Ribozymes are structured RNA molecules that act as catalysts in different biological reactions. From simple genome cleaving activities in satellite RNAs to more complex functions in cellular protein synthesis and gene regulation, ribozymes play important roles in all forms of life. Several naturally existing ribozymes have been modified for use as therapeutics in different conditions, with HIV-1 infection being one of the most studied. This chapter summarizes data from different preclinical and clinical studies conducted to evaluate the potential of ribozymes to be used in HIV-1 therapies. The different ribozyme motifs that have been modified, as well as their target sites and expression strategies, are described. RNA conjugations used to enhance the antiviral effect of ribozymes are also presented and the results from clinical trials conducted to date are summarized. Studies on anti-HIV-1 ribozymes have provided valuable information on the optimal expression strategies and clinical protocols for RNA gene therapy and remain competitive candidates for future therapy.

01 Dec 2013·Experimental and Therapeutic MedicineQ4 · MEDICINE

Biological influence of brain-derived neurotrophic factor (BDNF) on colon cancer cells

Q4 · MEDICINE

Article

Author: Wen Guo Jiang ; Tracey Amanda Martin ; Xiaomei Yang

Brain-derived neurotrophic factor (BDNF) has been observed to be elevated in solid tumors including colorectal cancer. The present study aimed to investigate the effect of modulation of BDNF at the transcription level on the cellular function of colorectal cells and to increase our understanding of its biological role in human colon cancer. An investigation of a cohort of human colorectal tissues (tumor n=66; normal n=88) using quantitative PCR and immunohistochemistry demonstrated that BDNF is aberrantly expressed in human colon cancer and a significantly raised level of BDNF is associated with its stage at diagnosis. The expression profile of BDNF in human colon cancer cell lines was evaluated using RT-PCR. A set of anti-BDNF ribozymes were used to transfect colon cancer cells in order to generate BDNF knockdown cells to evaluate the effect on growth and apoptosis. BDNF gene transcripts were successfully detected in the colon cancer cell lines, Caco-2 and HRT18. BDNF knockdown in Caco-2 and HRT18 cell lines resulted in decreased rates of growth and proliferation. Analysis of apoptosis showed that cell apoptosis was increased. It is concluded that BDNF, a neurotrophic growth factor aberrantly expressed in cancers such as colon cancer, has a profound impact on the cellular behavior of colon cancer cells and that BDNF is associated with a reduction in the apoptosis of colon cancer. BDNF is therefore a potential therapeutic target in colon cancer and its effect in human colon cancer requires further investigation.

01 Jan 2011·Journal of VirologyQ2 · MEDICINE

RNA Aptamers Directed to Human Immunodeficiency Virus Type 1 Gag Polyprotein Bind to the Matrix and Nucleocapsid Domains and Inhibit Virus Production

Q2 · MEDICINE

Article

Author: Ellington, Andrew ; Ramalingam, Dhivya ; Rein, Alan ; Prasad, Vinayaka R. ; Duclair, Sonald ; Datta, Siddhartha A. K.

ABSTRACT Gag orchestrates the assembly and release of human immunodeficiency virus type 1 (HIV-1) particles. We explored here the potential of anti-Gag RNA aptamers to inhibit HIV-1 replication. In vitro , RNA aptamers raised against an HIV-1 Gag protein, lacking the N-terminal myristate and the C-terminal p6 (DP6-Gag), could bind to matrix protein (MA), nucleocapsid protein (NC), or entire DP6-Gag protein. Upon cotransfection with pNL4-3.Luc molecular clone into 293T cells, six of the aptamers caused mild inhibition (2- to 3-fold) in the extracellular capsid levels, and one aptamer displayed 20-fold inhibition. The reduction was not due to a release defect but reflected Gag mRNA levels. We hypothesized that the aptamers influence genomic RNA levels via perturbation of specific Gag-genomic RNA interactions. Binding studies revealed that the “NC-binders” specifically compete with the packaging signal (ψ) of HIV-1 for binding to DP6-Gag. Therefore, we tested the ability of two NC-binders to inhibit viruses containing ψ-region deletions (ΔSL1 or ΔSL3) and found that the NC-binders were no longer able to inhibit Gag synthesis. The inability of these aptamers to inhibit ψ-deleted viruses correlated with the absence of competition with the corresponding ψ transcripts lacking SL1 or SL3 for binding DP6-Gag in vitro . These results indicate that the NC-binding aptamers disrupt Gag-genomic RNA interaction and negatively affect genomic RNA transcription, processing, or stability. Our results reveal an essential interaction between HIV-1 Gag and the ψ-region that may be distinct from that which occurs during the encapsidation of genomic RNA. Thus, anti-Gag aptamers can be an effective tool to perturb Gag-genomic RNA interactions.

100 Deals associated with Anti-gag ribozymes(City of Hope National Medical Center)

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Indication	Highest Phase	Country/Location	Organization	Date
Non-Hodgkin Lymphoma	Phase 2	-	Children's Hospital Los Angeles	-
Non-Hodgkin Lymphoma	Phase 2	-	Merck Sharp & Dohme Corp.	-
Non-Hodgkin Lymphoma	Phase 2	-	Chiron Corp.	-
Non-Hodgkin Lymphoma	Phase 2	-	City of Hope National Medical Center	-

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