Vectored Immunotherapeutics for Infectious Diseases: Can rAAVs Be The Game Changers for Fighting Transmissible Pathogens?

Zhan, Wenbin; Muhuri, Manish; Tai, Phillip W. L.; Gao, Guangping

doi:10.3389/fimmu.2021.673699

Cited by 25 publications

(20 citation statements)

References 284 publications

(277 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Considering the widely documented safety of AAV vector‐based gene therapies (reviewed in Borel et al ( 24 ) and Zhan et al ( 25 ) ) as well as the recent FDA approval of AAV vector‐based therapies for retinal dystrophy (Luxturna) ( 46 ) or spinal muscular atrophy (Zolgensma), ( 47 ) our proof‐of‐concept study to combine AAV and multiplexed shRNAs is, in principle, amenable to clinical translation. Ultimately, it could be used as an alternative treatment method for patients with chronic HEV who do not respond well to established therapies.…”

Section: Discussionmentioning

confidence: 99%

“…( 27 ) The proposed combination with AAV delivery, which has been established as a promising and safe vehicle for in vivo transduction including in humans, underlines its potential for clinical application. ( 24 , 25 )…”

Section: Discussionmentioning

confidence: 99%

“…Here, we screened a panel of shRNA for their potency in down‐regulating the HEV GT3 Kernow‐C1 p6 strain. To maximize clinical translatability, we used adeno‐associated viruses (AAVs) for shRNA delivery, which are safe and promising vectors for therapeutic gene transfer in humans (reviewed in Borel et al ( 24 ) and Zhan et al ( 25 ) ).…”

Section: Figmentioning

confidence: 99%

See 2 more Smart Citations

An RNA Interference/Adeno‐Associated Virus Vector–Based Combinatorial Gene Therapy Approach Against Hepatitis E Virus

et al. 2021

View full text Add to dashboard Cite

Hepatitis E virus (HEV) is a major public health problem with limited therapeutic options. Here, we engineered adeno‐associated viral vectors of serotype 6 (AAV6) to express short hairpin RNAs (shRNAs) against HEV transcripts with the prospect of down‐regulating HEV replication in vivo. We designed 20 different shRNAs, targeting the genome of the HEV genotype 3 (GT3) Kernow‐C1 p6 strain, for delivery upon AAV6 transduction. Using an original selectable HEV GT3 reporter replicon, we identified three shRNAs that efficiently down‐regulated HEV replication. We further confirmed their inhibitory potency with full‐length HEV infection. Seventy‐two hours following transduction, HEV replication in both systems decreased by up to 95%. The three most potent inhibitory shRNAs identified were directed against the methyltransferase domain, the junction region between the open reading frames (ORFs), and the 3´ end of ORF2. Targeting all three regions by multiplexing the shRNAs further enhanced their inhibitory potency over a prolonged period of up to 21 days following transduction. Conclusion: Combining RNA interference and AAV vector–based gene therapy has great potential for suppressing HEV replication. Our strategy to target the viral RNA with multiplexed shRNAs should help to counteract viral escape through mutations. Considering the widely documented safety of AAV vector–based gene therapies, our approach is, in principle, amenable to clinical translation.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

An RNA Interference/Adeno‐Associated Virus Vector–Based Combinatorial Gene Therapy Approach Against Hepatitis E Virus

et al. 2021

View full text Add to dashboard Cite

show abstract

“…A salient feature of mRNA platforms is the ability to up-scale their production quickly and their potency and efficacy at low doses, the latter lowering the volume required and thus the time and cost of manufacture [ 53 , 63 ]. Post-manufacturing storage and delivery is another important consideration; adenoviral vaccines are stable at room temperature short-term which is advantageous for vaccine deployment in countries where cold chain storage is limited [ 64 ]. Prior to the pandemic, aside from some frameworks, e.g.…”

Section: Vaccine Developmentmentioning

confidence: 99%

Clinical development and approval of COVID-19 vaccines

Kalinke

Barouch

Rizzi

et al. 2022

Expert Review of Vaccines

View full text Add to dashboard Cite

Introduction The coronavirus 19 (COVID-19) pandemic triggered a simultaneous global demand for preventative vaccines, which quickly became a high priority among governments as well as academia and the pharmaceutical industry. Within less than a year after COVID-19 was declared a pandemic, vaccines had received emergency approvals and vaccination campaigns were initiated. Areas covered We discuss the several factors that led to the unprecedented, accelerated development and approval of COVID-19 vaccines, which includes optimization of processes by regulatory authorities, redesign of sequential development processes, learnings from previous pandemics, and prior development of novel vaccine platforms. Expert Opinion Despite unanticipated and complex challenges presented by real-time vaccine development in the context of the evolving COVID-19 pandemic and subsequent ever-changing landscape of public health measures and recommendations, important milestones were reached within extraordinarily short periods and, following roll-out to billions worldwide, the approved vaccines have proven to be well tolerated and effective. Whilst this is an exceptional feat and an example of what can be achieved with collaboration and innovation, there are lessons that can still be learned, including the need for further harmonization between regulatory authorities, modes to react to the pandemic’s ever-evolving challenges, and ensuring equitable vaccine access among low-income countries.

show abstract

“…The sc configuration does, however, involve a 50% reduction in the transgene cassette capacity (~2.4 kb), thus limiting the choice of potential transgene candidates ( 136 ). As the cDNA of full-length mAbs occupies a minimum 2 kb of packaging space, A-MAD strategies using full length antibodies tend to accommodate a single copy of the antibody coding sequence in a single stranded genome ( 137 , 138 ), which also includes standard regulatory elements, such as promoter sequences, the polyA signal and the woodchuck hepatitis virus post-transcriptional regulatory element (WPRE, see Section ‘Enhancing VHH Expression’ below). On the contrary, mAbs derivatives, due to their small size, are optimal for incorporation into a scAAV system.…”

Section: Improvement Of Aav Vectors For A-mad: Optimizing the Transge...mentioning

confidence: 99%

AAV Vector-Mediated Antibody Delivery (A-MAD) in the Central Nervous System

Marino

Holt

2022

Front. Neurol.

View full text Add to dashboard Cite

In the last four decades, monoclonal antibodies and their derivatives have emerged as a powerful class of therapeutics, largely due to their exquisite targeting specificity. Several clinical areas, most notably oncology and autoimmune disorders, have seen the successful introduction of monoclonal-based therapeutics. However, their adoption for treatment of Central Nervous System diseases has been comparatively slow, largely due to issues of efficient delivery resulting from limited permeability of the Blood Brain Barrier. Nevertheless, CNS diseases are becoming increasingly prevalent as societies age, accounting for ~6.5 million fatalities worldwide per year. Therefore, harnessing the full therapeutic potential of monoclonal antibodies (and their derivatives) in this clinical area has become a priority. Adeno-associated virus-based vectors (AAVs) are a potential solution to this problem. Preclinical studies have shown that AAV vector-mediated antibody delivery provides protection against a broad range of peripheral diseases, such as the human immunodeficiency virus (HIV), influenza and malaria. The parallel identification and optimization of AAV vector platforms which cross the Blood Brain Barrier with high efficiency, widely transducing the Central Nervous System and allowing high levels of local transgene production, has now opened a number of interesting scenarios for the development of AAV vector-mediated antibody delivery strategies to target Central Nervous System proteinopathies.

show abstract

Vectored Immunotherapeutics for Infectious Diseases: Can rAAVs Be The Game Changers for Fighting Transmissible Pathogens?

Cited by 25 publications

References 284 publications

An RNA Interference/Adeno‐Associated Virus Vector–Based Combinatorial Gene Therapy Approach Against Hepatitis E Virus

An RNA Interference/Adeno‐Associated Virus Vector–Based Combinatorial Gene Therapy Approach Against Hepatitis E Virus

Clinical development and approval of COVID-19 vaccines

AAV Vector-Mediated Antibody Delivery (A-MAD) in the Central Nervous System

Contact Info

Product

Resources

About