Adeno-associated virus vector as a platform for gene therapy delivery

Wang, Dan; Tai, Phillip W. L.; Gao, Guangping

doi:10.1038/s41573-019-0012-9

Cited by 1,394 publications

(1,133 citation statements)

References 303 publications

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“…Keratinocytes are the main skin cell population involved (Pivarcsi, Kemény et al 2004, Pasparakis, Haase et al 2014, Bitschar, Wolz et al 2017); they express a variety of TLRs, which are primary sensors of innate immunity (Lee, Blaber et al 2011, Lee and Blaber 2013). The innate immune system can recognize pathogens and trigger the host response to eliminate them via the release cytokines (e.g., IL1-α and IL1-β) and AMPs (Pasparakis, Haase et al 2014, Simanski, Glaser et al 2014, Wang, Tai et al 2019, Wei, Wiggins et al 2019). AMPs are secreted by keratinocytes, sebocytes, T-cells and mast cells and can directly attack pathogens (e.g., bacteria, enveloped viruses, fungi) (Brogden 2005, Schittek, Paulmann et al 2008, Yamasaki and Gallo 2008, Clausen and Agner 2016).…”

Section: Discussionmentioning

confidence: 99%

Controlling the Growth of the Skin Commensal Staphylococcus epidermidis Using D-Alanine Auxotrophy

Whitfill

Dodds²,

Bose

et al. 2020

Preprint

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34Using live microbes as therapeutic candidates is a strategy that has gained traction across multiple 35 therapeutic areas. In the skin, commensal microorganisms play a crucial role in maintaining skin barrier 36 function, homeostasis, and cutaneous immunity. Alterations of the homeostatic skin microbiome are 37 associated with a number of skin diseases. Here, we present the design of an engineered commensal 38 organism, Staphylococcus epidermidis, for use as a live biotherapeutic product (LBP) candidate for skin 39 diseases. The development of novel bacterial strains whose growth can be controlled without the use of 40 antibiotics, or genetic elements conferring antibiotic resistance, enables modulation of therapeutic 41 exposure and improves safety. We therefore constructed an auxotrophic strain of S. epidermidis that 42 requires exogenously supplied D-alanine. The S. epidermidis strain, NRRL B-4268 65 66 Staphylococcus epidermidis, recently dubbed as the "microbial guardian of skin health" (Stacy and 67 Belkaid 2019), is a strong candidate for use as a live biotherapeutic product (LBP) for skin conditions. S. 68 epidermidis is a Gram-positive bacterium that is ubiquitous in the human skin and mucosal flora. As one 69 of the earliest colonizers of the skin after birth, S. epidermidis plays an important role in cutaneous 70 immunity and maintaining microbial community homeostasis (Naik, Bouladoux et al. 2015, Linehan, 71 Harrison et al. 2018). In the clinical setting, S. epidermidis has demonstrated activity as a potential 72 therapeutic (Iwase, Uehara et al. 2010, Nodake, Matsumoto et al. 2015, Nakatsuji, Chen et al. 2018). In 73 Japan, a double-blind, randomized clinical trial, topical application of autologous S. epidermidis in 74 healthy volunteers increased lipid content of the skin, suppressed water evaporation and improved skin 75 moisture retention while showing no signs of erythema (Nodake, Matsumoto et al. 2015). Others have 76 shown that S. epidermidis is capable of producing antimicrobial peptides (AMPs) that selectively target 77

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Section: Discussionmentioning

confidence: 99%

Controlling the Growth of the Skin Commensal Staphylococcus epidermidis Using D-Alanine Auxotrophy

Whitfill

Dodds²,

Bose

et al. 2020

Preprint

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“…AAV belongs to the Dependoparvovirus genus, Parvoviridae family. Due to the high safety of AAV, it has become the preferred platform for gene delivery[38, 39]. AAVs are present in a variety of spinal animals, including humans and NHPs.…”

Section: Discussionmentioning

confidence: 99%

“…Although AAVs itself does not cause disease, as a carrier of gene delivery in vivo , inflammatory reactions and immune barriers are inevitable problems. At present, AAVs are mainly used in the treatment of eyes and brain in clinical experiments[39]. AAV8 and AAV9 can target a variety of muscles throughout the body.…”

Section: Discussionmentioning

confidence: 99%

Extensive adaptive immune response of AAVs and Cas proteins in non-human primates

Xiao

Bai

Zhang

et al. 2019

Preprint

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16The CRISPR-mediated Cas system is the most widely used tool in gene editing 17 and gene therapy for its convenience and efficiency. Delivery of the CRISPR system 18 by adeno-associated viruses (AAVs) is currently the most promising approach to gene 19 therapy. However, pre-existing adaptive immune responses against CRISPR nuclease 20 (PAIR-C) and AAVs has been found in human serum, indicating that immune response 21 is a problem that cannot be ignored, especially for in vivo gene correction. Non-human 22 primates (NHPs) share many genetic and physiological traits with human, and are 23 considered as the bridge for translational medicine. However, whether NHPs have same 24 PAIR-C status with human is still unknown. Here, macaques (rhesus and cynomolgus), 25 including normal housed and CRISPR-SpCas9 or TALENs edited individuals, were 26 used to detect PAIR-C which covered SaCas9, SpCas9, AsCas12a and LbCas12a. Dogs 27 and mice were also detected to expand the range of species. In addition, pre-existing 28 adaptive antibodies to AAV8 and AAV9 were performed against macaques of different 29 ages. The results showed that adaptive immunity was pre-existing in the macaques 30 regardless of Cas proteins and AAVs. These findings indicate that the pre-existing 31 adaptive immune of AAV-delivered CRISPR construction and correction system 32 should be concerned for in vivo experiments. 2 33 34 The existing popular gene editing technologies mainly include zinc finger nuclease 35 (ZFN), transcription activator-like effector nucleases (TALENs), and clustered regular 36 interspaced short palindromic repeats (CRISPR) [1-3]. Through these techniques, target 37 genes can be knocked out or knocked in, and animal models of diseases caused by gene 38 mutations can be obtained[4-7]. Due to its convenient design, simple operation and high 39 efficiency, CRISRP system has become the most used gene editing system[8]. With the 40 further development of the CRISPR system, it has begun to be applied to preclinical 41 trials to treat or repair hereditary diseases caused by gene mutations[9]. Currently, there 42 are two main methods for applying the CRISPR system to therapeutic preclinical 43 experiments. One is in vitro editing. For example, stem cells are edited in vitro, and the 44 repaired cells are returned to diseased tissues and organs[10-12]. The other is in vivo 45 editing, using vectors to deliver the CRISPR system to the diseased area by intravenous, 46 intramuscular or intraperitoneal injection[13-15]. However, due to the inherent nature 47 of the CRISPR system, its safety such as off-target[16-18], immune response[19-21] 48 and toxicity[22-24] have not been well resolved, making it a huge challenge for clinic 49 application. 50 The CRISPR system is mainly derived from bacteria and archaea [25], which often 51 invade organisms as pathogens, and are recognized as an alien by the immune system 52 of these organisms, activates lymphocytes in the body to produce corresponding 53 effector cells, and removes them[26]. It is difficult f...

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“…Thus, PRV LAPs may be useful for the treatment of genetic CNS diseases after one-time viral-vector administration. 3,5,7,9,11,14,17,21,24,28,31,34,38,41,45,49,52,59,67,73,82, and 90 days post infection (dpi) with 3 x 10 11 vg. Data are represented as mean ± SEM; n = 3 SCG culture dishes per group.…”

Section: Discussionmentioning

confidence: 99%

Small Alphaherpesvirus Latency-Associated Promoters Drive Efficient and Long-Term Transgene Expression in the Central Nervous System

Maturana

Verpeut

Pisano

et al. 2019

Preprint

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AbstractRecombinant adeno-associated viral vectors (rAAV) are used as gene therapy vectors to treat central nervous system (CNS) diseases. Despite their safety and broad tropism, important issues need to be corrected such as the limited payload capacity and the lack of small gene promoters providing long-term, pan-neuronal transgene expression in the CNS. Commonly used gene promoters are relatively large and can be repressed a few months after CNS transduction, risking the long-term performance of single-dose gene therapy applications. We used a whole-CNS screening approach based on systemic delivery of AAV-PHP.eB, iDisco+ tissue-clearing and light-sheet microscopy, to identify three small latency-associated promoters (LAP) from the herpesvirus pseudorabies virus (PRV). These promoters are LAP1 (404bp), LAP2 (498bp) and LAP1_2 (880bp). They drive chronic transcription of the virus encoded latency-associated transcript (LAT) during productive and latent phases of PRV infection. We observed stable, pan-neuronal transgene transcription and translation from AAV-LAP in the CNS for six months post AAV transduction. In several CNS areas, the number of cells expressing the transgene was higher for LAP2 than the large conventional EF1α promoter (1264bp). Our data suggests that the LAP are suitable candidates for viral vector-based CNS gene therapies requiring chronic transgene expression after one-time viral-vector administration.

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Adeno-associated virus vector as a platform for gene therapy delivery

Cited by 1,394 publications

References 303 publications

Controlling the Growth of the Skin Commensal Staphylococcus epidermidis Using D-Alanine Auxotrophy

Controlling the Growth of the Skin Commensal Staphylococcus epidermidis Using D-Alanine Auxotrophy

Extensive adaptive immune response of AAVs and Cas proteins in non-human primates

Small Alphaherpesvirus Latency-Associated Promoters Drive Efficient and Long-Term Transgene Expression in the Central Nervous System

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