scholarly journals Expanding the Reach of RNAi Therapeutics with Next Generation Lipophilic siRNA Conjugates

2021 ◽  
Author(s):  
Kirk Brown ◽  
Jayaprakash Nair ◽  
Maja Janas ◽  
Yesseinia Anglero-Rodriguez ◽  
Haiyan Peng ◽  
...  
Keyword(s):  
Cell Types ◽  
Multiple Drug ◽  
Cell Type Specificity ◽  
New Class ◽  
Medical Needs ◽  
Efficient Delivery ◽  
Rnai Therapeutics ◽  
Gene Transcripts ◽  
The Central Nervous System ◽  
Unmet Medical Needs

Abstract RNA interference (RNAi) therapeutics are a new class of medicines that can address unmet medical needs by silencing disease-causing gene transcripts. While delivery of short interfering RNAs (siRNAs) to hepatocytes has yielded multiple drug approvals, novel delivery solutions are needed to expand the reach of RNAi therapeutics. Here we report that conjugation of 2'-O-hexadecyl (C16) to siRNAs enables efficient silencing in the central nervous system (CNS), eye, and lung of multiple nonclinical species with broad cell type specificity. Intrathecally delivered C16-siRNAs are active across CNS regions and cell types, with sustained silencing for at least three months, which is an especially important outcome considering the challenging dosing route. Similarly, intravitreal and intranasal administration of C16-siRNAs resulted in potent and sustained knockdown in the eye and lung, respectively. Efficient delivery facilitated through C16 conjugation to optimized siRNA designs has enabled candidate selection for investigational human clinical trials assessing therapeutic silencing beyond the liver with infrequent (e.g. bi-annual) dosing.

scholarly journals Development of Triantennary N-Acetylgalactosamine Conjugates as Degraders for Extracellular Proteins

2020 ◽  
Author(s):  
Yaxian Zhou ◽  
peng teng ◽  
Weiping Tang
Keyword(s):  
Extracellular Proteins ◽  
Extracellular Protein ◽  
Therapeutic Modality ◽  
Cell Type ◽  
Cell Type Specificity ◽  
Protein Targets ◽  
New Class ◽  
Efficient Delivery ◽  
Lysosomal Targeting ◽  
Significant Attention

<br>Targeted protein degradation (TPD) technology has drawn significant attention from researchers in both academia and industry. It is rapidly evolved as a new therapeutic modality and also a useful chemical tool in selectively depleting various protein targets. As most efforts focus on cytosolic proteins using PROteolysis TArgeting Chimera (PROTAC), LYsosome TArgeting Chimera (LYTAC) recently emerged as a promising technology to deliver extracellular protein targets to lysosome for degradation through cation-independent mannose-6-phosphate receptor (CI-M6PR). In this study, we exploited the potential of asialoglycoprotein receptor (ASGPR), a lysosomal targeting receptor specifically expressed on liver cells, for the degradation of extracellular proteins. The ligand of ASGPR, triantennary N-acetylgalactosamine (tri-GalNAc), was conjugated to biotin, antibodies, or fragments of antibodies to generate a new class of degraders. We demonstrated that the extracellular protein targets could be successfully internalized and delivered into lysosome for degradation in a liver cell line specifically by these degraders. We also observed that more efficient delivery could be achieved for smaller degrader/target complexes. This work will add a new dimension to the TPD with cell type specificity.<br>

scholarly journals Development of Triantennary N-Acetylgalactosamine Conjugates as Degraders for Extracellular Proteins

2020 ◽  
Author(s):  
Yaxian Zhou ◽  
peng teng ◽  
Weiping Tang
Keyword(s):  
Extracellular Proteins ◽  
Extracellular Protein ◽  
Therapeutic Modality ◽  
Cell Type ◽  
Cell Type Specificity ◽  
Protein Targets ◽  
New Class ◽  
Efficient Delivery ◽  
Lysosomal Targeting ◽  
Significant Attention

<br>Targeted protein degradation (TPD) technology has drawn significant attention from researchers in both academia and industry. It is rapidly evolved as a new therapeutic modality and also a useful chemical tool in selectively depleting various protein targets. As most efforts focus on cytosolic proteins using PROteolysis TArgeting Chimera (PROTAC), LYsosome TArgeting Chimera (LYTAC) recently emerged as a promising technology to deliver extracellular protein targets to lysosome for degradation through cation-independent mannose-6-phosphate receptor (CI-M6PR). In this study, we exploited the potential of asialoglycoprotein receptor (ASGPR), a lysosomal targeting receptor specifically expressed on liver cells, for the degradation of extracellular proteins. The ligand of ASGPR, triantennary N-acetylgalactosamine (tri-GalNAc), was conjugated to biotin, antibodies, or fragments of antibodies to generate a new class of degraders. We demonstrated that the extracellular protein targets could be successfully internalized and delivered into lysosome for degradation in a liver cell line specifically by these degraders. We also observed that more efficient delivery could be achieved for smaller degrader/target complexes. This work will add a new dimension to the TPD with cell type specificity.<br>

scholarly journals Neural Stem Cells: What Happens When They Go Viral?

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1468
Author(s):  
Yashika S. Kamte ◽  
Manisha N. Chandwani ◽  
Alexa C. Michaels ◽  
Lauren A. O’Donnell
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Viral Infections ◽  
Wide Spectrum ◽  
Cell Types ◽  
Developmental Abnormalities ◽  
Multipotent Progenitor Cells ◽  
The Central Nervous System ◽  
Simplex Virus ◽  
The Brain

Viruses that infect the central nervous system (CNS) are associated with developmental abnormalities as well as neuropsychiatric and degenerative conditions. Many of these viruses such as Zika virus (ZIKV), cytomegalovirus (CMV), and herpes simplex virus (HSV) demonstrate tropism for neural stem cells (NSCs). NSCs are the multipotent progenitor cells of the brain that have the ability to form neurons, astrocytes, and oligodendrocytes. Viral infections often alter the function of NSCs, with profound impacts on the growth and repair of the brain. There are a wide spectrum of effects on NSCs, which differ by the type of virus, the model system, the cell types studied, and the age of the host. Thus, it is a challenge to predict and define the consequences of interactions between viruses and NSCs. The purpose of this review is to dissect the mechanisms by which viruses can affect survival, proliferation, and differentiation of NSCs. This review also sheds light on the contribution of key antiviral cytokines in the impairment of NSC activity during a viral infection, revealing a complex interplay between NSCs, viruses, and the immune system.

scholarly journals NF-κB in Cancer Immunity: Friend or Foe?

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 355
Author(s):  
Guilhem Lalle ◽  
Julie Twardowski ◽  
Yenkel Grinberg-Bleyer
Keyword(s):  
Immune Responses ◽  
Therapeutic Potential ◽  
Cell Types ◽  
Transcriptional Activators ◽  
New Class ◽  
Complex Interactions ◽  
Cancer Immunity ◽  
Distinct Cell ◽  
Cancer Initiation ◽  
Cancer Outcome

The emergence of immunotherapies has definitely proven the tight relationship between malignant and immune cells, its impact on cancer outcome and its therapeutic potential. In this context, it is undoubtedly critical to decipher the transcriptional regulation of these complex interactions. Following early observations demonstrating the roles of NF-κB in cancer initiation and progression, a series of studies converge to establish NF-κB as a master regulator of immune responses to cancer. Importantly, NF-κB is a family of transcriptional activators and repressors that can act at different stages of cancer immunity. In this review, we provide an overview of the selective cell-intrinsic contributions of NF-κB to the distinct cell types that compose the tumor immune environment. We also propose a new view of NF-κB targeting drugs as a new class of immunotherapies for cancer.

scholarly journals The Microbiota–Gut–Brain Axis and Alzheimer Disease. From Dysbiosis to Neurodegeneration: Focus on the Central Nervous System Glial Cells

2021 ◽  
Vol 10 (11) ◽  
pp. 2358
Author(s):  
Maria Grazia Giovannini ◽  
Daniele Lana ◽  
Chiara Traini ◽  
Maria Giuliana Vannucchi
Keyword(s):  
Alzheimer Disease ◽  
Glial Cells ◽  
Cell Types ◽  
The Past ◽  
The Central Nervous System ◽  
Diseased State ◽  
The Brain ◽  
Alzheimer Disease Pathogenesis ◽  
Brain Homeostasis

The microbiota–gut system can be thought of as a single unit that interacts with the brain via the “two-way” microbiota–gut–brain axis. Through this axis, a constant interplay mediated by the several products originating from the microbiota guarantees the physiological development and shaping of the gut and the brain. In the present review will be described the modalities through which the microbiota and gut control each other, and the main microbiota products conditioning both local and brain homeostasis. Much evidence has accumulated over the past decade in favor of a significant association between dysbiosis, neuroinflammation and neurodegeneration. Presently, the pathogenetic mechanisms triggered by molecules produced by the altered microbiota, also responsible for the onset and evolution of Alzheimer disease, will be described. Our attention will be focused on the role of astrocytes and microglia. Numerous studies have progressively demonstrated how these glial cells are important to ensure an adequate environment for neuronal activity in healthy conditions. Furthermore, it is becoming evident how both cell types can mediate the onset of neuroinflammation and lead to neurodegeneration when subjected to pathological stimuli. Based on this information, the role of the major microbiota products in shifting the activation profiles of astrocytes and microglia from a healthy to a diseased state will be discussed, focusing on Alzheimer disease pathogenesis.

scholarly journals Nanoparticles as Drug Delivery Systems of RNAi in Cancer Therapy

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2380
Author(s):  
Diedie Li ◽  
Chengzhi Gao ◽  
Meiyan Kuang ◽  
Minhao Xu ◽  
Ben Wang ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Drug Delivery Systems ◽  
Therapeutic Strategy ◽  
Target Gene ◽  
Treatment Approach ◽  
Systemic Delivery ◽  
Efficient Delivery ◽  
Rnai Therapeutics ◽  
Cellular Machinery ◽  
Tumor Delivery

RNA interference (RNAi) can mediate gene-silencing by knocking down the expression of a target gene via cellular machinery with much higher efficiency in contrast to other antisense-based approaches which represents an emerging therapeutic strategy for combating cancer. Distinct characters of nanoparticles, such as distinctive size, are fundamental for the efficient delivery of RNAi therapeutics, allowing for higher targeting and safety. In this review, we present the mechanism of RNAi and briefly describe the hurdles and concerns of RNAi as a cancer treatment approach in systemic delivery. Furthermore, the current nanovectors for effective tumor delivery of RNAi therapeutics are classified, and the characteristics of different nanocarriers are summarized.

scholarly journals Made to Measure: Patient-Tailored Treatment of Multiple Sclerosis Using Cell-Based Therapies

2021 ◽  
Vol 22 (14) ◽  
pp. 7536
Author(s):  
Inez Wens ◽  
Ibo Janssens ◽  
Judith Derdelinckx ◽  
Megha Meena ◽  
Barbara Willekens ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Autoimmune Diseases ◽  
Stromal Cells ◽  
Mononuclear Cells ◽  
Treatment Options ◽  
Cell Types ◽  
Peripheral Blood Mononuclear ◽  
Tailored Treatment ◽  
Key Issues ◽  
The Central Nervous System

Currently, there is still no cure for multiple sclerosis (MS), which is an autoimmune and neurodegenerative disease of the central nervous system. Treatment options predominantly consist of drugs that affect adaptive immunity and lead to a reduction of the inflammatory disease activity. A broad range of possible cell-based therapeutic options are being explored in the treatment of autoimmune diseases, including MS. This review aims to provide an overview of recent and future advances in the development of cell-based treatment options for the induction of tolerance in MS. Here, we will focus on haematopoietic stem cells, mesenchymal stromal cells, regulatory T cells and dendritic cells. We will also focus on less familiar cell types that are used in cell therapy, including B cells, natural killer cells and peripheral blood mononuclear cells. We will address key issues regarding the depicted therapies and highlight the major challenges that lie ahead to successfully reverse autoimmune diseases, such as MS, while minimising the side effects. Although cell-based therapies are well known and used in the treatment of several cancers, cell-based treatment options hold promise for the future treatment of autoimmune diseases in general, and MS in particular.

scholarly journals Factors Affecting Health-Related Quality of Life in Multimorbidity

Healthcare ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 334
Author(s):  
Eunmi Lee ◽  
Sunkyung Cha ◽  
Geun Myun Kim
Keyword(s):  
Quality Of Life ◽  
Health Behaviors ◽  
Private Insurance ◽  
Subjective Health ◽  
Health Related Quality ◽  
Medical Needs ◽  
Related Quality ◽  
Health Related ◽  
Unmet Medical Needs

We investigated the effect of predisposing, enabling, need factors, and health behaviors on health-related quality of life (HRQoL) of patients with multimorbidity according to Andersen’s model. This study is a secondary analysis of population-based cross-sectional surveys. Data from 328 patients with multimorbidity (≥3 co-occurring chronic diseases) from the 6th/7th Korea National Health and Nutrition Examination Surveys were analyzed using logistic regression. Patients ≥65 years, without private insurance, with poor subjective health, unmet medical needs, and/or limited activity were more likely to experience mobility problems. Self-care problems were more likely among those without private insurance and/or with limited activity. Patients lacking living security, with poor subjective health, limited activity, and/or who smoked were more likely to experience problems performing usual activities. Pain/discomfort was more likely among females, Medicaid beneficiaries, and patients with limited activity and/or with poor subjective health. Patients with poor subjective health, limited activity, and/or unmet medical needs were more likely to experience anxiety/depression. The investigation of HRQoL in multimorbidity should consider predisposing, enabling, need factors, and health behaviors. Interventions addressing movement restrictions and personalized care based on HRQoL domains should be prioritized.

scholarly journals The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration

2020 ◽  
Author(s):  
Paymaan Jafar-nejad ◽  
Berit Powers ◽  
Armand Soriano ◽  
Hien Zhao ◽  
Daniel A Norris ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Cell Types ◽  
Rnase H ◽  
Central Administration ◽  
Spinal Motor Neurons ◽  
New Class ◽  
Wide Range ◽  
Therapeutic Development

Abstract Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.

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