bims-limsir 2022-11-06 papers

on Lipophilic modified siRNAs

Issue of 2022–11–06
six papers selected by
Ivan V. Chernikov, Institute of Сhemical Biology and Fundamental Medicine of the SB RAS

Clinical Pharmacology of RNAi-based Therapeutics: A Summary Based On FDA-Approved Small-interfering RNAs.
Cholesterol-Conjugated Short-Interfering RNA Silencing Tnf for the Treatment of Liver Macrophage-Mediated Acute Inflammation in Nonalcoholic Fatty Liver Disease.
Interventions and outcomes of multiple myeloma patients receiving salvage treatment after BCMA-directed CAR T therapy.
Toxicities following CAR-T therapy for hematological malignancies.
Cholesterol-conjugated siRNAs silence gene expression in mucosal dendritic cells in cervicovaginal tissue in mice.
Chimeric Antigen Receptor T-Cell (CAR T-Cell) Therapy for Primary and Secondary Central Nervous System Lymphoma: A Systematic Review of Literature.

Drug Metab Dispos. 2022 Nov 04. pii: DMD-MR-2022-001107. [Epub ahead of print]

Clinical Pharmacology of RNAi-based Therapeutics: A Summary Based On FDA-Approved Small-interfering RNAs.

Xing Jing, Vikram Arya, Kellie Schoolar Reynolds, Hobart Rogers.

  RNA-based oligonucleotide therapeutics are revolutionizing drug development for disease treatment. This class of therapeutics differ from small molecules and protein therapeutics in various ways including both its mechanism of action and clinical pharmacology characteristics. These unique characteristics, along with evolving oligonucleotide-associated conjugates allowing specific tissue targeting, have fueled interest in the evaluation of RNA-based oligonucleotide therapeutics in a rapidly increasing number of therapeutic areas. With these unique attributes as well as growing therapeutic potential, oligonucleotide therapeutics have generated significant interest from a clinical pharmacology perspective. The Food and Drug Administration (FDA) previously published results of a survey that summarized clinical pharmacology studies supporting oligonucleotide therapies approved and in development between 2012 and 2018. Since the first approval of a small-interfering RNA (siRNA) therapeutic in 2018, this class of modalities has gained momentum in various therapeutic areas. Hence, a comprehensive examination of the clinical pharmacology of FDA-approved siRNA therapeutics would benefit the path forward for many stakeholders. Thus, in this current review, we thoroughly examine and summarize clinical pharmacology data of the FDA-approved siRNA therapeutics approved from 2018 (year of first approval) to 2022, aimed at facilitating future drug development and regulatory decision making. Significance Statement This review systematically summarizes the clinical pharmacology information of FDA-approved siRNA therapeutics from 2018 (year of first approval) to 2022. SiRNAs are revolutionizing the drug development field. Unique clinical pharmacology characteristics represent a differentiating factor for this class of therapeutics. FDA recently published a draft guidance for clinical pharmacology considerations for developing oligonucleotide therapeutics. As clinical development of this class of therapeutics is fast growing, this review will inform discovery and clinical-stage evaluation of upcoming siRNA-associated drug candidates.

Keywords:  RNA/siRNA; clinical pharmacology; pharmacokinetic / pharmacodynamic modeling

DOI:  https://doi.org/10.1124/dmd.122.001107
Nucleic Acid Ther. 2022 Oct 31.

Cholesterol-Conjugated Short-Interfering RNA Silencing Tnf for the Treatment of Liver Macrophage-Mediated Acute Inflammation in Nonalcoholic Fatty Liver Disease.

Kevin Craig, Marc Abrams, Mansoor Amiji.

  Despite wide recognition as a disease of pandemic proportions, effective treatments for nonalcoholic fatty liver disease (NAFLD) remain elusive. Most of the current clinical programs aim to reduce hepatic fat accumulation and, thus, prevent downstream inflammation and fibrosis. To date, this therapeutic approach has helped identify a potential disconnect between steatosis reduction and disease resolution. Mounting preclinical evidence indicates liver inflammation may play a major role in steatosis development and fibrosis but has not garnered the same clinical representation. This may be owing to deficiencies in standard therapeutic modalities that limit their application in NAFLD. RNA interference (RNAi) is an attractive approach to targeting liver inflammation owing to its clinical safety profile, target specificity, and limited biodistribution. In this study, we characterize a simple cholesterol-short-interfering RNA (siRNA) conjugate system targeting Tnf mRNA in liver macrophages for the treatment of NAFLD. First, we observed delivery and anti-inflammatory activity in an acute liver inflammation model. In a follow-up murine NAFLD model, we observed total prevention of nearly all hallmarks of this disease: steatosis, inflammation, and fibrosis. This simple conjugate siRNA delivery system may be the first to show RNAi activity in liver macrophages and provide evidence for a novel therapeutic approach to inflammation in NAFLD.

Keywords:  Kupffer cells; NAFLD; NASH; Tnf; anti-inflammatory; macrophages; siRNA delivery; siRNA therapeutics

DOI:  https://doi.org/10.1089/nat.2022.0038
Blood. 2022 Nov 03. pii: blood.2022017848. [Epub ahead of print]

Interventions and outcomes of multiple myeloma patients receiving salvage treatment after BCMA-directed CAR T therapy.

Oliver Van Oekelen, Karthik Nath, Tarek H Mouhieddine, Tasmin Farzana, Adolfo Aleman, David T Melnekoff, Yogita Ghodke-Puranik, Gunjan L Shah, Alexander M Lesokhin, Sergio A Giralt, Santiago Thibaud, Adriana Rossi, Cesar Rodriguez, Larysa Sanchez, Joshua Richter, Shambavi Richard, Hearn Jay Cho, Ajai Chari, Saad Z Usmani, Sundar Jagannath, Urvi A Shah, Sham Mailankody, Samir Parekh.

B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy (CAR T) has demonstrated remarkable efficacy in patients with relapsed/refractory multiple myeloma, and there are now two FDA-approved BCMA-directed CAR T products. However, despite high initial response rates, most patients eventually relapse. The outcomes of patients with disease recurrence after BCMA-directed CAR T have not been comprehensively studied and such an analysis would help define optimal treatment strategies. We analyzed the salvage treatments and outcomes of 79 patients with multiple myeloma from two academic institutions who had progression of disease after treatment with BCMA-directed CAR T. A total of 237 post-CAR T salvage treatment lines were used, and patients received a median of 2 (range, 1-10) treatment lines. The median overall survival from the date of relapse post-CAR T was 17.9 months (95% confidence interval (CI), 14.0-NE). The overall response rate to the first salvage regimen was 43.4%, with a median progression-free survival of 3.5 months (CI, 2.5-4.6). Thirty-five (44.3%) patients received a T cell-engaging therapy (bispecific antibody or subsequent CAR T) as salvage treatment. The overall survival in patients that received a subsequent T cell-engaging therapy was not reached after a median follow-up of 21.3 months. Patients with multiple myeloma who relapse after BCMA-directed CAR T have a limited prognosis but can be potentially treated with multiple lines of salvage therapy. T cell-engaging therapies appear to maintain pronounced clinical activity in this setting.

DOI: https://doi.org/10.1182/blood.2022017848
Cancer Treat Rev. 2022 Oct 22. pii: S0305-7372(22)00148-7. [Epub ahead of print]111 102479

Toxicities following CAR-T therapy for hematological malignancies.

Rafael Hernani, Ana Benzaquén, Carlos Solano.

  Chimeric antigen receptor T-cell (CAR-T) therapy has improved outcomes in patients with relapsed/refractory hematological malignancies. Research is also extending to other diseases, including solid tumors, infections and autoimmune disorders. As living drugs, CAR-T cells are associated with potentially life-threatening immunological toxicities, which frequently require a multidisciplinary team approach. Cytokine-release syndrome, immune effector cell-associated neurotoxicity syndrome, infections and hematotoxicity (including cytopenias, immune reconstitution dysfunction and hypogammaglobulinemia) are associated with significant morbidity and mortality. This review takes a practical approach to summarize current knowledge on CAR-T toxicity, addressing pathogeny, risk factors, and prophylactic and therapeutic strategies.

Keywords:  Chimeric antigen receptor T-cell (CAR-T); Cytokine-release syndrome (CRS); Hematotoxicity; Immune effector cell-associated neurotoxicity syndrome (ICANS); Infections

DOI:  https://doi.org/10.1016/j.ctrv.2022.102479
J Eur Acad Dermatol Venereol. 2022 Nov 04.

Cholesterol-conjugated siRNAs silence gene expression in mucosal dendritic cells in cervicovaginal tissue in mice.

E B Basar, B S Shum, Ask Skaletz-Rorowski, Y W Wu, S N Nambiar, Nhb Brockmeyer.

BACKGROUND: RNA interference (RNAi) provides a powerful way to investigate the role of genes in disease pathogenesis and modulate gene expression to treat disease. In 2018, the FDA approved patisiran, the first RNAi-based drug, hence paving the way for a novel class of RNAi therapeutics. Harnessing RNAi to inhibit vaginal HIV transmission requires effective gene silencing in immune cells, which remains difficult. Knockdown in accessible mucosal tissues may be easier than systemic gene silencing. Vaginally applied cholesterol-conjugated small inter-fering RNAs (chol-siRNAs) blocked herpes simplex virus transmission in mice without tissue damage or immuno-stimulation.
OBJECTIVES & METHODS: To investigate using flow cytometry, confocal microscopy, and quantitative imaging if chol-siRNAs silence gene expression in vaginal immune cells in mice.
RESULTS: Although chol-siRNAs and lipoplexed-siRNAs silence gene expression in dendritic cells (DCs) in vitro, most internalized siRNAs concentrate within multivesicular bodies, where they are inaccessible to the cellular RNAi machinery. When applied intravaginally in vivo, chol-siRNAs penetrate the vaginal mucosa, including the lamina propria, and are efficiently internalized by intraepithelial (IE) and lamina propria (LP) DCs, and CD11b+ CD45+ cells, but not by T cells. Chol-siRNAs induce partial gene silencing in IE and LP DCs throughout the genital mucosa in vivo but are inactive in F4/80+ CD11b+ macrophages and T cells.
CONCLUSION: As mucosal DCs play an essential role for mucosal viral entry and dissemination, chol-siRNAs could be harnessed to target various host factors that are critical for viral uptake, DC migration and trans-infection of virions to T cells, hence allowing the development of a preventive vaginal HIV microbicide. Furthermore, chol-siRNAs could help elucidate the pathways of HIV transmission and understand the immunologic function of DCs in the genital tract.

DOI: https://doi.org/10.1111/jdv.18718
Clin Lymphoma Myeloma Leuk. 2022 Oct 07. pii: S2152-2650(22)01687-1. [Epub ahead of print]

Chimeric Antigen Receptor T-Cell (CAR T-Cell) Therapy for Primary and Secondary Central Nervous System Lymphoma: A Systematic Review of Literature.

Noureen Asghar, Adeel Masood, Armaan Dhaliwal, Sharad Khurana, James Davis, Hamza Hashmi, Muhammad Husnain.

  Relapsed/refractory central nervous system (CNS) lymphoma, whether primary or secondary, is associated with poor prognosis with currently available treatment modalities, including high-dose chemotherapy-autologous stem cell transplantation. The pivotal ZUMA-1 and JULIET trials that led to FDA approval of Axicabtagene ciloleucel and Tisagenlecleucel for relapsed refractory large cell lymphoma excluded patients with CNS involvement due to concerns of increased toxicity. However, TRANSCEND study for Lisocabtagene maraleucel in relapsed refractory large cell lymphoma allowed patients with CNS involvement and reported manageable CNS toxicities in these patients. In the real-world experience, chimeric antigen receptor T-cell (CAR T) therapy has been deemed safe and effective for these patients with poor prognosis. In this systematic review, we analyzed available literature to evaluate the role of CAR T-cell therapy in both primary and secondary CNS lymphoma using Embase, Cochrane, and PubMed databases. A total of 14 studies, including 8 retrospective analyses and 6 prospective studies/clinical trials, were included in the qualitative synthesis to study the safety and efficacy of CAR T. Based on our analysis, CAR T-cell therapy appears to be associated with reasonable efficacy and a manageable safety for primary and secondary CNS lymphoma.

Keywords:  Axicabtagene ciloleucel; Chimeric antigen receptor T-cell therapy; Lisocabtagene maraleucel; Primary CNS lymphoma; Relapsed and refractory; Secondary CNS lymphoma; Tisagenlecleucel

DOI:  https://doi.org/10.1016/j.clml.2022.09.008