scholarly journals Adeno-Associated Virus Mediated Gene Therapy for Corneal Diseases

Pharmaceutics ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 767
Author(s):  
Prabhakar Bastola ◽  
Liujiang Song ◽  
Brian C. Gilger ◽  
Matthew L. Hirsch
Keyword(s):  
Gene Therapy ◽  
Targeted Delivery ◽  
Viral Vector ◽  
Corneal Transplantation ◽  
Genetic Material ◽  
The United States ◽  
Human Diseases ◽  
World Health ◽  
Eye Drops ◽  
Adeno Associated Virus

According to the World Health Organization, corneal diseases are the fourth leading cause of blindness worldwide accounting for 5.1% of all ocular deficiencies. Current therapies for corneal diseases, which include eye drops, oral medications, corrective surgeries, and corneal transplantation are largely inadequate, have undesirable side effects including blindness, and can require life-long applications. Adeno-associated virus (AAV) mediated gene therapy is an optimistic strategy that involves the delivery of genetic material to target human diseases through gene augmentation, gene deletion, and/or gene editing. With two therapies already approved by the United States Food and Drug Administration and 200 ongoing clinical trials, recombinant AAV (rAAV) has emerged as the in vivo viral vector-of-choice to deliver genetic material to target human diseases. Likewise, the relative ease of applications through targeted delivery and its compartmental nature makes the cornea an enticing tissue for AAV mediated gene therapy applications. This current review seeks to summarize the development of AAV gene therapy, highlight preclinical efficacy studies, and discuss potential applications and challenges of this technology for targeting corneal diseases.

scholarly journals Mapping an Adeno-associated Virus 9-Specific Neutralizing Epitope To Develop Next-Generation Gene Delivery Vectors

2018 ◽  
Vol 92 (20) ◽  
Author(s):  
April R. Giles ◽  
Lakshmanan Govindasamy ◽  
Suryanarayan Somanathan ◽  
James M. Wilson
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Neutralizing Antibodies ◽  
Viral Vector ◽  
The United States ◽  
Single Amino Acid ◽  
Fold Axis ◽  
Next Generation ◽  
Adeno Associated Virus ◽  
Neutralizing Epitopes

ABSTRACTRecent clinical trials have demonstrated the potential of adeno-associated virus (AAV)-based vectors for treating rare diseases. However, significant barriers remain for the translation of these vectors into widely available therapies. In particular, exposure to the AAV capsid can generate an immune response of neutralizing antibodies. One approach to overcome this response is to map the AAV-specific neutralizing epitopes and rationally design an AAV capsid able to evade neutralization. To accomplish this, we isolated a monoclonal antibody against AAV9 following immunization of BALB/c mice and hybridoma screening. This antibody, PAV9.1, is specific for intact AAV9 capsids and has a high neutralizing titer of >1:160,000. We used cryo-electron microscopy to reconstruct PAV9.1 in complex with AAV9. We then mapped its epitope to the 3-fold axis of symmetry on the capsid, specifically to residues 496-NNN-498 and 588-QAQAQT-592. Capsid mutagenesis demonstrated that even a single amino acid substitution within this epitope markedly reduced binding and neutralization by PAV9.1. In addition,in vivostudies showed that mutations in the PAV9.1 epitope conferred a “liver-detargeting” phenotype to the mutant vectors, unlike AAV9, indicating that the residues involved in PAV9.1 interactions are also responsible for AAV9 tropism. However, we observed minimal changes in binding and neutralizing titer when we tested these mutant vectors for evasion of polyclonal sera from mice, macaques, or humans previously exposed to AAV. Taken together, these studies demonstrate the complexity of incorporating mapped neutralizing epitopes and previously identified functional motifs into the design of novel capsids able to evade immune response.IMPORTANCEGene therapy utilizing viral vectors has experienced recent success, culminating in U.S. Food and Drug Administration approval of the first adeno-associated virus vector gene therapy product in the United States: Luxturna for inherited retinal dystrophy. However, application of this approach to other tissues faces significant barriers. One challenge is the immune response to viral infection or vector administration, precluding patients from receiving an initial or readministered dose of vector, respectively. Here, we mapped the epitope of a novel neutralizing antibody generated in response to this viral vector to design a next-generation capsid to evade immune responses. Epitope-based mutations in the capsid interfered with the binding and neutralizing ability of the antibody but not when tested against polyclonal samples from various sources. Our results suggest that targeted mutation of a greater breadth of neutralizing epitopes will be required to evade the repertoire of neutralizing antibodies responsible for blocking viral vector transduction.

scholarly journals Controlled Release of rAAV Vectors from APMA-Functionalized Contact Lenses for Corneal Gene Therapy

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 335 ◽  
Author(s):  
Fernando Alvarez-Rivera ◽  
Ana Rey-Rico ◽  
Jagadeesh K Venkatesan ◽  
Luis Diaz-Gomez ◽  
Magali Cucchiarini ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Contact Lenses ◽  
Viral Vector ◽  
Controlled Delivery ◽  
Eye Drops ◽  
Adeno Associated Virus ◽  
Vector Titer ◽  
First Time ◽  
Steam Heat

As an alternative to eye drops and ocular injections for gene therapy, the aim of this work was to design for the first time hydrogel contact lenses that can act as platforms for the controlled delivery of viral vectors (recombinant adeno-associated virus, rAAV) to the eye in an effective way with improved patient compliance. Hydrogels of hydroxyethyl methacrylate (HEMA) with aminopropyl methacrylamide (APMA) (H1: 40, and H2: 80 mM) or without (Hc: 0 mM) were synthesized, sterilized by steam heat (121 °C, 20 min), and then tested for gene therapy using rAAV vectors to deliver the genes to the cornea. The hydrogels showed adequate light transparency, oxygen permeability, and swelling for use as contact lenses. Loading of viral vectors (rAAV-lacZ, rAAV-RFP, or rAAV-hIGF-I) was carried out at 4 °C to maintain viral vector titer. Release in culture medium was monitored by fluorescence with Cy3-rAAV-lacZ and AAV Titration ELISA. Transduction efficacy was tested through reporter genes lacZ and RFP in human bone marrow derived mesenchymal stem cells (hMSCs). lacZ was detected with X-Gal staining and quantified with Beta-Glo®, and RFP was monitored by fluorescence. The ability of rAAV-hIGF-I-loaded hydrogels to trigger cell proliferation in hMSCs was evaluated by immunohistochemistry. Finally, the ability of rAAV-lacZ-loaded hydrogels to transduce bovine cornea was confirmed through detection with X-Gal staining of β-galactosidase expressed within the tissue.

scholarly journals How Far Are Non-Viral Vectors to Come of Age and Reach Clinical Translation in Gene Therapy?

2021 ◽  
Vol 22 (14) ◽  
pp. 7545
Author(s):  
Myriam Sainz-Ramos ◽  
Idoia Gallego ◽  
Ilia Villate-Beitia ◽  
Jon Zarate ◽  
Iván Maldonado ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Practice ◽  
Gene Delivery ◽  
Viral Vectors ◽  
Viral Vector ◽  
Clinical Success ◽  
Genetic Material ◽  
Viral Gene ◽  
Promising Alternative ◽  
Vector Systems

Efficient delivery of genetic material into cells is a critical process to translate gene therapy into clinical practice. In this sense, the increased knowledge acquired during past years in the molecular biology and nanotechnology fields has contributed to the development of different kinds of non-viral vector systems as a promising alternative to virus-based gene delivery counterparts. Consequently, the development of non-viral vectors has gained attention, and nowadays, gene delivery mediated by these systems is considered as the cornerstone of modern gene therapy due to relevant advantages such as low toxicity, poor immunogenicity and high packing capacity. However, despite these relevant advantages, non-viral vectors have been poorly translated into clinical success. This review addresses some critical issues that need to be considered for clinical practice application of non-viral vectors in mainstream medicine, such as efficiency, biocompatibility, long-lasting effect, route of administration, design of experimental condition or commercialization process. In addition, potential strategies for overcoming main hurdles are also addressed. Overall, this review aims to raise awareness among the scientific community and help researchers gain knowledge in the design of safe and efficient non-viral gene delivery systems for clinical applications to progress in the gene therapy field.

scholarly journals Characterization of Recombinant Adeno-Associated Viruses (rAAVs) for Gene Therapy Using Orthogonal Techniques

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 586
Author(s):  
Liam Cole ◽  
Diogo Fernandes ◽  
Maryam T. Hussain ◽  
Michael Kaszuba ◽  
John Stenson ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Light Scattering ◽  
Dynamic Light Scattering ◽  
Viral Vector ◽  
Structural Characteristics ◽  
Genetic Material ◽  
Label Free ◽  
Gene Therapies ◽  
Multiple Challenges

Viruses are increasingly used as vectors for delivery of genetic material for gene therapy and vaccine applications. Recombinant adeno-associated viruses (rAAVs) are a class of viral vector that is being investigated intensively in the development of gene therapies. To develop efficient rAAV therapies produced through controlled and economical manufacturing processes, multiple challenges need to be addressed starting from viral capsid design through identification of optimal process and formulation conditions to comprehensive quality control. Addressing these challenges requires fit-for-purpose analytics for extensive characterization of rAAV samples including measurements of capsid or particle titer, percentage of full rAAV particles, particle size, aggregate formation, thermal stability, genome release, and capsid charge, all of which may impact critical quality attributes of the final product. Importantly, there is a need for rapid analytical solutions not relying on the use of dedicated reagents and costly reference standards. In this study, we evaluate the capabilities of dynamic light scattering, multiangle dynamic light scattering, and SEC–MALS for analyses of rAAV5 samples in a broad range of viral concentrations (titers) at different levels of genome loading, sample heterogeneity, and sample conditions. The study shows that DLS and MADLS® can be used to determine the size of full and empty rAAV5 (27 ± 0.3 and 33 ± 0.4 nm, respectively). A linear range for rAAV5 size and titer determination with MADLS was established to be 4.4 × 1011–8.7 × 1013 cp/mL for the nominally full rAAV5 samples and 3.4 × 1011–7 × 1013 cp/mL for the nominally empty rAAV5 samples with 3–8% and 10–37% CV for the full and empty rAAV5 samples, respectively. The structural stability and viral load release were also inferred from a combination of DLS, SEC–MALS, and DSC. The structural characteristics of the rAAV5 start to change from 40 °C onward, with increasing aggregation observed. With this study, we explored and demonstrated the applicability and value of orthogonal and complementary label-free technologies for enhanced serotype-independent characterization of key properties and stability profiles of rAAV5 samples.

Gene Therapy: Paving New Roads in the Treatment of Hemophilia

2019 ◽  
Vol 45 (07) ◽  
pp. 743-750 ◽  
Author(s):  
Gabriela G. Yamaguti-Hayakawa ◽  
Margareth C. Ozelo
Keyword(s):  
Gene Therapy ◽  
Animal Models ◽  
Pediatric Patients ◽  
Viral Vector ◽  
Monogenic Disease ◽  
Adeno Associated Virus ◽  
Underlying Liver Disease ◽  
Experimental Animal Models ◽  
The Road ◽  
Gene Therapy Application

AbstractHemophilia is a monogenic disease with robust clinicolaboratory correlations of severity. These attributes coupled with the availability of experimental animal models have made it an attractive model for gene therapy. The road from animal models to human clinical studies has heralded significant successes, but major issues concerning a previous immunity against adeno-associated virus and transgene optimization remain to be fully resolved. Despite significant advances in gene therapy application, many questions remain pertaining to its use in specific populations such as those with factor inhibitors, those with underlying liver disease, and pediatric patients. Here, the authors provide an update on viral vector and transgene improvements, review the results of recently published gene therapy clinical trials for hemophilia, and discuss the main challenges facing investigators in the field.

scholarly journals Anti-angiogenesis Therapy in Cancer Treatment

2019 ◽  
Vol 35 (1) ◽  
Author(s):  
Thi Thanh Binh Nguyen ◽  
Dang Thi Ngan ◽  
Nguyen Thanh Hai
Keyword(s):  
Growth Factor ◽  
Cancer Therapy ◽  
Targeted Delivery ◽  
Cancer Control ◽  
The United States ◽  
World Health ◽  
International Agency ◽  
Clinical Cancer Research ◽  
Health Organization ◽  
Endothelial Growth Factor

Angiogenesis plays a crucial role in the proliferation, invasion and metastasis of cancer cells. Unlike conventional chemotherapy, anti-angiogenesis drugs inhibit the formation of new blood vessels, reduce the nutrition and oxygen supply to the tumour, thus halting disease progression. In the last fifteen years, Food and Drug Administration of the United States has approved more than ten anti-cancer drugs of this group, namely the monoclonal antibody bevacizumab and small molecules drugs such as temsirolimus, sunitinib, axitinib and sorafenib. Other anti-angiogenesis agents are currently undergoing clinical trials. In addition to treating cancer, these agents have also potential applications in the treatment of complications related to angiogenesis in diabetes, arthritis, psoriasis and collagen-related diseases. Keywords Anti-angiogenesis, angiogenesis, cancer, metastasis, treatment. References [1] International Agency for Research on Cancer WHO, International agency for research on cancer – world health organization. https://www.iarc.fr/featured-news/latest-global-cancer-data-cancer-burden-rises-to-18-1-million-new-cases-and-9-6-million-cancer-deaths-in-2018 (accessed 19 February 2019).[2] International Agency for Research on Cancer France, Cancer today - International agency for research on cancer – world health organization. https://gco.iarc.fr(accessed 19 February 2019).[3] D.W. Siemann, M.C. Bibby, G.G. Dark, A.P. Dicker, FALM. Eskens, et al. Differentiation and Definition of Vascular-Targeted Therapies. Clinical Cancer Research. 11(2) (2005) 416–420.[4] J. Folkman, Tumor angiogenesis: therapeutic implications, The New England Journal of Medicine. 285(21) (1971) 1182-1186.[5] D. Hanahan, J. Folkman. Patterns of emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 86(3) (1996) 353–64.[6] G. Gasparini. The rationale and future potential of angiogenesis inhibitors in neoplasia. Drugs. 58(1) (1999) 17-38.[7] J. Folkman, E. Braunwald, A.S. Fauci, D.L. Kasper, S.L. Hauser, D.L. Longo, J.L. Jameson, editors. Angiogenesis. Harrison’s textbook of internal medicine. fifteen ed. McGraw-Hill, New York, 2001. pp. 517–530.[8] J. Folkman. Angiogenesis research: From Laboratory to clinic. Forum Genova. 9(3) (1999) 59–62.[9] S. Liekens, E. De Clercq, J. Neyts. Angiogenesis: Regulators and clinical applications. Biochemical Pharmacology. 61(3) (2001) 253–270.[10] L. Rosen. Clinical experience with angiogenesis signaling inhibitors: Focus on vascular endothelial growth factor (VEGF) blockers, Cancer Control. 9(2) (2002) 36-44.[11] A.L. Harris. Angiogenesis as a new target for cancer control. European Journal of Cancer Supplements. 1(2) (2003) 1-12.[12] D.W. Siemann. Vascular Targeting Agents. horizons in cancer therapeutics from bench to bedside. 3(2) (2002) 4–15.[13] B.G. Wouters, S.A. Weppler, M. Koritzinsky, W. Landuyt, S. Nuyts, et al. Hypoxia as a target for combined modality treatments, European Journal of Cancer. 38(2) (2002) 240–257.[14] P. Carmeliet, R.K. Jain. Angiogenesis in cancer and other diseases. Nature. 407(6801) (2000) 249-257.[15] J.W. Rak, B.D. St. Croix, R.S. Kerbel. Consequences of angiogenesis for tumor progression, metastasis and cancer therapy. Anticancer Drugs. 6(1) (1995) 3–18.[16] J. Hamada, P.G. Cavanaugh, O. Lotan, G.L. Nicolson. Separable growth and migration factors for large-cell lymphoma cells secreted by microvascular endothelial cells derived from target organs for metastasis. British Journal of Cancer. 66(2) (1992) 349-54.[17] J. Denekamp. Vascular attack as a therapeutic strategy for cancer. Cancer and Metastasis Reviews. 9(3) (1990) 267–282.[18] J. Denekamp. Angiogenesis, neovascular proliferation and vascular pathophysiology as targets for cancer therapy. The British Institute of Radiology. 66(783) (1993) 181–186.[19] H.P. Eikesdal, H. Sugimoto, G. Birrane, Y. Maeshima, V.G. Cooke, et al. Identification of amino acids essential for the antiangiogenic activity of tumstatin and its use in combination antitumor activity. Proceedings of the National Academy of Sciences of the United States of America. 105(39) (2008) 15040–15045.[20] F. Ciardiello, R. Caputo, R. Bianco, V. Damiano, G. Fontanini, et al. Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa),a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clinical Cancer Research. 7(5) (2001) 1459–1465.[21] T. Kamba, D.M. McDonald. Mechanisms of adverse effects of anti-VEGF therapy for cancer. British Journal of Cancer. 96(12) (2007) 1788–1795.[22] S.M. Gressett, S.R. Shah. Intricacies of bevacizumab-induced toxicities and their management. Annals of Pharmacotherapy. 43(3) (2009) 490–501[23] S. Goel, D.G. Duda, L. Xu, L.L. Munn, Y. Boucher, et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiological Reviews. 91(3) (2011) 1071–1121.[24] T. Sudha, D.J. Bharali, M. Yalcin, N.H. Darwish, M.D. Coskun, et al. Targeted delivery of paclitaxel and doxorubicin to cancer xenografts via the nanoparticle of nano-diamino-tetrac. International Journal of Nanomedicine. 12(3) (2017) 1305–1315.[25] T. Sudha, D.J. Bharali, M. Yalcin, N.H. Darwish, M.D. Coskun, et al. Targeted delivery of cisplatin to tumor xenografts via the nanoparticle component of nano-diamino-tetrac. Nanomedicine. 12(3) (2017) 195–205.[26] M.Rajabi, S.A. Mousa. The Role of Angiogenesis in Cancer Treatment. Biomedicines. 5(2) (2017) 34-45.[27] J.Y. Hsu, H.A. Wakelee. Monoclonal antibodies targeting vascular endothelial growth factor: Current status and future challenges in cancer therapy. BioDrugs. 23(5) (2009) 289–304.[28] M. Zhou, P. Yu, X. Qu, Y. Liu, J. Zhang. Phase III trials of standard chemotherapy with or without bevacizumab for ovarian cancer: A meta-analysis, Plos One. 8(12) (2013) e81858.[29] D.H. Johnson, L. Fehrenbacher, W.F. Novotny, R.S. Herbst, J.J. Nemunaitis, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. Journal of Clinical Oncology. 22(11) (2004) 2184–2191.[30] B.J. Giantonio, D.E. Levy, P.J. O’Dwyer, N.J. Meropol, P.J. Catalano, et al. A phase II study of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group study E2200, Annals of Oncology. 17(9) (2006) 1399–1403.

scholarly journals Gene Therapy Approaches

2021 ◽  
Vol 1 (1) ◽  
pp. 52-56
Author(s):  
Hogir Saadi
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Nuclear Translocation ◽  
Viral Vector ◽  
Ex Vivo ◽  
Genetic Material ◽  
Target Tissue ◽  
Human Beings ◽  
Vector Systems

Gene therapy can be described broadly as the transfer of genetic material to control a disease or at least to enhance a patient's clinical status. The transformation of viruses into genetic shuttles is one of the core principles of gene therapy, which will introduce the gene of interest into the target tissue and cells. To do this, safe strategies have been invented, using many viral and non-viral vector delivery. Two major methods have emerged: modification in vivo and modification ex vivo. For gene therapeutic approaches which are focused on lifelong expression of the therapeutic gene, retrovirus, adenovirus, adeno-associated viruses are acceptable. Non-viral vectors are much less successful than viral vectors, but because of their low immune responses and their broad therapeutic DNA ability, they have advantages. The addition of viral functions such as receptor-mediated uptake and nuclear translocation of DNA may eventually lead to the development of an artificial virus in order to improve the role of non-viral vectors. For human use in genetic conditions, cancers and acquired illnesses, gene transfer techniques have been allowed. The ideal delivery vehicle has not been identified, although the accessible vector systems are capable of transporting genes in vivo into cells. Therefore, only with great caution can the present viral vectors be used in human beings and further progress in the production of vectors is required. Current progresses in our understanding of gene therapy approaches and their delivery technology, as well as the victors used to deliver therapeutic genes, are the primary goals of this review. For that reason, a literature search on PubMed and Google Scholar was carried out using different keywords.

scholarly journals Polymeric Nanoparticles in Gene Therapy: New Avenues of Design and Optimization for Delivery Applications

Polymers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 745 ◽  
Author(s):  
Raj Rai ◽  
Saniya Alwani ◽  
Ildiko Badea
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Targeted Delivery ◽  
Polymeric Nanoparticles ◽  
Genetic Material ◽  
Delivery Systems ◽  
Viral Gene ◽  
Cationic Polymers ◽  
Natural Polymers ◽  
Viral Gene Delivery

The field of polymeric nanoparticles is quickly expanding and playing a pivotal role in a wide spectrum of areas ranging from electronics, photonics, conducting materials, and sensors to medicine, pollution control, and environmental technology. Among the applications of polymers in medicine, gene therapy has emerged as one of the most advanced, with the capability to tackle disorders from the modern era. However, there are several barriers associated with the delivery of genes in the living system that need to be mitigated by polymer engineering. One of the most crucial challenges is the effectiveness of the delivery vehicle or vector. In last few decades, non-viral delivery systems have gained attention because of their low toxicity, potential for targeted delivery, long-term stability, lack of immunogenicity, and relatively low production cost. In 1987, Felgner et al. used the cationic lipid based non-viral gene delivery system for the very first time. This breakthrough opened the opportunity for other non-viral vectors, such as polymers. Cationic polymers have emerged as promising candidates for non-viral gene delivery systems because of their facile synthesis and flexible properties. These polymers can be conjugated with genetic material via electrostatic attraction at physiological pH, thereby facilitating gene delivery. Many factors influence the gene transfection efficiency of cationic polymers, including their structure, molecular weight, and surface charge. Outstanding representatives of polymers that have emerged over the last decade to be used in gene therapy are synthetic polymers such as poly(l-lysine), poly(l-ornithine), linear and branched polyethyleneimine, diethylaminoethyl-dextran, poly(amidoamine) dendrimers, and poly(dimethylaminoethyl methacrylate). Natural polymers, such as chitosan, dextran, gelatin, pullulan, and synthetic analogs, with sophisticated features like guanidinylated bio-reducible polymers were also explored. This review outlines the introduction of polymers in medicine, discusses the methods of polymer synthesis, addressing top down and bottom up techniques. Evaluation of functionalization strategies for therapeutic and formulation stability are also highlighted. The overview of the properties, challenges, and functionalization approaches and, finally, the applications of the polymeric delivery systems in gene therapy marks this review as a unique one-stop summary of developments in this field.

scholarly journals Gene therapy: advances, challenges and perspectives

2017 ◽  
Vol 15 (3) ◽  
pp. 369-375 ◽  
Author(s):  
Giulliana Augusta Rangel Gonçalves ◽  
Raquel de Melo Alves Paiva
Keyword(s):  
Gene Therapy ◽  
Germ Line ◽  
Genetic Material ◽  
The United States ◽  
In Vivo Studies ◽  
Basic Unit ◽  
Target Cells ◽  
Site Specific ◽  
Genomic Editing

ABSTRACT The ability to make site-specific modifications to the human genome has been an objective in medicine since the recognition of the gene as the basic unit of heredity. Thus, gene therapy is understood as the ability of genetic improvement through the correction of altered (mutated) genes or site-specific modifications that target therapeutic treatment. This therapy became possible through the advances of genetics and bioengineering that enabled manipulating vectors for delivery of extrachromosomal material to target cells. One of the main focuses of this technique is the optimization of delivery vehicles (vectors) that are mostly plasmids, nanostructured or viruses. The viruses are more often investigated due to their excellence of invading cells and inserting their genetic material. However, there is great concern regarding exacerbated immune responses and genome manipulation, especially in germ line cells. In vivo studies in in somatic cell showed satisfactory results with approved protocols in clinical trials. These trials have been conducted in the United States, Europe, Australia and China. Recent biotechnological advances, such as induced pluripotent stem cells in patients with liver diseases, chimeric antigen receptor T-cell immunotherapy, and genomic editing by CRISPR/Cas9, are addressed in this review.

scholarly journals Gene Replacement Therapy: A Primer for the Health-system Pharmacist

2019 ◽  
Vol 33 (6) ◽  
pp. 846-855 ◽  
Author(s):  
John Petrich ◽  
Dominic Marchese ◽  
Chris Jenkins ◽  
Michael Storey ◽  
Jill Blind
Keyword(s):  
Gene Therapy ◽  
Replacement Therapy ◽  
Expert Opinion ◽  
Viral Vectors ◽  
Professional Associations ◽  
The United States ◽  
Gene Replacement ◽  
World Health ◽  
Risk Level ◽  
Gene Replacement Therapy

Purpose: Comprehensive review of gene replacement therapy with guidance and expert opinion on handling and administration for pharmacists. Summary: There are currently ∼2600 gene therapy clinical trials worldwide and 4 Food and Drug Administration (FDA)-approved gene therapy products available in the United States. Gene therapy and its handling are different from other drugs; however, there is a lack of guidance from the National Institutes of Health (NIH), FDA, Centers for Disease Control and Prevention (CDC), World Health Organization (WHO), and professional associations regarding their pharmaceutical application. Although the NIH stratifies the backbone biologicals of viral vectors in gene therapies into risk groups, incomplete information regarding minimization of exposure and reduction of risk exists. In the absence of defined guidance, individual institutions develop their own policies and procedures, which often differ and are often outdated. This review provides expert opinion on the role of pharmacists in institutional preparedness, as well as gene therapy handling and administration. A suggested infrastructural model for gene replacement therapy handling is described, including requisite equipment acquisition and standard operating procedure development. Personnel, patient, and caregiver education and training are discussed. Conclusion: Pharmacists have a key role in the proper handling and general management of gene replacement therapies, identifying risk level, establishing infrastructure, and developing adequate policies and protocols, particularly in the absence of consensus guidelines for the handling and transport of gene replacement therapies.

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