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Genome Editing and Gene Therapies: Complex and Expensive Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
The adeno-associated virus is a small particle with a diameter of just 20 nm and belongs to the Parvoviridae family, genus Dependovirus, a designation considering the fact that a productive infection depends on co-infection helper viruses such as adenovirus or herpes simplex virus. The non-enveloped AAV possesses a ssDNA genome, about 5 kb in length, containing the 145 nt long inverted terminal repeats (ITRs) at both ends and two open reading frames with the upstream one encoding four replication proteins (rep), and the second one coding for three capsid proteins which are all translated from one RNA. As has been shown recently, AAV capsid assembly of different AAV serotypes also requires the expression of a virally encoded assembly-activating protein (AAP) (Sonntag et al., 2011).
Recombinant DNA technology
Published in Firdos Alam Khan, Biotechnology Fundamentals, 2018
One of the major hurdles in treating cancer patients is to deliver genes, and success in gene therapy primarily depends on how effectively genes can be delivered to the target site. In the future, gene therapy may provide a way to cure genetic disorders such as severe combined immunodeficiency, cystic fibrosis, or even Hemophilia A. Because these diseases result from mutations in the DNA sequence of specific genes, gene therapy trials have used viruses to deliver unmutated copies of these genes to the cells of the patient’s body. There have been a huge number of laboratory successes with gene therapy. However, several problems of viral gene therapy must be overcome before it gains widespread use Immune response to viruses not only impedes the delivery of genes to target cells but can also cause severe complications for the patient. One of the early gene therapy trials in 1999 led to the death of Jesse Gelsinger, who was treated using an adenoviral vector. Some viral vectors, such as lentivi-ruses, insert their genomes at a seemingly random location on one of the host chromosomes, which can disturb the function of cellular genes and lead to cancer. In a severe combined immunodeficiency retroviral gene therapy trial conducted in 2002, two of the patients developed leukemia as a consequence of the treatment. Adeno-associated virus (AAV)-based vectors are much safer in this respect, as they always integrate at the same site in the human genome.
Nanomaterials for the Delivery of Therapeutic Nucleic Acids
Published in Klaus D. Sattler, st Century Nanoscience – A Handbook, 2020
Michael Riley, Wilfred Vermerris
Adeno-associated vectors (AAVs) were designed to overcome the shortcomings of both retroviral and adenoviral vectors. AAV is a single-stranded DNA virus (ssDNA) from the family Parvoviridae, with a genome of about 4.7 kb. One of the features that makes AAV an attractive vector choice is its reliable and stable integration into human chromosome 19. This is in contrast to retroviruses, which integrate randomly, potentially causing disruption of the gene in which they integrate. Another benefit is that AAV has limited pathogenicity compared to adenovirus and retro-viruses. However, AAV has limited capacity, restricting its use in gene therapy to applications involving relatively short DNA sequences.
Diagnosis and management of implant debris-associated inflammation
Published in Expert Review of Medical Devices, 2020
Stuart B. Goodman, Jiri Gallo, Emmanuel Gibon, Michiaki Takagi
Osteoprotegerin (OPG) is a natural soluble decoy protein that has the ability to inhibit the Receptor Activator of NF-κB Ligand (RANKL). In a mouse calvarial model of osteolysis, Ulrich-Vinther et al. investigated a gene therapy drug using a recombinant adeno-associated virus (rAAV) to induce production of OPG in myocytes [113]. Titanium-implanted mice treated with the rAAV showed high levels of OPG and significantly decreased numbers of osteoclasts and bone resorption. Yang et al. [114] exposed implanted bone tissue, within established pouches in BALB/c mice, with UHMWPE particles. AAV encoding the human OPG gene (rAAV-hOPG) or the β galactosidase marker gene (rAAV-LacZ) was then injected into the air pouches. This resulted in significantly less mRNA expression of osteoclast markers in OPG-transduced pouches, compared with rAAV-LacZ-transduced pouches. The transduction and expression of OPG also considerably decreased the gene copies of the biologic RANK. Similar results were obtained by Kim et al. [115].
Recent developments in imaging and surgical vision technologies currently available for improving vitreoretinal surgery: a narrative review
Published in Expert Review of Medical Devices, 2023
Elham Sadeghi, Sashwanthi Mohan, Danilo Iannetta, Jay Chhablani
Inherited retinal dystrophies, including retinitis pigmentosa and Leber’s congenital amaurosis, and degenerative diseases, including age-related macular dystrophy (ARMD), are a group of bilateral progressive retinal diseases that cause profound vision loss and may progress to blindness [191]. There is much ongoing research in developing gene or cell therapy via subretinal or intravitreal injections for inherited retinal disorders and ARMD. Voretigene neparvovec-rzyl (Luxturna, Spark therapeutics) is the only FDA-approved replacement gene therapy delivering the RPE65 gene subretinally using an adeno-associated virus (AAV) vector [192]. ADVM-022 uses AAV2 to deliver a gene encoding aflibercept to the retinal cells in patients with ARMD [193].
Lipid-based nanocarrier mediated CRISPR/Cas9 delivery for cancer therapy
Published in Journal of Biomaterials Science, Polymer Edition, 2023
Aisha Aziz, Urushi Rehman, Afsana Sheikh, Mohammed A. S. Abourehab, Prashant Kesharwani
There are insufficient techniques for accurately and timely detecting many diseases and disorders. The application of CRISPR/Cas9 technology has shown great promise in advancing these techniques for the diagnosis of infectious diseases and their treatment. Suzuki et al. described the synthesis of LNP based CRISPR/Cas delivery system for gene editing in the case of HBV-infected hepatitis. This system showed better therapeutic action compared to adeno-associated virus type 2 in HepG2 cells, in significantly inhibiting HBV DNA and cccDNA replication. Other lipid-like nanoparticles were developed by Li et al. to escort Cas9 mRNA/sgRNA complex to treat HBV infection. It showed high gene knockout and significant gene editing [82].