Gene editing and elimination of latent herpes simplex virus in vivo DOI Creative Commons
Martine Aubert, Daniel E. Strongin, Pavitra Roychoudhury

и другие.

Nature Communications, Год журнала: 2020, Номер 11(1)

Опубликована: Авг. 18, 2020

Abstract We evaluate gene editing of HSV in a well-established mouse model, using adeno-associated virus (AAV)-delivered meganucleases, as potentially curative approach to treat latent infection. Here we show that AAV-delivered but not CRISPR/Cas9, mediate highly efficient HSV, eliminating over 90% from superior cervical ganglia. Single-cell RNA sequencing demonstrates both and individual AAV serotypes are non-randomly distributed among neuronal subsets ganglia, implying improved delivery all may lead even more complete elimination HSV. As predicted, meganucleases triple serotype combination results the greatest decrease ganglionic loads. The levels observed these studies, if translated humans, would likely significantly reduce reactivation, shedding, lesions. Further optimization meganuclease activity is possible, offer pathway cure for

Язык: Английский

The Biology of the HIV-1 Latent Reservoir and Implications for Cure Strategies DOI Creative Commons
Lillian B. Cohn, Nicolas Chomont, Steven G. Deeks

и другие.

Cell Host & Microbe, Год журнала: 2020, Номер 27(4), С. 519 - 530

Опубликована: Апрель 1, 2020

Antiretroviral therapy (ART) inhibits HIV replication but is not curative. During ART, the integrated genome persists indefinitely within CD4+ T cells and perhaps other cells. Here, we describe mechanisms thought to contribute its persistence during treatment highlight findings from numerous recent studies describing importance of cell proliferation in that process. Continued progress elucidating biology will enhance our ability develop effective curative interventions.

Язык: Английский

Процитировано

220
Novel CRISPR–Cas Systems: An Updated Review of the Current Achievements, Applications, and Future Research Perspectives DOI Open Access

Sweta Nidhi,

Uttpal Anand,

Patrik Olekšák

и другие.

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(7), С. 3327 - 3327

Опубликована: Март 24, 2021

According to Darwin’s theory, endless evolution leads a revolution. One such example is the Clustered Regularly Interspaced Palindromic Repeats (CRISPR)–Cas system, an adaptive immunity system in most archaea and many bacteria. Gene editing technology possesses crucial potential dramatically impact miscellaneous areas of life, CRISPR–Cas represents suitable strategy. The has ignited revolution field genetic engineering. ease, precision, affordability this akin Midas touch for researchers genomes. Undoubtedly, applications are endless. extensively employed treatment infectious diseases, metabolic disorders, curing cancer, developing sustainable methods fuel production chemicals, improving quality quantity food crops, thus catering global demands. Future will provide benefits everyone save countless lives. evolving rapidly; therefore, overview continuous improvement important. In review, we aim elucidate current state tailor-made format from its discovery exciting breakthroughs at application level further upcoming trends related opportunities challenges including ethical concerns.

Язык: Английский

Процитировано

184
Gene editing and CRISPR in the clinic: current and future perspectives DOI Open Access
Matthew P. Hirakawa, Raga Krishnakumar, Jerilyn A. Timlin

и другие.

Bioscience Reports, Год журнала: 2020, Номер 40(4)

Опубликована: Март 24, 2020

Genome editing technologies, particularly those based on zinc-finger nucleases (ZFNs), transcription activator-like effector (TALENs), and CRISPR (clustered regularly interspaced short palindromic repeat DNA sequences)/Cas9 are rapidly progressing into clinical trials. Most use of to date has focused ex vivo gene cells followed by their re-introduction back the patient. The approach is highly effective for many disease states, including cancers sickle cell disease, but ideally genome would also be applied diseases which require modification in vivo. However, technologies can confounded problems such as off-target editing, inefficient or delivery, stimulation counterproductive immune responses. Current research addressing these issues may provide new opportunities space. In this review, we examine current status scientific basis trials featuring ZFNs, TALENs, CRISPR-based known limitations humans, developing engineering space that should lay groundwork further translation application.

Язык: Английский

Процитировано

167
In vivo delivery of CRISPR-Cas9 therapeutics: Progress and challenges DOI Creative Commons

Matthew Behr,

Jing Zhou, Bing Xu

и другие.

Acta Pharmaceutica Sinica B, Год журнала: 2021, Номер 11(8), С. 2150 - 2171

Опубликована: Май 26, 2021

Within less than a decade since its inception, CRISPR-Cas9-based genome editing has been rapidly advanced to human clinical trials in multiple disease areas. Although it is highly anticipated that this revolutionary technology will bring novel therapeutic modalities many diseases by precisely manipulating cellular DNA sequences, the low efficiency of vivo delivery must be enhanced before potential can fully realized. Here we discuss most recent progress CRISPR-Cas9 systems, highlight innovative viral and non-viral technologies, emphasize outstanding challenges, provide updated perspectives.

Язык: Английский

Процитировано

155
Curing HIV: Seeking to Target and Clear Persistent Infection DOI Creative Commons
David M. Margolis, Nancie M. Archin, Myron S. Cohen

и другие.

Cell, Год журнала: 2020, Номер 181(1), С. 189 - 206

Опубликована: Март 26, 2020

Язык: Английский

Процитировано

154
Targeting herpes simplex virus with CRISPR–Cas9 cures herpetic stromal keratitis in mice DOI
Di Yin,

Sikai Ling,

Dawei Wang

и другие.

Nature Biotechnology, Год журнала: 2021, Номер 39(5), С. 567 - 577

Опубликована: Янв. 11, 2021

Язык: Английский

Процитировано

134
Immunomodulation—a general review of the current state-of-the-art and new therapeutic strategies for targeting the immune system DOI Creative Commons
Martyna Strzelec, Jan Detka,

Patrycja Mieszczak

и другие.

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Март 9, 2023

In recent years, there has been a tremendous development of biotechnological, pharmacological, and medical techniques which can be implemented in the functional modulation immune system components. Immunomodulation attracted much attention because it offers direct applications both basic research clinical therapy. Modulation non-adequate, amplified response enables to attenuate course disease restore homeostasis. The potential targets modulate immunity are as multiple components system, thus creating various possibilities for intervention. However, immunomodulation faces new challenges design safer more efficacious therapeutic compounds. This review cross-sectional picture currently used newest pharmacological interventions, genomic editing, tools regenerative medicine involving immunomodulation. We reviewed available experimental evidence prove efficiency, safety, feasibility vitro vivo. also advantages limitations described techniques. Despite its limitations, is considered therapy itself or an adjunct with promising results developing potential.

Язык: Английский

Процитировано

84
CRISPR editing of CCR5 and HIV-1 facilitates viral elimination in antiretroviral drug-suppressed virus-infected humanized mice DOI Creative Commons
Prasanta K. Dash, Chen Chen, Rafal Kaminski

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(19)

Опубликована: Май 1, 2023

Treatment of HIV-1 ADA -infected CD34+ NSG-humanized mice with long-acting ester prodrugs cabotegravir, lamivudine, and abacavir in combination native rilpivirine was followed by dual CRISPR-Cas9 C-C chemokine receptor type five (CCR5) proviral DNA gene editing. This led to sequential viral suppression, restoration absolute human CD4 + T cell numbers, then elimination replication-competent virus 58% infected mice. Dual CRISPR therapies enabled the excision integrated cells contained within live animals. Highly sensitive nucleic acid nested droplet digital PCR, RNAscope, outgrowth assays affirmed elimination. not detected blood, spleen, lung, kidney, liver, gut, bone marrow, brain virus-free Progeny from adoptively transferred CRISPR-treated neither nor recovered. Residual fragments were easily seen untreated viral-rebounded No evidence off-target toxicities recorded any treated Importantly, therapy demonstrated statistically significant improvements cure percentages compared single treatments. Taken together, these observations underscore a pivotal role combinatorial editing achieving infection.

Язык: Английский

Процитировано

50
Target product profile for cell-based and gene-based therapies to achieve a cure for HIV DOI
Sharon R. Lewin,

Cathy Bansbach,

Dominic Kemps

и другие.

The Lancet HIV, Год журнала: 2025, Номер 12(2), С. e154 - e162

Опубликована: Янв. 5, 2025

Язык: Английский

Процитировано

2
HIV infects astrocytes in vivo and egresses from the brain to the periphery DOI Creative Commons

Victoria Lutgen,

Srinivas D. Narasipura,

Hannah J. Barbian

и другие.

PLoS Pathogens, Год журнала: 2020, Номер 16(6), С. e1008381 - e1008381

Опубликована: Июнь 11, 2020

HIV invades the brain during acute infection. Yet, it is unknown whether long-lived infected cells release productive virus that can egress from to re-seed peripheral organs. This understanding has significant implication for as a reservoir and most importantly interplay between Given sheer number of astrocytes in human their controversial role infection, we evaluated infection vivo support We developed two novel models chimeric astrocyte/human blood mononuclear cells: NOD/scid-IL-2Rgc null (NSG) mice (huAstro/HuPBMCs) whereby transplanted (non-pseudotyped or VSVg-pseudotyped) uninfected primary fetal (NHAs) an astrocytoma cell line (U138MG) into neonate adult NSG reconstituted animals with (PBMCs). also PBMCs mimic biological course. As expected, xenotransplanted did not escape/migrate out barrier (BBB) was intact this model. demonstrate organs, at least part, through trafficking CD4+ T brain. Astrocyte-derived persists, albeit low levels, under combination antiretroviral therapy (cART). Egressed evolved pattern rate typical Lastly, analysis cortical hippocampal regions donors cART revealed harbor 0.4–5.2% integrated gag DNA 2–7% are mRNA positive. These studies establish paradigm shift dynamic interaction organs which inform eradication reservoirs.

Язык: Английский

Процитировано

133