous systems are still partly understood. Despite advances in the knowledge of nervous system function, treatment of neurological disorders with modern medical as well as surgical procedures remains difficult for several reasons, such as complexity of the central nervous system, low regeneration ability of brain tissue, and difficulty in the blood-brain barrier permeability of drugs. Gene therapy is an emerging approach for the management of neurological disorders. This special thematic issue discusses and explores the currently available and upcoming gene therapy strategies as tools for neuroprotection and neurorestoration in neurological disorders.

Rehman et al. [1] represented the prospects of gene therapy in psychiatric disorders, their benefits, and pitfalls. They also highlight the importance of nanoparticle-based gene therapy for the effective management of psychiatric disorders.

Nabi et al. [2] discussed the different types of gene therapy explored so far for the management of acquired immune deficiency syndrome and its associated neurological conditions. The mechanism related to the activity of the anti-human immunodeficiency virus gene lies in their intrinsic property to impart resistance to the HIV infection by targeting the viral entry channels.

Shah et al. [3] presented the beneficial role of voglibose via in-silico, in-vitro to in-vivo studies in improving the postprandial glycaemic state by protection against stroke-prone type 2 diabetes. In-silico molecular docking and virtual screening studies and in-vivo studies in middle cerebral artery occlusion-induced stroke animal model consequences support the strong antistroke signature for possible neuroprotective therapeutics.

Iqubal et al. [4] elucidated the current status of gene therapy in neurological disorders along with its clinical relevance, challenges, and future prospective. There are some limitations such as immunogenic reactions non-specificity of viral vectors and lack of effective biomarkers to understand the efficacy of therapy are also discussed in their study.

Behl et al. [5] summarized the significant role of glial cell-line derived neurotrophic factor in alleviating motor symptoms and loss of dopaminergic neurons in Parkinson’s disease. The review also focused on the problems and challenges of glial cellline derived neurotrophic factor delivery and essential measures to overcome them.

Agarwal et al. [6] explored the exosome-mediated gene therapy into developing an effective therapy with the refinement of isolation, purification, loading, delivery, and targeting protocols. This appraisal discussed several facets that contribute towards developing an efficient therapeutic regime for gene therapy, highlighting limitations and drawbacks associated with current gene therapy and suggested therapeutic regimes.

The subject of Gene therapy has been blooming for 5 years. Over 10 new gene therapy drugs or products have been authorized by drug regulatory agencies from various countries since Talimogene Laherparepvec (Imlgic) was approved by the United States Food and Drug Administration in 2015 [1, 2]. Gene therapy technology and vectors, including bioinformatics, RNA interference (RNAi), chimeric antigen receptor (CAR) T cells, adeno-associated virus, plasmid and nanoparticle, are utilizing to treat cancer, genetic disorders, arthritis, vascular diseases, etc. In the special issue, experts from the fields mentioned above will provide their opinion or researches on gene therapy [2]. In this thematic issue, Gene Therapy (Part II), gene therapy for cancers, metabolic diseases and genetic diseases were addressed. Molecular targeted therapy and immunotherapy have exhibited good efficacy for various cancers in the clinic. For example, Cabozantinib and Ramucirumab were authorized for the second-line targeted treatment after hepatocellular carcinoma progression on sorafenib, and Nivolumab were approved for the first-line treatment of hepatocellular carcinoma [3]. However, cancer therapy needs to develop new targets and treatments all the same, and gene therapy is a promising approach for cancer therapy. Neurofibromin and cluster of differentiation 24 (CD24) as potential biomarkers and potent targets were reviewed in this thematic issue [4, 5]. Neurofibromin, a tumor suppressor encoded by neurofibromatosis type 1 (NF1) gene, played a critical role in the regulation of cell fate and function. Truncated NF1 sequences could be delivered by viral vectors for gene therapy of NF1, which might improve the outcome of NF1 patients [4]. CD24 was expressed in ovarian cancer, breast cancer, gastric cancer, lung cancer, pancreatic cancer, etc., thus CD24 was an attractive target for cancer therapy. In preclinical studies, CD24 target therapies using monoclonal antibodies, siRNA and shRNA based on RNA interference and cell therapy, have displayed potentials for the anti-tumor application [5]. Considered as the first commercial gene therapy drug in the world, the recombinant human p53 adenovirus particle (Gendicine) has been used for more than 10 years and for 30, 000 patients with advanced lung cancer, advanced liver cancer, gynecological malignant tumor, soft tissue sarcoma, etc. Xia et al. summarized the clinical use and confirmed the efficacy of Gendicine. Furthermore, Gendicine combination regimens had longer progression-free survival times than conventional treatments alone [6]. Therefore, gene therapy should be an alternative for cancer therapy. Both metabolic diseases and genetic diseases are the important indications for gene therapy. For metabolic bone disease - osteoporosis, Li et al. reported that γ-aminobutyric acid (GABA) might promote osteogenic differentiation of mesenchymal stem cells by inducing TNFAIP3. Also, GABA treatment positively regulated osteogenic differentiation by upregulating TNFAIP3, which supplied a potential gene therapy for osteoporosis and low bone mineral density [7]. For genetic disease - hemophilia A, professor Liang’s team reviewed the recent progress of gene therapy for hemophilia A via viral and nonviral delivery vectors, and then discussed the new raising issues involving liver toxicity, pre-existing neutralizing antibodies of viral approach, and the selection of the target cell type for nonviral delivery [8].

Gene therapy has been blooming for 5 years. Over 10 new gene therapy drugs or products have been authorized by drug regulatory agencies from various countries since Talimogene Laherparepvec (Imlgic) was approved by the United States Food and Drug Administration in 2015 [1]. Gene therapy technology and vectors, including bioinformatics, RNA interference (RNAi), chimeric antigen receptor (CAR) T cells, adeno-associated virus, plasmid and nanoparticle, are utilizing to treat cancer, genetic disorders, arthritis, vascular diseases, etc. In this special issue, experts from the fields mentioned above will provide their opinion or researches on gene therapy. In this mini-thematic issue, Gene Therapy (Part I), two parts of research on bioinformatics and one research on clinical data analysis were presented. Bioinformatics was a valuable approach to find potential biomarkers or targets of therapy. In the first research article [2], Chen et al. identified potential prognostic gene markers of malignant skin melanoma by weighted gene coexpression network analysis. CCNB2, ARHGAP30, and SEMA4D could be considered as emerging targets for theranostics of malignant skin melanoma. In the second research article [3], Mo et al. reported the anti-proliferative effects and underlying molecular mechanisms of Caffeic acid phenethyl ester (CAPE) on small cell lung cancer (SCLC). By integrated analysis of mRNA-seq and miRNA-seq, c-MYC, YAP1 and miR-3960 were identified as major players in the anticancer effects of CAPE in human SCLC cells. The finding might be helpful to develop gene therapy for SCLC. Naked plasmid DNA (Collategene) encoding hepatocyte growth factor (HGF) was conditionally approved by the Japanese Ministry of Health, Labour and Welfare in 2019. Dr. Morishita, the inventor of Collategene, provided a manuscript for this mini-thematic issue [4]. In the manuscript, Dr. Morishita and his team analyzed data from 5 clinical trials on HGF gene therapy to treat critical limb ischemia in Japan. The patients with critical limb ischemia or Buerger’s disease were treated with Collategene at 2 mg or 4 mg via 2 or 3 intramuscular injections. At 12 weeks after the initial injection, combined evaluation of visual analog scale and ischemic ulcer size suggested a significant improvement in Collategene group as compared to placebo group. Collategene would provide an alternative therapy for patients with critical limb ischemia.

Neurological disorders represent one of the prominent reasons of disability worldwide. Currently, about 100 million people are affected by neurological disorders globally. These devastating disorders make up about 20% of the global burden of disease. The common neurological disorders are Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, stroke, brain tumors, brain trauma, etc. Inherited genetic mutations are often responsible for neurological disorders that result in atypical development of the nervous system, neurodegeneration, or disruption of typical neuronal function. Furthermore, genetic and epigenetic alterations triggered by disease-related events, inflammatory processes, and/or environmental insults, can augment the disease process. In order to treat most of the neurological diseases, till now there are no appropriate pharmaceuticals as well as standard medical and surgical practices. Gene therapy is an emerging powerful approach with potential to treat and even cure the burden of neurological disorders. Current understanding in the underlying disease pathogenesis, predominantly those concerning sensory neurons, and also by the progress of design of gene vector, selection of therapeutic gene, and the most suitable methods of delivery, etc. has made gene therapy a promising virtue for potential protection/restoration of neurological disorders. Therefore, this special thematic issue discusses and explores the currently available and upcoming gene therapy strategies as tools for neuroprotection and neurorestoration in neurological disorders. Tsagkaris et al. studied gene therapy approaches to Angelman syndrome (AS). Understanding UBE3A imprinting unravels the path to an etiologic treatment of AS. Gene therapy models tested on mice appeared less effective than anticipated pointing out that activation of paternal UBE3A cannot counteract the existing CNS defects. On the other hand, targeting abnormal downstream cell signaling pathways has provided promising rescue effects. Perhaps, combined reinstatement of paternal UBE3A expression with abnormal signaling pathways-oriented treatment is expected to provide better therapeutic effects. However, AS gene therapy remains debatable in pharmacoeconomics and ethics context [1]. Pottoo et al. explored gene therapy to generate anti-epileptogenic, anti-seizure and disease-modifying effects. Specific targeting of the epileptogenic region is facilitated by gene therapy, hence sparing the adjacent healthy tissue and decreasing the adverse effects that frequently go hand in hand with antiepileptic medication [2]. Islam et al. summarized the gene therapy approaches attempted in different animal models towards treating multiple sclerosis (MS). MS is the most common autoimmune demyelinating disease of the CNS. It is a multifactorial disease which develops in an immune-mediated way under the influences of both genetic and environmental factors. In last two decades, there have been some remarkable successes of gene therapy approaches on the experimental mice model of MS - experimental autoimmune encephalomyelitis which suggests that it is not far that the gene therapy approaches would start in human subjects ensuring the highest levels of safety and efficacy [3].

With the rapid development of sequencing technologies, it is more efficient to reveal the variations and expression levels of molecules in the genome, transcriptome, and proteome, which have greatly helped to expose the risk factors of human diseases. To achieve the goal, in addition to the biological research of the wet laboratory, more knowledge needs to be mined from a large amount of sequencing data. To this end, bioinformatics methods have been introduced to help researchers identify more etiological genes, biomarkers associated with clinical molecular subtypes and prognosis. Whereas, most of the methods focus on analyzing single omics data, only providing a partial reference to human diseases. Therefore, the major challenge is how to mine novel causal genes and phenotypes of diseases based on the fusing multi-level omics data using system biology approaches, improving the efficacy of gene therapy. Here, a Special Issue of Current Gene Therapy around the topic Computational and Biological Methods for Gene Therapy is proposed. In total, five outstanding works were presented in this thematic issue. Yang et al. investigated the effects of HKC on DN in the SD rat model and its molecular mechanism. Their results showed that the rats treated with HKC had an improved general state and reduced creatinine, blood urea nitrogen and 24-hour urinary protein levels. The deterioration of renal function was delayed due to the treatment with HKC. They utilized HE staining to observe that HKC can improve histopathological findings in the kidney tissues of DN rats, including kidney fibrosis. Results of western blot and qRT-PCR showed that HKC can inhibit the expressions of SPARC in the rat model of DN. Therefore, their findings demonstrated that HKC inhibited SPARC level and had significant therapeutic effects on DN [1]. Zhao et al. used genes as the bridge to connect AD and miRNAs to infer the AD-related miRNAs. The semi-clustering method was used to avoid the difficulty of obtaining negative samples. They identified 257 potential AD-related miRNAs with a high AUC. Several case studies proved the effectiveness of their results. The method they purposed would be a useful bioinformatics tool to discover novel knowledge-based on huge data [2]. Liu et al. provided a solid piece of evidence to determine the causal relationship between infant length (IL) and type 2 diabetes (T2D) risk through a two-sample Mendelian randomization (MR) protocol. By screening 29, 150 and 12 genetic variants in Diabetes Genetics Replication and Meta-analysis (DIAGAM), they constructed suitable IVs and confirmed that shorter IL contributes no additional risk to T2DM using the inverse-variance weighted (IVW) method. This study innovatively uses MR for the identification of pathogenic phenotypes, which is fast and accurate, and provides a powerful method for the discovery of early prevention strategies and treatment targets for T2D [3]. Deng et al. proposed PCHS, an effective computational method to predict comorbidity using HeteSim scores. PCHS utilized the HeteSim measure to calculate the relatedness scores of different disease pairs across the global heterogeneous network. The prediction model was built using the support vector machine (SVM) based on the HeteSim scores. The results showed that PCHS performed significantly better than previous state-of-the-art approaches and achieved an AUC score of 0.90 in 10-fold crossvalidation. Furthermore, some predictions have been verified in the literature, indicating the effectiveness of the proposed method [4]. Wu et al. combined experimental results on 50 singleton patients with CVM and the published literatures, identified SOX9 mutation (p.M469V) may contribute to CVM without other systematic deformities, which provided important implications and better understanding of phenotypic variability in SOX9-related skeletal deformities [5]. Each paper in this special issue was extensively peer-reviewed by two external reviewers. I would like to thank all the authors for contributing their work to our hot thematic issue and all the reviewers for their time and efforts. At last, I would like to thank the Editor- in-Chief of Current Gene Therapy, and Editorial Office of Bentham Science Publishers, for their support during the whole process.

Cell and gene therapy are emerging fields in both laboratory and clinical settings. Recently, Car-T therapy has been applied in clinic for cancer treatment. In transplantation, cell therapy is an important method for immune tolerance induction. Cell is not just an inanimate molecule or protein, cells used in therapy are alive. After infusion, cells can be recognized and interact with thousands of immune cells. Effects of cell therapy could be attributed by cell-cell contact and/or secretion of cytokines. Similarly, gene therapy not only affects a single gene, but also changes the cells and immune microenvironment nearby. In addition, epigenetic intervention, which involves DNA modification, covalent histone modification and RNA interference, results in the heritable down-regulation or silencing of gene expression without changes in the DNA sequences. Therefore, understanding how cell and gene therapy interact with the immune system will make us more confident in the development of treatment for the next-generation. I believe this issue which covers basic and clinical researches will provide new insights and inspirations for readers in their research fields. The first review is Cell Therapy in Solid Organ Transplantation by Dr. Cai and Prof. Chandraker. Current immunosuppressive drugs are non-donor specific, and the chronic toxicity deteriorate the allograft kidney, heart and pancreas. Cell therapy appears to be an innovative and promising strategy to minimize the use of immunosuppressive drugs in transplantation and to improve the long-term graft survival. The ONE study which was initiated in Europe is worldwide cell therapy for anti-rejection multicenter study [1]. This review will summarize the potential therapeutic use of regulatory cells in transplantation. The 2nd review Correlation between MDSC and Immune Tolerance in Transplantation: Cytokines, Pathways and Cell-cell interaction by Yang et al. discussed the innate regulatory cell MDSC in transplantation. Besides Treg, Breg and Mreg, MDSC also has huge potential in prolonging graft survival and reducing rejection. Here, you can find how MDSC suppresses effector immune cells, and the interaction between MDSC and other immune cells. They also discussed the different function between MDSC and Tregs in transplantation [2]. After the two reviews on cell therapy, Dr. Zhang et al. reviewed Understanding Gene Therapy in Acute Respiratory Distress Syndrome. ARDS is a severe disease which has a high mortality. Limitations of effective pulmonary gene therapy still exist, including the safety of viral vectors and the pulmonary defense mechanisms against inhaled particles. Here, they summarized the mechanism of gene therapy for ARDS and its application. Innate immunity plays a key role in the immune system. High mobility group box 1 (HMGB1) is an evolutionary conserved protein with comprehensive immune regulatory property [3]. HMGB1 triggers inflammatory response whereas intracellular HMGB1 controls the balance between autophagy and apoptosis. The 4th review entitled High Mobility Group Box 1: An Immune-regulatory Protein by Dr. Zhao et al. summarized and discussed the immunomodulatory effect of HMGB1. Although HMGB1 is known to induce apoptosis, sometimes regulatory cell death plays a more important role in diseases [4]. Ferroptosis is a kind of necroptosis. In the 5th review The Relationship between Ferroptosis and Tumors - A Novel Landscape for Therapeutic Approach, Dr. Xia et al. provides an overview of ferroptosis summarizing the mechanisms and signaling pathways of ferroptosis and the relationship between inducers of ferroptosis with diverse tumors, to provide novel prospects for cancer management. Autoimmune disease is an inflammatory condition in which the human body’s autoimmune system attacks normal cells, resulting in decreased and abnormal immune function, which eventually leads to tissue damage or organ dysfunction [5]. In the last review Functional Immunoregulation by Heme Oxygenase 1 in Juvenile Autoimmune Diseases, Dr. Zhang et al. introduced the role of heme oxygenase-1 (HO-1), which is an enzyme in heme degradation, in juvenile autoimmune diseases [6]. I believe all the reviews in this issue will attract your attention and give you some inspirations for your further research.

In recent years, Genome-Wide Association Studies (GWAS) and next-generation sequencing technologies have been widely used to detect the common genetic variants of diseases. Despite these successes, the majority of the genetic architecture of human complex diseases remains unknown. In the post-genome era, the major challenge is to mine novel disease risks from multi-level omics data using system biology methods, which may expand our knowledge of the causes of genetic disease. Therefore, we (Liang Cheng, and Yang Hu) conducted a Special Issue of Current Gene Therapy about the topic 'human disease system biology'. In this thematic issue, five outstanding works were presented from P.R. China and USA. Cancerlectin plays a key role in the process of tumor cells interacting with each other e.g. cell adhesion, cell growth, tumor cell differentiation, metastasis and cellular infection. With the avalanche of peptide sequences generated in the postgenomic age, it is urgent and challenging to develop an automated method for rapidly and accurately identifying cancerlectins based on their sequences information alone. The review provided the development of a machine learning method in cancerlectin prediction [1]. The authors developed a deep forest-based protein location algorithm relying on sequence information. A random forest network with a multi-layered structure that has a significantly smaller number of parameters was used to identify the subcelluar regions of the protein. It achieved a high accuracy outperforming current state-of-art algorithm given only the protein sequence [2]. System biology methods have been widely used to dissect the mechanisms underpinning human diseases. Here Wang et al. performed an RNA immunoprecipitation (RIP)-seq to profile the EZH2-binding lncRNAs in different tissues including brain, lung, heart, liver, kidney, intestine, spleen, testis, muscle and blood. As a result, Wang et al. identified 1,328 EZH2-binding lncRNAs, among which 470 were shared in at least two tissues while 858 were only detected in single tissue. In addition, to validate those EZH2-binding lncRNAs being previously reported, results uncover numerous novel tissue-specific lncRNAs interacting with EZH2. The findings suggest a critical role of epigenetic regulation by lncRNAs during cell differentiation and maturation [3]. Li et al. explored autophagic activity between normal endometrium and Endometriosis (EMs) lesion endometrium during different menstrual phases and EMs stages. After conducting an observational study on 73 women including 30 healthy individuals and 43 patients with EMs, they observed that the periodicity-losing in EMs and the decreased autophagic activity in ectopic endometrium may exert a potential role in the pathogenesis of EMs. And down-regulated autophagy of ectopic endometrium in secretory phase may be related to the progression of EMs [4] Xu et al. proposed a valid keystone species identification method named Spread Intensity (SI) which try to identify the key potential microbes in gut microbiota associated with adiposity. SI assembled three correlation metrics to calculate the interspecies correlation, applied network deconvolution to remove indirect correlations and used Molecular Ecological Network Analysis (MENA) to construct the co-occurrence network. Then SI combined topological properties of the microbial ecological network and characteristics of the microbial community to identify the key nodes in networks. For evaluating the accuracy of SI, they compared SI algorithm with existing methods by simulated data and got an obvious better performance than the other results. Also, the experimental results in gut microbiota datasets show that SI has an excellent performance in identifying highly correlated species in gut microbiome to adiposity [5]. We wish to end this editorial by thanking Dr. Lung-Ji Chang and Dr. Alfred S. Lewin, the Editor(s) in Chief, as well as Ms. Uroosa Aziz, the Journal Manager. We furthermore, extend our thanks to all peer reviewers for their time and expertise in revising individual contributions.

Lysosomial Storage Disorders (LSDs) are genetic diseases due to a lysosomial dysfunction [1]. LSDs are generally caused by mutations on gene transcribing for a crucial enzyme involved in a metabolic or catabolic biochemical step of a metabolic pathway driving to the accumulation of the not cabolized enzymatic target within the lysosome. Owing to this progressive intralysosomial accumulation lysosomial diseases are characterized by several organ symptoms involving specific or multiple organs [2]. Since this pathogenetic basis of LSDs, they are potential target for gene therapy in order to obtain the single gene induction into some target cells aiming to improve the clinical course of progressive end-organ damage due to continous substrate accumulation [3]. Other possible therapeutic approaches have been reported such as Bone Marrow Transplantation (BMT) or Enzyme Replacement Therapy (ERT) and these therapeutic ways have been reported as able to modify with a various degree the he systemic disease associated with LSDs in some patients. Nevertheless, Central Nervous System (CNS) involvement still appear as a maior therapeutic a major challenge. With regard of treatment of neurologic complications of LSDs cene therapy could be evaluated as a promising future approach for the treatment of CNS disease in order to provide a effective and persistent improvement of the deficient enzyme [4]. Direct intracranial injection of viral gene transfer vectors represents a possible effective therapeutical approach on the basis of promising results reported in some animal models of LSDs such as canine and feline models of lysosomial accumulation diseases. Aim of this mini-thematic issue is to review the state of art of gene therapy in LSDs In the first review, Simonetta et al. [5] reviewed genetics and the role of genetic therapy in Anderson-fabry Disease (AFD). Because of its multisystemic involvement, Fabry’s disease may present a large spectrum of clinical manifestations as acroparesthesias, hypohidrosis, angiokeratomas, signs and symptoms of cardiac, renal, cerebrovascular involvement (renal insufficiency, proteinuria, left ventricular hypertrophy, strokes) [5-10]. Enzyme replacement therapy with recombinant α-galactosidase A is actually the specific therapy for Fabry’s disease but recently viral gene therapy has recently been addressed with great interest or the last innovative method, that is to say, for delivering recombination enzyme into the main involved tissues and promising results have been reported in animal models. In the second review, Sestito et al. [11] reviewed the role of genetics and genetic therapy in Hunter syndrome. Hunter syndrome is a rare X-linked lysosomal storage disorder due to a mutation in the gene encoding the lysosomal enzyme iduronate-2- sulfatase. The Author reported that In vitro studies firstly aimed at the demonstration that viral vector-mediated IDS gene expression could lead to high levels of enzyme activity in trasduced cells, whereas in vivo studies in which recombinant vectors are directly administered, systematically or by direct injection into the Central Nervous System, also ex vivo gene therapy, consisting of the transplantation of autologous hematopoietic stem cells, modified in vitro, into the animal or patient, indicate future promising results. In the third review, Cachón-González et al., [12] reviewed genetics and gene therapy in GM2 Gangliosidosis. There is no effective treatment beyond palliative care, and while the genetic basis of GM2 gangliosidosis is well established, the molecular and cellular events, from disease-causing mutations and glycosphingolipid storage to disease manifestations, remain to be fully delineated. Several therapeutic approaches have been attempted in patients, including enzymatic augmentation, bone marrow transplantation, enzyme enhancement, and substrate reduction therapy. Animal models of GM2 gangliodidosis have facilitated in-depth evaluation of innovative applications such as gene transfer, which in contrast to other interventions, show great promise.

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