ISSN (Print): 1566-5232
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Volume 20, 5 Issues, 2020
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ISSN (Print): 1566-5232
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Special Issue Submission
"Timely reviews, extensive, in-depth coverage of all of gene therapy; a great way to get and stay up-to-date."
Keck U.S.C. School of Medicine, USA
In my opinion contributing for Bentham Science was the best that I had experienced till now. You were too much supporting and speedy. I can't believe that the acceptance process had been performed in only 2 months. That is incredible.
Touba Eslaminejad (Kerman University of Medical Sciences kerman, kerman, Iran.)
Has contributed: Glioblastoma Targeted Gene Therapy Based on pEGFP/p53-Loaded Superparamagnetic Iron Oxide Nanoparticles.
11 Articles Ahead of Print are available electronically
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.
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 .
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 . 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 . 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 . 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 . 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 . 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 .
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 . 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 , 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 , 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 . 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 .
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 .
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 .
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 .
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 .
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 .
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
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 .
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 . 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 . 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
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 . 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 . 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 .
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
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
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
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
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 
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 .
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
Lysosomial Storage Disorders (LSDs) are genetic diseases due to a lysosomial dysfunction . 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
. 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
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 .
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
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. 
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,
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.  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
In the third review, Cachón-González et al.,  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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