Monthly Archives: March 2021

Background

After DNA helical structure discovery, the world continuous staircase outburst of several advanced technologies, which are currently heading toward translation into clinical practice. Over the last decades, several molecular techniques developed that help to edit the DNA codes and modify mRNA by post-transcriptional modifications. Gene therapy is the delivery of specific genetic material to modify the encoding of a gene product or to change the biological properties of tissues for the management of various disorders.1 Gene therapy overcomes the limitations associated with the recombinant therapeutic use of peptides, such as low bioavailability, instability, severe toxicity, clearance rates, and high production cost.2 Gene therapies act by different mechanisms including, replacing malfunction genes with the therapeutic genes, gene knockdown, or deactivating problem genes, and insert a new gene to treat a disease.3 Gene therapy can be done in either somatic or germline cells. In somatic cells, gene therapy only the modified tissues will be affected, but in germline cell gene therapy, genetic changes transmit to the offspring. So, there is no clinical trial on human germline gene therapy.4 Currently, somatic gene therapy is safe for the management of several disorders in human beings. Gene therapy effectively treats several diseases due to increased understanding of disease pathogenesis and improved gene delivery technologies.5 Gene therapy uses genetic material (ie, RNA or DNA) via a vector that facilitates the delivery of foreign genetic material into the host organ. The genetic material is administered into the target organ (in vivo gene therapy) or used to modify cells taken from the host that are then re-administered (ex vivo gene therapy). Gene therapy aims to provide a functional gene copy of the damaged gene(s), increase the availability of disease-modifying genes or suppress the activity of a damaged gene.6,7 Gene therapy has a broad spectrum of applications, from gene replacement and knockdown for genetic disorders including cancer, hemophilia, hypercholesterolemia, and neurodegenerative diseases to vaccination, each with different requirements for gene administration.8 Gene delivery systems consist of three components: a gene that expresses essential therapeutic peptides, a plasmid-based gene encoding system that regulates the activity of a gene in the target organ, and a gene delivery system that regulates the administration of the encoding gene to host tissue.9

Conventional gene therapy mostly depends on viral-based delivery of genes that either randomly integrates into the host genome (eg retroviruses) or remains as extrachromosomal DNA copy (eg AAV]) and expresses a protein that is missing or mutated in human disorder. In contrast to traditional gene therapy, gene editing provides more versatile tools for gene therapy, for example, precisely correct point variants, place an extra, healthy gene at a safe genomic location or disrupt a gene. The Current gene-editing process depends on the introduction of endogenous double-strand DNA breaks (DSBs) and repair mechanisms. When DSBs occur by nucleases, cellular DNA repair mechanisms are activated. There are two main mechanisms for repairing double-strand breaks, non-homologous end joining (NHEJ) and homology-directed repair (HDR). Genome-editing nucleases can be modified to recognize and break the genome at specific DNA sequences, resulting in DSBs, which are efficiently repaired by either NHEJ or HDR.10,11

NHEJ repair damaged DNA without a homologous template. Due to this reason, NHEJ may lead to deletions or insertions of nucleotides in the damaged loci; thus, it is error-prone. HDR differs from NHEJ since it repairs DNA damages using a homologous template. Generally, having used a homologous sequence, this form of DNA repair has less chance to cause errors. From a clinical viewpoint, HDR is favorable for restoring mutations in genes or for integrating genes for therapeutic purposes.1013

Currently, there are four different gene-editing nuclease enzymes available based on their structures: meganucleases, zinc-finger nucleases, transcription activator-like effector nucleases, and CRISPR-associated nucleases.

Are sequence-specific endonucleases that recognize unique large (1440 bp) target sites. It has low cytotoxicity that makes it an attractive tool for genome editing. Existing engineering techniques include the creation of fusion protein from existing MN domains and engineering MN specificity via the direct alteration of protein residues in the DNA-binding domain. The complexity in re-engineering and low editing efficiency limits the uses of MNs.14

Artificially produced by fusing site-specific zinc finger protein with the non-specific cleavage domain of the FokI restriction endonuclease. The DNA-binding component has 36 zinc finger repeats, and each can identify between 9 and 18 base pairs. ZFN has three zinc fingers that each identifies three base pair DNA sequence to form a three-finger array that attaches to nine base pair target sites and the non-specific cleavage domain.14,15 ZFPs deliver a site-specific DSB to the genome and facilitate local homologous recombination that enhances targeted genome editing. The ZFN-encoding plasmid-based targeted administration of the required genes decreases the limitations of viral administration. If ZFNs are not specific at the target site, off-target break may occur. Such off-target breakage may cause DBS that causes cell death. An Off-target break may facilitate the random integration of donor DNA.15,16

Are artificial DNA nucleases formed by fusing a DNA-binding domain with a nonspecific nuclease domain derived from Fok I endonuclease that specifically cut the required DNA sequence.15 TALE effectors DNA-binding domain has a repeating unit of 3335 conserved amino acids. Each repeat is similar, except positions 12 and 13, which are variable and have a strong correlation with specific nucleotide recognition. DNA cleavage domain is nonspecific from FokI endonuclease. The FokI domain acts as a dimer that needs two constructs with unique DNA binding for sites in the target genome. Both the number of amino acids between the TALE DNA binding domain and the FokI cleavage domain are essential for better activity. TALEN uses to edit genomes by inducing DSB that cells respond to with repair mechanisms.17,18

CRISPR is a heritable, adaptive immune system of bacteria that provides them with the memory of previous virus infections and defends against re-infection. Contrary to the human adaptive immune system, CRISPR is passed on to the next generation of bacteria, rendering the colony immune to future virus infections. CRISPR immunity depends on the integration of the invaders DNA (virus or plasmid) into the bacterial genome.19 CRISPR helps the bacterium to identify the viral sequences and break. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats, which are interrupted by spacer sequences. These spacer sequences are viral sequences integrated during past viral infections when transcribed into short RNA sequences, are capable of guiding the Cas endonuclease to complementary sequences of viral DNA. Upon target identification, Cas binds to the viral DNA and cleaves it, protecting the prokaryotic cell from infection.20,21 CRISPR immune system modified to create a gene-editing tool that can target changes to the DNA. The most common is CRISPR/Cas9, which posses the Cas9 endonuclease and a short noncoding guide RNA (gRNA) that contains two components: a target-specific CRISPR RNA (crRNA) and a helper trans-activating RNA (tracrRNA). The gRNA unit guides Cas9 to a specific genomic locus via base pairing between the crRNA sequence and the target sequence.22 CRISPR-Cas-mediated gene repair, disruption, insertion, or deletion are thus finding applications in several areas of biomedical research, medicine, agriculture, and biotechnology.22,23

Since the emergence of recombinant DNA technology that helps gene-therapy, how to effectively and safely administer gene products is the major challenge. Vector is a vehicle that uses to deliver the gene of interest. An ideal vector can administer a gene to a specific tissue, accommodate enough foreign gene size, achieve the level and duration of transgenic expression enough to correct the defect gene, non-immunogenic, and safe. Delivery of the gene products done by Viral Vectors, Bactofection, and none viral Vectors (chemical and physical) method as summarized in Figure 1.24 The most important step in achieving gene therapy is choosing the vectors.

Figure 1 Overview of the delivery systems used in gene therapy.

Viruses were the first and the most widely used vectors to administer genes into the target tissue. Viral vectors ensure that almost all cells can infect, without affecting cell viability. Viruses have distinctive features that make them suitable for gene delivery in clinical practice. Surface proteins on viruses interact with their host receptors, which activate endocytosis. Once entered, viruses release their genome into the nucleus for viral gene expression.25,26 Herpes simplex virus (HSV), adenovirus (Ad), adeno-associated virus (AAV), and lentivirus (LV) are the most important viral vectors.27,28

Some bacteria specifically target tumor cells leading to RNA interference (RNAi) and gene silencing by inhibiting RNA activity, such as protein synthesis. Several in vivo and in vitro studies revealed that intracellular bacteria such as Salmonella spp., Listeria monocytogenes, Shigella flexneri, Bifidobacterium longum, E. coli, and Yersinia enterocolitica use to deliver plasmids pro-drug converting enzymes and cytotoxic agents into the target cell.29 Phase I trial is undergoing by using Listeria, Bifidobacterium, Salmonella, Shigella, and Clostridium gene therapy against cancer. Another clinical trial is ongoing on the effects of Lactococcus synthesizing interleukin 10 against colitis in Phase II.30,31

Viral-vectors-based gene transfer displays better and long-term gene encoding but has some limitations like immunogenicity, less specific to the target cell, carcinogenicity, high cost and cannot deliver large genome size. Non-viral methods display better advantages due to relatively safe, can deliver a large genome, and ease for production.3235 Chemical vectors, also known as non-viral vectors grouped as organic and inorganic vectors. The organic vectors consist of cationic lipid-based vectors: synthetic cationic polymers-based vector and peptide-based vectors. These cationic organic vectors form complexes with negatively charged DNA via an electrostatic bond. The complexes protect the genomic material and enhance cell uptake and intracellular delivery. Generally, non-viral vectors help to deliver small DNA, large DNA (plasmid DNA), and RNA (Si RNA, m RNA) into the target tissue.3638 Physical methods use different mechanical forces to facilitate the administration of gene material into the host tissues. It is an alternative to viral and chemical methods to decrease barriers that limit DNA delivery into the host tissues.39 It is feasible to deliver genes into target tissues by mechanical force. Indeed, there are several methods, and most have a similar mode of gene delivery, ie, physically formed transient pores in the cell membrane through which the genetic material enters into the host cell.40,41 Needle and jet injection, hydrodynamic gene transfer, electroporation, sonoporation, magnetofection, and gene gun bombardment are examples of physical DNA delivering methods.4244

Cancer occurs due to disrupting the normal cell proliferation and apoptosis process. Advances in cancer therapy need a novel therapeutic agent with novel mode of action, several mechanisms of cell death, and synergy with conventional management. Gene therapies possess all these profiles. Several gene therapy approaches were developed for the management of cancer, including anti-angiogenic gene therapy, suicide gene therapy, immunotherapy, siRNA therapy, pro-apoptotic gene therapy, oncolytic virotherapy, and gene directed-enzyme prodrug therapy.45 By November 2017, greater than 2597 clinical trials were conducted on gene therapy in the world. Among these trials, greater than 65% are associated with cancer, followed by monogenetic and cardiovascular diseases.8 The use of CAR T cell therapy showed promising results for the management of both myeloid and lymphoid leukemia. Until August 2019, only 22 gene products were approved for the treatment of different disorders. Most gene products used for the treatment variety types of cancers as shown in Table 1. Immuno-gene therapy is a potential treatment approach for the treatment of p53-deficient tumors (Imlygic, Gendicine, Yescarta, and Kymriah.47

Table 1 Gene Therapies Products Approved for Therapeutic Use

Oncolytic virotherapy (OV) is the most promising approach for tumor immunotherapy. OV uses replication-competent viruses that can proliferate selectively at tumor cells. Oncolytic viruses grouped as naturally occurring or genetically modified viruses. Natural occurring viruses like parvoviruses, and Newcastle disease viruses that selectively replicate in tumor cell without genetic modification. The second virus category, such as vesicular stomatitis viruses, adenoviruses, measles viruses, HSV and vaccinia viruses, genetically modified to improve the safety, tumor-specificity, and decrease virus pathogenicity. The therapeutic use of oncolytic viruses for cancer treatment is an immune-related treatment alternative. Oncolytic viruses act by directly lyses tumor cells and by introducing wild-type tumor suppressor genes into cells that lack the tumor suppressor gene.48,49 Change in p53 gene function is present in half of all malignancies, and the induction of wild-type p53 gene re-establishes the normal p53 expression. Several recombinant OVs expressing p53 were developed with the aim of producing more potent OVs that act in combination with host immunity or with other treatments modality to destroy tumor cells.49,50

Was the first approved gene product for the management of neck and head squamous cell carcinoma in 2003.50 Gendicine is a non-replicative an adenoviral vector, where the E1 gene is replaced with the tumor suppressor p53 cDNA gene. The expression of p53 in tumor cells triggers the antitumor effect by activating the apoptotic pathway, inhibit damaged DNA repair, and anti-apoptotic activity. P53 gene mutation is prevalent in several cancers. Therefore, Gendicine induces the expression of p53 restores its activity and destroys the tumor cells. Generally, Gendicine management showed 3040% complete response and 5060% partial response with a total response rate of 90%96% in different therapeutic use. Up-to-date greater than 30,000 patients managed by Gendicine.50,51

It is the first replicative, oncolytic recombinant ad5 (rAd5-H101) approved to treat refractory nasopharyngeal cancer. Loss of p53 gene linked with drug resistance and survival rate reduction in non-small cell cancer patients.50 Oncorine is an ad5 virus with a deletion in the E1B 55K gene. Host cell p53 gene inactivation is essential for wild-type to block the activation of apoptotic pathway. The removal of the E1B 55K gene inhibits viral proliferation in normal cells, allowing only proliferate in p53-deficient host cells. In tumor cells, viral proliferation causes oncolysis that is the mechanism to treat solid tumors. Following cancer cell lysis, adenoviruses release and infect another cell activating a serious of Oncorine-mediated cell death.52,53

It is a genetically modified oncolytic HSV-1 approved in Europe in 2015 for the management of non-resectable metastatic melanoma. Imlygic is the first oncolytic virus used for the management of advanced melanoma.48 The replacement of 34.5 and 47 genes with the human granulocyte-macrophage colony-stimulating factor (GM-CSF) gene modifies the HSV-1 gene. The 34.5 gene deletion causes tumor cell-selective replication and suppression of pathogenicity. The 34.5 gene blocks protein synthesis of the host cell during viral infection. Thus, suppressing 34.5 seizes the virus proliferation in normal cells. In tumor cells, the 34.5 gene deleted HSV-1 can replicate. The 47gene inhibits the host cell transporter associated with antigen presentation. The depletion of 47gene reduces MHC class I expression that increases antitumor immune activity.53 Besides, two human GM-CSF genes inserted into the virus providing high levels of GM-CSF production, and stimulate immune responses. Administration of Imlygic causes apoptosis of tumor cell enhanced antigen presentation and increased antitumor response.49,54

Is the first targeted injectable vector approved for the management of metastatic cancers. It is a replication-incompetent retroviral vector showing a SIG-binding peptide to bind to abnormal Signature (SIG) proteins in the tumor cell that increase vector concentration in tumor cells and express a dominant-negative human cyclin G1 inhibitor. After the entrance into the tumor cells, Rexin-G synthesizes cytocidal dnG1 proteins that inhibit the cell cycle in the G1 phase resulting in apoptosis of cancer cells.55,56

T cells destroy infected and tumor cells by detecting nonself antigens with the T cell receptor (TCR). CAR T is a T cell transduced with a chimeric antigen receptor specific to a tumor-associated antigen. CAR is chimeric because it contains the antigen-binding site of the B cell receptor and an intracellular TCR activation domain. CAR has three domains, an extracellular domain that has cancer-specific epitopes (scfv region) made from light (VL) and heavy (VH) chains of immunoglobin that target antigen (such as CD19), a transmembrane domain, and intracellular TCR derived stimulatory domains as showed in Figure 2. The scfv component binds to the target antigen in the MHC independent way leading to CAR clustering and stimulating T-cell via intracellular region that posses the TCR-derived CD3 chain, with or without co-stimulatory domains. Stimulated CAR T-cells give target-specific memory cells that inhibit tumor relapse.57 CD19targeted CAR T cells were the first CARs to be studied. CD19 is a promising target due to its expression limited to the B cell. Firstgeneration, CD19targeted CAR T cells were safe but ineffective. Second-generation CARs have a costimulatory domain with the CD3 activation domain show enhanced T cell activity. Two secondgeneration, CD19targeted CARs are in clinical use contain a 41BB costimulatory domain (19BBz) and a CD28 costimulatory domain and those with more than one additional co-stimulatory molecule are known as third-generation CAR.5759

Figure 2 Schematic diagram of CAR-T-cell products.

It is the first FDA approved CAR T-cell-based gene product to treat relapsed B-cell acute lymphoblastic leukemia. Kymriah has autologous T cells, modified with the lent virus to encode a CAR consist of a murine single-chain antibody fragment (scFv) selective for CD19, an intracellular domain 41BB (CD137), and CD3 zeta with CD8 transmembrane hinge. After binding to CD19 antigen-expressing cells, Kymriah initiates the antitumor effect via the CD3 domain. The intracellular 41BB co-stimulatory domains enhance the antitumor activity. The CD19 antigen is a 95-kD glycoprotein encoded as a surface antigen in diffuse large B-cell lymphoma (DLBCL) and other B-cell lymphomas.60,61 High response rates were recorded in patients with refractory DLBCL in Phase 2 clinical trials. The response rate was 50% at 3 months, 43% with a complete response at 6 months, and there were no patients with a complete response at 6 months who had a relapse by the median of 28.6 months.62

It is another CAR T-cell therapy used for the management of aggressive non-Hodgkin lymphoma. It is CD19 antigen-specific ex-vivo modified autologous T cells infected with a gamma-retroviral. It encodes a CAR comprising an extracellular murine anti-CD19 single-chain variable fragment fused to a cytoplasmic domain that possesses CD28 and CD3-zeta co-stimulatory domains.63,64

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) uses for the management of several hematopoietic malignancies. But, acute graft-versus-host-disease (aGvHD) and Graft rejection are barriers to its success. The treatment strategy for haplo-HSCT depends on T-cell depletion or administration of lymphotoxin agents like cyclophosphamide after stem cell infusion to selectively deplete activated alloreactive lymphocytes but causes prolonged immunodeficiency post-transplantation. Thus, treatment to enhance immune reconstitution after transplantation is necessary.65 Zalmoxis is a genetically modified allogeneic T cell using a retroviral vector encoding a human low-affinity nerve growth factor receptor (LNGFR) and HSV-TK Mut2 to transduce the allogeneic T immune cells. The LNGFR expression uses as a marker of the transduced T cells, and the HSV-TK Mut2 expression provides the suicide gene induction during the administration of the prodrug ganciclovir (GCV). Administration of the genetically modified donor T cells to T cell-depleted transplant patients (HSCT) reconstitutes the immunity to defend from infections. But, donor cells may specifically act as the host cells leading to Graft Versus Host Disease (GVHD). In this case, induction of suicide gene by GCV administration may kill the donor T cells encoding HSV-TK and control GVHD. Zalmoxis is a potential curative agent for HSCT patients when the matched donor does not exist. Zalmoxis provides post-transplant GvHD control, Graft versus Leukemia (GvL) improvement, relapse decrease, and immune reconstitution causes reduced infection.52,66

Gene silencing therapy is RNA interference (RNAi)-mediated knockdown of specific genes in tumor cells. RNAi is single or double-stranded noncoding RNAs (21 ribonucleotides) that induce sequence-specific degradation of complementary mRNAs via the cells internal machinery.67 siRNA is vital because most genes do not have inhibitors due to a lack of ligand binding sites and amino acid sequence homology with other proteins that limit target selectivity. RNAi consists of microRNA (miRNA), Small Interfering RNA (siRNA) and short hairpin RNA (shRNA). Two decades later after the discovery of RNAi, ONPATTRO (patisiran) approved for the first time for the management of the polyneuropathy of hereditary transthyretinmediated (hATTR) amyloidosis.68 Tumor suppressor genes, oncogenes, genes involved in cancer progression, and drug-resistance are promising targets for gene silencing by RNAi-based cancer treatment due to selective gene silencing effect and relatively fewer adverse effects than conventional chemotherapy.69 The merits of RNAi in cancer treatment are targeting several genes of different cellular pathways involved in cancer progression and develop a drug for a specific patient.70 Several studies conducted on animals revealed that targeting vital proteins in the cell cycle, such as Protein kinase N3 (PKN3), kinesin spindle protein (KSP), and polo-like kinase 1 (PLK1) by siRNA displayed a potent antitumor effect. Several liposomal siRNA dose preparations are in Phase 1 trials, such as treatments for pancreatic cancer (PKN3 siRNA), liver cancer (CEBPA siRNA), and neuroendocrine tumors (PLK1 siRNA).71

Suicide gene therapy uses viral or bacterial genes into malignant cells that metabolize non-toxic prodrug into a toxic compound. Several suicide gene systems were identified including the HSV-thymidine kinase gene (HSV-TK) with ganciclovir (GCV) and the cytosine deaminase gene (CD) with 5-fluorocytosine (5-FC).72 Gene-mediated cytotoxic immunotherapy is one strategy where an adenoviral vector possessing the herpes virus thymidine kinase gene (AdV-TK) is administered locally into the tumor site that causes local expression of the HSV-TK gene to the synthesis of viral thymidine kinase that converts GCV to GCV monophosphate. The next step is the administration of GCV that is a substrate of HSV-TK and phosphorylated to produce GCV monophosphate. Then, cellular kinases metabolize GVC-monophosphate into GVC-triphosphate. GCV triphosphate is a deoxyguanosine triphosphate analog, incorporated into the DNA chain causing chain termination and tumor cell death.73

The anti-tumor effect of the TK/GCV system showed promising results in animal models. A study on hormone-refractory prostate cancer patients treated with HSV-TK delivered by adenovirus followed by GCV. The result showed response was at the surrogate marker level and safe. Several studies are in Phase III trials.74 The cytosine deaminase (CD) enzyme exists in fungi and bacteria but not in mammalian cells, metabolizes cytosine into uracil. CD metabolizes the non-toxic prodrug 5-FC into 5-FU, which is subsequently metabolized by cellular enzymes into 5-FdUMP, 5-FdUTP, and 5-FUTP. Inhibition of thymidylate synthase and production of (5-FU) DNA and RNA are the mode of cell death induced by the CD/5-FC suicide system. 5-FU uses for cancer treatment but requires a high dose. This suicide system results in tumor-targeted chemotherapy with few side effects. The CD/5-FC system improved by the inclusion uracil phosphoribosyltransferase (UPRT) gene that phosphorylates 5-FU to 5-fluorouridine mono-phosphate, the first step of its pathway to activation.75 The anti-tumor effect of the CD/5-FC combination showed a better efficacy in animal models. A study on refractory cancer patients that involved intratumoral administration of TAPET-CD attenuated Salmonella bacterium encoding the E. coli CD gene in three patients. The study showed a significant effect and lack of side effects. An oncolytic adenovirus possessing a CD/HSV-1 TK gene was used in a phase I study in patients with prostate cancer. The result showed that the transgene encoding persistence in the prostate for 3 weeks after administration.76

Tumor-driven angiogenesis several growth factors are involved, such as vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), angiopoietins or IL-8, to secure oxygen and nutrients supply. Two major approaches are being pursued to block tumor angiogenesis. The first approach is down-regulation of pro-angiogenic factors expression, such as VEGF, and the second approach is up-regulation of expression of anti-angiogenic factors such as angiostatin, endostatin, and human soluble FMS-like tyrosine kinase receptor. Despite the successful therapeutic use of mAb like Bevacizumab for targeted therapy of cancer, the production and administration of therapeutic mAb are limited due to costly production. Therefore, gene-based studies were done to develop an angiogenesis-targeted cancer treatment.77,78

Gene therapy represents a novel alternative for the management of diseases that have no satisfactory cure. Gene therapy for cancer treatment has good progress in the last three decades, few drugs approved, while others are still in trials. Relatively gene therapy has better safety with tolerable adverse effects than chemotherapy for the treatment of cancer. In the future, tumor genomic analysis, assessment of host humoral and cellular immunity will facilitate a better selection of the most appropriate patient for gene therapy. Recent progress in developing safe and effective vectors for gene delivery, and understanding the activity of nucleases facilitate future genome editing as new treatment approaches for untreatable diseases like cancer.

The success of using autologous and allogenic chimeric antigen receptor integrated T-lymphocytes in mediating adoptive immunotherapy enhances the safety and effectiveness of gene therapy. Besides, the enhanced biological research, cheaper gene vectors will be available in the market, which increases gene therapy accessibility for most cancer patients. This will change the future of cancer treatment, from generalized cancer treatment strategies to individualized cancer treatment, based on the patients specific genome, immune status, and genetic profile of the tumor. Gene therapy is expected to be fast, effective, less toxic, and inexpensive, with higher cure rates. In November 2017, more than 2597 clinical trials are ongoing in several countries and a few of them are listed in Table 2. Until August 2019, 22 gene medicines had been approved by the drug regulatory agencies from various countries.79 Gene therapy gradually accepted by the government and the public since the 1980s and has become an important alternative to the existing treatments in the past few years. Therefore, gene therapy drugs, with safe vectors and advanced biotechnologies, would play a greater role in the prophylaxis and management of cancer in the future.

Table 2 Gene Therapies Products Candidates Under Clinical Trial

ADA, adenosine deaminase; Ad, adenovirus; AAV, adeno-associated virus; aGvHD, acute graft-versus-host-disease; allo-HSCT, allogeneic hematopoietic stem cell transplantation; CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats; CAR, chimeric antigen receptor; DSBs, double-strand breaks; ERT, enzyme replacement therapy; HDR, homology-directed repair; HSV, herpes simplex virus; IRDs, inherited retinal degenerations; LV, lentivirus; NHEJ, non-homologous end joining; NMDs, neuromuscular disorders; OV, oncolytic virotherapy; tracrRNA, trans-activating RNA; TCR, T cell receptor; MNs, meganucleases.

All data are provided in the manuscript or found from published papers as cited.

I would like to acknowledge Mrs Fasika Abu for editing the manuscript for English Style.

The authors declare no competing interests in this work.

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[Full text] Current status of gene therapy for the treatment of cancer | BTT - Dove Medical Press

-- Protein expression in muscle was sustained for two years following treatment in the low dose cohort, with mean beta-sarcoglycan expression of 54% at 24 months, compared to 36% at Day 60, as measured by western blot ---- Mean NSAD score improvement of 5.7 points from baseline was sustained through 24 months in low-dose cohort, and mean NSAD score improvement of 4.0 points from baseline at one year in high-dose cohort ---- Results in both cohorts continue to reinforce the safety and tolerability profile of SRP-9003 --

CAMBRIDGE, Mass., March 18, 2021 (GLOBE NEWSWIRE) -- Sarepta Therapeutics, Inc.(NASDAQ:SRPT), the leader in precision genetic medicine for rare diseases, today shared new results from the ongoing study of SRP-9003 (rAAVrh74.MHCK7.hSGCB), the Companys investigational gene therapy for limb-girdle muscular dystrophy Type 2E (LGMD2E). In the first look at expression data from biopsies taken two years after a single administration of SRP-9003, results found sustained protein expression in muscle tissue. In functional outcomes assessments taken two years following treatment in Cohort 1 (low-dose cohort) and one year after treatment in Cohort 2 (high-dose cohort), patients continued to demonstrate stability in their NSAD (North Star Assessment for Dysferlinopathies) total score and improvements on timed function tests. Results are being presented today at the 2021 Muscular Dystrophy Association (MDA) Annual Clinical and Scientific Conference.

SRP-9003 is in development for the treatment of LGMD2E (also known as beta-sarcoglycanopathy and LGMDR4), a devastating monogenic neuromuscular disease caused by a lack of beta-sarcoglycan (beta-SG) proteins. SRP-9003 is a gene therapy construct that transduces skeletal and cardiac muscle, delivering a gene that codes for the full-length beta-SG protein, the absence of which is the sole cause of the progressive degeneration and a shortened lifespan characterized by the disease.

This data is the first look at longer-term expression data with any gene therapy for muscular dystrophy. The meaningful and sustained levels of beta-sarcoglycan protein expression at two years and continued strength of the functional outcomes measured are tremendously positive and support continued advancement of this investigational treatment for patients, said Louise Rodino-Klapac, Ph.D., executive vice president and chief scientific officer, Sarepta Therapeutics. In Cohort 2, we also saw strong expression of delta-sarcoglycan and gamma-sarcoglycan proteins in addition to beta-sarcoglycan, which suggests that SRP-9003 is working to restore the dystrophin associated protein complex, or DAPC, which provides biological support for the sustained functional benefits observed in both cohorts. LGMD2E is one of the most severe forms of LGMD and causes significant disability in children while frequently leading to early mortality and the data continue to suggest this treatment could bring much needed hope to these patients.

Efficient transduction in skeletal muscle and robust beta-sarcoglycan protein expression were seen in both dose cohorts following infusion with SRP-9003, and significant creatine kinase (CK) reductions were observed.

Cohort 1 (Dosed at 1.851013 vg/kg), 24 months following treatment:

Cohort 2 (Dosed at 7.411013 vg/kg), 12 months following treatment:

In an exploratory evaluation of all SRP-9003 treated patients compared to a natural history cohort; patients treated with SRP-9003 demonstrated significant improvements in functional outcomes after 24 months. The mean decline in total NSAD score for patients in the natural history cohort was 4.6 points while SRP-9003 treated patients demonstrated a mean improvement of 4.6 points for a clinically meaningful difference of 9.2 points.

Since the last update from this study in October 2020, there have been no new drug-related safety signals observed, and no decreases in platelet counts outside of the normal range and no evidence of clinical complement activation observed in either dose cohort.

About SRP-9003 and the StudySRP-9003 uses the AAVrh74 vector, which is designed to be systemically and robustly delivered to skeletal, diaphragm and cardiac muscle, making it an ideal candidate to treat peripheral neuromuscular diseases. AAVrh74 has lower immunogenicity rates than reported with other human AAV vectors. The MHCK7 promoter has been chosen for its ability to robustly express in the heart, which is critically important for patients with limb-girdle muscular dystrophy Type 2E (LGMD2E), also known as beta-sarcoglycanopathy and LGMDR4, many of whom die from pulmonary or cardiac complications.

This open label, first-in-human study is evaluating a single intravenous infusion of SRP-9003 among children with LGMD2E between the ages of 4 and 15 years with significant symptoms of disease. The SRP-9003 study has two cohorts, each studying a different dose-per-kilogram based on the weight of the patient. Three participants in the low-dose cohort (Cohort 1) were treated with a one-time infusion of SRP-9003 dosed at 1.851013 vg/kg and an additional three participants in the high-dose cohort (Cohort 2) received a one-time infusion dosed at 7.411013 vg/kg based on linear standard qPCR titer method. The six participants were between the ages of 4 and 13. Post-treatment biopsies were taken at 60 days.

Sarepta has exclusive rights to the LGMD2E gene therapy program initially developed at the Abigail Wexner Research Institute at Nationwide Childrens Hospital.

About Limb-girdle Muscular DystrophyLimb-girdle muscular dystrophies are genetic diseases that cause progressive, debilitating weakness and wasting that begin in muscles around the hips and shoulders before progressing to muscles in the arms and legs.

Patients with limb-girdle muscular dystrophy Type 2E (LGMD2E) begin showing neuromuscular symptoms such as difficulty running, jumping and climbing stairs before age 10. The disease, which is an autosomal recessive subtype of LGMD, progresses to loss of ambulation in the teen years and often leads to early mortality. There is currently no treatment or cure for LGMD2E.

Sarepta has five LGMD gene therapy programs in development, including subtypes for LGMD2E, LGMD2D, LGMD2C, LGMD2B and LGMD2L, and holds an option for a sixth program for LGMD2A.

AboutSarepta TherapeuticsAt Sarepta, we are leading a revolution in precision genetic medicine and every day is an opportunity to change the lives of people living with rare disease. The Company has built an impressive position in Duchenne muscular dystrophy (DMD) and in gene therapies for limb-girdle muscular dystrophies (LGMDs), mucopolysaccharidosis type IIIA, Charcot-Marie-Tooth (CMT), and other CNS-related disorders, with more than 40 programs in various stages of development. The Companys programs and research focus span several therapeutic modalities, including RNA, gene therapy and gene editing. For more information, please visitwww.sarepta.comor follow us onTwitter,LinkedIn,InstagramandFacebook.

Forward-Looking StatementsThis press release contains "forward-looking statements." Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Words such as "believes," "anticipates," "plans," "expects," "will," "intends," "potential," "possible" and similar expressions are intended to identify forward-looking statements. These forward-looking statements include statements regarding, SRP-9003 being the ideal candidate to treat peripheral neuromuscular diseases; the potential benefits of SRP-9003, including its potential to restore the dystrophin associated protein complex (DAPC); the potential benefits of MHCK7 and the AAVrh74 vector, including its potential to be systemically and robustly delivered to skeletal, diaphragm and cardiac muscle; and potential market opportunities.

These forward-looking statements involve risks and uncertainties, many of which are beyond our control. Known risk factors include, among others: success in preclinical trials and clinical trials, especially if based on a small patient sample, does not ensure that later clinical trials will be successful; the data presented in this release may not be consistent with the final data set and analysis thereof or result in a safe or effective treatment benefit; different methodologies, assumptions and applications we utilize to assess particular safety or efficacy parameters may yield different statistical results, and even if we believe the data collected from clinical trials of our product candidates are positive, these data may not be sufficient to support approval by the FDA or foreign regulatory authorities; if the actual number of patients suffering from LGMD is smaller than estimated, our revenue and ability to achieve profitability may be adversely affected; we may not be able to execute on our business plans and goals, including meeting our expected or planned regulatory milestones and timelines, clinical development plans, and bringing our product candidates to market, due to a variety of reasons, some of which may be outside of our control, including possible limitations of company financial and other resources, manufacturing limitations that may not be anticipated or resolved for in a timely manner, regulatory, court or agency decisions, such as decisions by the United States Patent and Trademark Office with respect to patents that cover our product candidates and the COVID-19 pandemic; and even if Sareptas programs result in new commercialized products, Sarepta may not achieve the expected revenues from the sale of such products; and those risks identified under the heading Risk Factors in Sareptas most recent Annual Report on Form 10-K for the year ended December 31, 2020 filed with the Securities and Exchange Commission (SEC) as well as other SEC filings made by the Company which you are encouraged to review.

Any of the foregoing risks could materially and adversely affect the Companys business, results of operations and the trading price of Sareptas common stock. For a detailed description of risks and uncertainties Sarepta faces, you are encouraged to review the SEC filings made by Sarepta. We caution investors not to place considerable reliance on the forward-looking statements contained in this press release. Sarepta does not undertake any obligation to publicly update its forward-looking statements based on events or circumstances after the date hereof.

InternetPosting of InformationWe routinely post information that may be important to investors in the 'For Investors' section of our website atwww.sarepta.com.Weencourageinvestorsandpotentialinvestorsto consult our website regularly for important information about us.

Source:Sarepta Therapeutics, Inc.

Sarepta Therapeutics, Inc.

Investors:Ian Estepan, 617-274-4052iestepan@sarepta.com

Media:Tracy Sorrentino, 617-301-8566tsorrentino@sarepta.com

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Sarepta Therapeutics' Investigational Gene Therapy SRP-9003 for the Treatment of Limb-Girdle Muscular Dystrophy Type 2E Shows Sustained Expression and...

Dive Brief:

Biotech as a whole had a strong year in 2020. The Nasdaq Biotechnology index, which tracks the industry's stock market performance, rose by nearly 25%, recovering from a spring slump as COVID-19 became a pandemic to regain ground strongly.

Cell and gene therapy companies did even better, according to ARM, which calculated in its report stock performance that surpassed the broader NBI index.

The regenerative medicine sector, which includes tissue-based treatments as well as cell- and gene-based medicines, got larger, too. ARM counted roughly 1,100 developers worldwide, up about 100 from 2019.

"The future is now," said Janet Lambert, ARM's CEO, in an interview. "It's not like we're waiting for there to be a big and meaningful cell and gene therapy sector. There is a big and meaningful cell and gene therapy sector."

Recently, however, some of the most advanced companies have run into regulatory roadblocks or revealed disappointing study results. Cancer cases reported in trials of two closely followed gene therapies have renewed safety concerns, even if it appears the experimental treatments have not played a causative role.

Setbacks are to be expected amid the sector's fast growth, said Lambert, who noted the roughly 150 late-stage studies now ongoing. Many of those programs likely won't succeed, given the usual rates of clinical trial failure in biotech.

Unlike in the past, however, the pipeline of cell and gene therapies is so broad, and the number of companies involved so high, that setbacks for any one program are less likely to slow the entire sector than in past decades. And while the Food and Drug Administration has not cleared any new gene therapies since landmark approvals for Roche's inherited blindness treatment Luxturna and Novartis's spinal muscular atrophy therapy Zolgensma, the agency recently OK'd new CAR-T cell therapies for types of lymphoma.

Across Europe, the U.S. and China, regulators are expected to decide on approvals for eight regenerative medicine therapies this year, according to ARM. In the U.S., cancer cell therapies from Bristol Myers Squibb and Johnson & Johnson could reach market, as well as a tissue-based treatment from Mallinckrodt for severe burns.

Developers and regulators are also learning quickly, particularly in areas like manufacturing and quality control.

"One of the important things we need to work on is how best to regulate the [chemistry, manufacturing and control] aspects of cell and gene therapy," said Lambert.

"It's clearly a place we've struggled," she added, noting recent disagreements between the FDA and developers over CMC issues like testing assays.

ARM members are hoping to have more conversations with the agency earlier, Lambert said, although the FDA division in charge of cell and gene therapies has been stretched thin. In comments to the agency, ARM has advocated for the division to receive more resources and staff in renegotiations for the next FDA user fee agreement that will start in 2023.

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Record funding flowed into cell, gene therapy companies last year - BioPharma Dive

-- Ten abstracts, including four podium presentations, reflect Sareptas ongoing commitment to advancing genetic medicine for rare neuromuscular disease and facilitating greater understanding of these devastating conditions --

CAMBRIDGE, Mass., March 15, 2021 (GLOBE NEWSWIRE) -- Sarepta Therapeutics, Inc. (NASDAQ:SRPT), the leader in precision genetic medicine for rare diseases, will present at the Muscular Dystrophy Association (MDA) Annual Clinical and Scientific Conference, which will take place virtually March 15-18, 2021. Among the research that will be presented:

All posters are available on-demand throughout the Congress beginning on Monday, March 15, 2021 at 6:00 a.m. ET. Podium presentations will take place on Thursday, March 18, 2021. The full MDA 2021 Virtual Congress program is available here: https://mdaconference.org.

Podium Presentations:

Poster Presentations:

Presentations will be archived on the events and presentations page in the Investor Relations section of http://www.sarepta.com for one year following their presentation at MDA.

AboutSarepta TherapeuticsAt Sarepta, we are leading a revolution in precision genetic medicine and every day is an opportunity to change the lives of people living with rare disease. The Company has built an impressive position in Duchenne muscular dystrophy (DMD) and in gene therapies for limb-girdle muscular dystrophies (LGMDs), mucopolysaccharidosis type IIIA, Charcot-Marie-Tooth (CMT), and other CNS-related disorders, with more than 40 programs in various stages of development. The Companys programs and research focus span several therapeutic modalities, including RNA, gene therapy and gene editing. For more information, please visitwww.sarepta.com or follow us on Twitter, LinkedIn, Instagram and Facebook.

Internet Posting of Information

We routinely post information that may be important to investors in the 'For Investors' section of our website atwww.sarepta.com. We encourage investors and potential investors to consult our website regularly for important information about us.

Source: Sarepta Therapeutics, Inc.

Sarepta Therapeutics, Inc.

Investors:Ian Estepan, 617-274-4052, iestepan@sarepta.com

Media:Tracy Sorrentino, 617-301-8566, tsorrentino@sarepta.com

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Sarepta Therapeutics to Present Results from its Gene Therapy and RNA Platforms at the 2021 Annual MDA Clinical and Scientific Conference -...

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Be Biopharma (Be Bio), whose mission is to pioneer the emerging new category of engineered B cells as medicines, today announced that Joanne Smith-Farrell, Ph.D., has been appointed Chief Executive Officer and Director. Dr. Smith-Farrell will be joined by Chief Scientific Officer, Richard Morgan, Ph.D., a leading expert in cell and gene therapies.

Be Bios rapidly growing team of scientists, drug developers, manufacturing experts, and business builders is leading the creation of a new category of cellular therapies, engineered B cell medicines. B cells are exquisitely designed by nature to embody a unique mix of functionalities, including prolific protein production, tissue targeting, and durable engraftment in cellular niches. Be Bio was founded by Longwood Fund in October 2020 with a $52 million Series A investment led by Atlas Ventures and RA Capital, and joined by Alta Partners and Takeda Ventures to unlock this rich biology by precisely engineering B cells as therapies to develop a broad pipeline of potent and potentially curative cellular medicines.

Prior to joining Be Bio as Chief Executive Officer, Dr. Smith-Farrell was Chief Operating Officer and Business Unit Head, Oncology, at bluebird bio, where she led the growth of bluebird Oncology from an early single-candidate effort into a leading oncology cell therapy business. Prior to this, she held executive leadership roles as Chief Business Officer of bluebird bio, Vice President of Transactions at Merck, and Vice President of Business Development at Pfizer, as well as executive positions in public and private biotechs. Prior to entering the biopharmaceutical industry, she worked in the healthcare practice at The Boston Consulting Group. Dr. Smith-Farrell did her postdoctoral research in Biomedical Engineering in Bob Langers lab at the Harvard-MIT Division for Health Science and Technology and holds a Ph.D. in Physics from The Catholic University of America and a B.S. in Physics and Mathematics from Vanderbilt University.

Be Bios mission - to unleash the power of B cells, natures protein factories, on many of humanitys most challenging diseases is an inspiring and humbling journey to be joining, said Dr. Smith-Farrell. It has been a great privilege to participate in the birth of the first generation of cell therapies to come to market, and to witness, first-hand, cell therapys power to transform the lives of patients with devastating diseases. Be Bios aspiration, fueled by the broad utility of engineered B cell medicines to offer previously impossible solutions across a wide array of therapeutic areas, takes the potential of cell therapy to an entirely new level.

Rick Morgan, Ph.D., joins Be Bio as Chief Scientific Officer, and brings decades of experience as one of the pioneers of cell and gene therapy. Most recently, Dr. Morgan was Senior Vice President of Immunogenetics at Editas Medicine, where he focused on genome engineering to produce off-the-shelf cell medicines for cancer. Prior to that, he was Vice President of Immunotherapy at bluebird bio in 2013, where he led pre-clinical activities for bluebirds first oncology medicine, the anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy idecabtagene vicleucel (ide-cel)the first CAR-T for the treatment of multiple myeloma filed in the U.S. and Europe. He started his career at the National Institutes of Health, where he conducted groundbreaking research in the development of gene therapy for genetic diseases such as hemophilia, HIV/AIDS, and cancer immunotherapy. He was a member of the team that published the first approved human gene transfer experiment in 1990, and was also the first to report the successful use of T-cell receptor gene therapy for the treatment of cancer in 2006.

By exploiting the intrinsic drug-like properties of B cells, we can make redosable medicines with superior pharmacokinetic profiles that can be administered without toxic conditioning regimens, said Dr. Morgan. Be Bios ability to engineer B cells is a true paradigm shift in gene therapy that creates major opportunities to treat diseases such as cancer, autoimmune conditions, infectious disease, and protein deficiencies. As CSO, I am excited to have the rare opportunity to shape the development of a new class of medicine from the very start.

Extraordinary science attracts extraordinary leaders, said David Steinberg, Longwood General Partner, Director and and outgoing Chief Executive Officer, Be Bio. For over 25 years, Dr. Smith-Farrell has been leading teams that are committed to conquering cancer and rare diseases, most recently at bluebird bio where she built a 400 person oncology cell therapy business unit. We are very fortunate to have her joining alongside Dr. Morgan, an internationally recognized trailblazer in cell and gene therapy and a member of an elite group of scientists who have successfully developed these groundbreaking medicines. Together, Joanne and Rick will be invaluable to Be Bio as they lead our efforts to unlock the potential of B cell medicines, bringing transformational therapies to patients in need.

About Be Biopharma

Be Biopharma is a leader in developing B cells as medicines, treating disease with the human bodys native protein factories. We precisely engineer B cells to harness their intrinsic drug-like properties remarkable protein production, selective tissue targeting, and fine control of their cellular environment to forge a new category of cell therapy. These medicines are designed to be durable, re-dosable and administered without toxic conditioning, creating new avenues to halt or reverse severe diseases like cancer, autoimmune conditions, and enzyme deficiency. Founded by Longwood Fund and B cell engineering pioneers David Rawlings, M.D., and Richard James, Ph.D., Be Biopharma is re-imagining medicine based on the power of B cell therapy. For more information, please visit Be Biopharma.

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Be Bio Announces Appointment of Cell and Gene Therapy Veterans Joanne Smith-Farrell, Ph.D., as Chief Executive Officer and Rick Morgan, Ph.D., as...

CAMBRIDGE, Mass.--(BUSINESS WIRE)--ElevateBio, a cell and gene therapy technology company focused on powering transformative cell and gene therapies, today announced that the companys Chief Scientific Officer of Regenerative Medicine, Dr. Melissa Carpenter, has been appointed to the International Society for Stem Cell Research (ISSCR) Board of Directors. In this role, Dr. Carpenter will work with the ISSCR officers and board to advance the organizations mission of bringing together researchers, clinicians, academics, and industry to promote excellence in stem cell science and applications to human health.

I am honored to have been elected to, and serve on the Board of, the ISSCR and foster the continued progress in advancing stem cell science alongside this impressive leadership and fellow board members, said Melissa Carpenter, PhD, Chief Scientific Officer of Regenerative Medicine at ElevateBio. Collaboration across the stem cell professional community is critical to our ability to translate promising stem cell research and regenerative medicine science into treatments that can have dramatic benefit for global human health globally.

Dr. Carpenter served on the ISSCR Task Force to revise the Guidelines for Stem Cell Research and Clinical Translation that will be released in May and advocated in support of the value of stem cell research as part of the Societys 2019 Advocacy Day, meeting with members of the U.S. Congress. She has also served on the Clinical Translation Committee.

We are delighted to welcome Melissa Carpenter to the ISSCR Board of Directors, said Christine Mummery, ISSCR President. Melissas dedication to supporting the translation of stem cell discoveries into therapeutics and her leadership has been crucial for advancing the clinical development of multiple therapies. Her experience will be an asset to the Board as the field of stem cell science continues to rapidly evolve.

The International Society for Stem Cell Research is the preeminent global, cross-disciplinary, science-based organization dedicated to stem cell research and its translation to the clinic. With nearly 4,000 members from more than 60 countries, the ISSCR mission is to promote excellence in stem cell science and applications to human health.

About ElevateBio:

ElevateBio is a cell and gene therapy technology company built to power the development of transformative cell and gene therapies today and for many decades to come. The company has assembled industry-leading talent, built world-class facilities, and integrated diverse technology platforms necessary for rapid innovation and commercialization of cell, gene, and regenerative therapies. The company has built an initial technology stack, including gene editing, induced pluripotent stem cells, and protein, viral, and cellular engineering. At the center of the business model is ElevateBio BaseCamp, a centralized R&D and manufacturing company that offers research and development (R&D), process development (PD), and Current Good Manufacturing Practice (CGMP) manufacturing capabilities. The company is focused on increasing long-term collaborations with industry partners while also continuing to develop its own highly innovative cell and gene therapies. ElevateBio's team of scientists, drug developers, and company builders are redefining what it means to be a technology company in the world of drug development, blurring the line between technology and healthcare.

ElevateBio is headquartered in Cambridge, Mass, with ElevateBio BaseCamp located in Waltham, Mass. For more information, visit us at http://www.elevate.bio, or follow Elevate on LinkedIn, Twitter, or Instagram.

*As of the date of this press release, SoftBank Group Corp. has made capital contributions to allow investments by SoftBank Vision Fund 2 ("SVF 2") in certain portfolio companies. The information included herein is made for informational purposes only and does not constitute an offer to sell or a solicitation of an offer to buy limited partnership interests in any fund, including SVF 2. SVF 2 has yet to have an external close, and any potential third-party investors shall receive additional information related to any SVF 2 investments prior to closing.

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ElevateBio Announces Chief Scientific Officer of Regenerative Medicine, Melissa Carpenter, PhD, Elected to the International Society for Stem Cell...