By: Rita Metrani, Data Analyst, Aissel Solutions
RNA interference (RNAi), an accurate and potent gene-silencing method, was first experimentally documented in 1998 in Caenorhabditis elegans by Fire et al., who subsequently were awarded the 2006 Nobel Prize in Medicine. The discovery of 21-23 nucleotide RNA duplexes, called small interference RNA (siRNA) may be one of the transforming events in biology in the past decade. RNAi can result in gene silencing or even in removing of sequences from the genome. Efforts to understand its mode of action have revealed a central role in gene regulation and host defense. The specificity, efficiency and potency of RNAi make it an attractive tool for analyzing the function of genes. This focuses on the potential therapeutic use of RNAi for various diseases, the current understanding of RNAi biology and how RNAi has been utilized to study the role of different genes in the pathogenesis of cancer, HIV, infectious diseases, Hepatitis B virus (HBV), cardiovascular and cerebral diseases, neurogenerative diseases, malaria, etc..
Chemoresistance is a major obstacle in cancer treatment. Although a number of chemotherapeutic treatments have been shown to be effective at inhibiting or eliminating cancer cell growth in preclinical studies, clinical applications are often limited due to the toxic side effects associated with anticancer drugs. Patients are often unable to tolerate the level of a drug needed to effectively eliminate malignant cells while levels that can be tolerated are insufficient therapeutically. As a result, chemoresistance and tumor recurrence are the outcome of such therapies. An example of this is the use of taxanes (paclitaxel and its semi-synthetic analogue, docetaxel) in the treatment of a variety of cancers including ovarian, breast, prostate, and non-small cell lung cancers. While surgery along with taxane and platinum-based chemotherapy for advanced ovarian cancer has allowed up to 80% of women to achieve a clinical response, cancers in most patients initially diagnosed with late stage disease eventually recur.
Targeted cancer therapy by RNA interference (RNAi) is a relatively new approach that can be used to reversibly silence genes in vivo by selectively targeting genes such as the epidermal growth factor receptor (EGFR), which has been shown to increase the sensitivity of cancer cells to taxane chemotherapy. Targeted therapies that enhance cancer cell sensitivity to chemotherapeutic agents have the potential to increase drug efficacy while reducing toxic effects on untargeted cells. However, the inability of these molecules to cross the cellular membrane and delivery to target site are the main hurdle for the development of RNAi therapeutics. This is where nanoparticle approaches have an advantage as multiple functionalities, including cellular uptake, membrane crossing ability and triggered nanoparticle disassembly, can be engineered into them. Hence delivery of siRNAs protected by nanogels to the cancer cell may be a promising strategy to increase the efficacy of chemotherapy drugs for the treatment of cancer. [1]
The epidermal growth factor receptor (EGFR) is the cell-surface receptor and is activated by binding of its specific ligands like epidermal growth factor and transforming growth factor α. Mutations affecting EGFR expression or activity could result in cancer. Many therapeutic approaches are aimed at the EGFR. Reports of inhibition of EGFR with tyrosine kinase inhibitors (e.g. gefitinib) and monoclonal antibodies (e.g. cetuximab) have demonstrated that silencing of receptor activity increases Chemosensitization of tumor cells. However, monoclonal antibody treatment for cancer may cause side effects which can be very serious like Infusion reactions, Severe low blood cell counts, Heart problems, Bleeding etc. These results highlight the need for further targeted approaches. Based on these findings, siRNA could be selectively delivered to cancer cells using a nanoparticle carrier.
Development of methods to avoid resistance may ultimately improve the impact of adjuvant therapy, resulting in prolonged disease-free intervals and survival. Novel targeted therapies that interfere with specific molecular signaling pathways affecting cancer cell survival are being developed as potential treatment options to render cancer cells more sensitive to cytotoxic chemotherapy. This offer the benefits of lowering unwanted side effects and increasing the likelihood of destroying resistant cells while avoiding healthy cells where there is little or no expression of the targeted entity.
Recent studies have shown that sensitivity of ovarian cancer cells to the taxane, paclitaxel, is enhanced when the drug is administered in combination with an inhibitor of EGFR. EGFR and its ligand, epidermal growth factor (EGF), play critical roles in the progression of ovarian cancer through their effects on cellular proliferation, apoptosis, angiogenesis, and metastasis. EGFR is overexpressed or dysregulated in many solid tumors and high levels are expressed in 33-98% of all epithelial ovarian cancers. Their high expression is believed to mitigate the effectiveness of taxane chemotherapy alone. Targeted cancer therapy by RNAi is a relatively new approach, and silencing EGFR by RNAi would show promising results. The method is based on core/shell hydrogel nanoparticle (nanogel) siRNA carriers, which represent a convenient and versatile structure for targeted drug delivery.
Results published in the January 11, 2010, online edition of the journal BMC Cancer revealed that treatment of EphA2 positive Hey cells with siRNA-loaded, peptide-targeted nanogels decreased EGFR expression levels and significantly increased the sensitivity of this cell line to docetaxel [2].
CALAA-01 Calando's leading drug candidate (combination of RONDEL™ and a patented siRNA) [3] carried out Phase I trial which was completed on March 2011 for evaluating safety, toxicity and maximum tolerated dose when administered intravenously to patients with relapsed or refractory cancer. Results revealed that 15 patients with a variety of solid cancers have been treated with CALAA-01. Importantly, the safety profile shows that it is well tolerated, including at the highest dose tested so far, and therefore confirms the pre-clinical results [4]. Non-viral carrier systems, especially nanoparticles, have been investigated extensively for siRNA delivery, and may be utilized in clinical applications in the future. So far, a few preliminary clinical trials of nanoparticles have produced promising results. However, further research is still required to pave the way to successful clinical applications. The most important issues that need to be focused on include encapsulation efficiency, formulation stability of siRNA, degradation in circulation, endosomal escape and delivery efficiency, targeting, toxicity and off-target effects. Pharmacology and pharmacokinetic studies also present another great challenge for nanoparticle delivery systems, owing to the unique nature of siRNA oligonucleotides compared with small molecules.
The epidermal growth factor receptor (EGFR) is the cell-surface receptor and is activated by binding of its specific ligands like epidermal growth factor and transforming growth factor α. Mutations affecting EGFR expression or activity could result in cancer. Many therapeutic approaches are aimed at the EGFR. Reports of inhibition of EGFR with tyrosine kinase inhibitors (e.g. gefitinib) and monoclonal antibodies (e.g. cetuximab) have demonstrated that silencing of receptor activity increases Chemosensitization of tumor cells. However, monoclonal antibody treatment for cancer may cause side effects which can be very serious like Infusion reactions, Severe low blood cell counts, Heart problems, Bleeding etc. These results highlight the need for further targeted approaches. Based on these findings, siRNA could be selectively delivered to cancer cells using a nanoparticle carrier.
Development of methods to avoid resistance may ultimately improve the impact of adjuvant therapy, resulting in prolonged disease-free intervals and survival. Novel targeted therapies that interfere with specific molecular signaling pathways affecting cancer cell survival are being developed as potential treatment options to render cancer cells more sensitive to cytotoxic chemotherapy. This offer the benefits of lowering unwanted side effects and increasing the likelihood of destroying resistant cells while avoiding healthy cells where there is little or no expression of the targeted entity.
Recent studies have shown that sensitivity of ovarian cancer cells to the taxane, paclitaxel, is enhanced when the drug is administered in combination with an inhibitor of EGFR. EGFR and its ligand, epidermal growth factor (EGF), play critical roles in the progression of ovarian cancer through their effects on cellular proliferation, apoptosis, angiogenesis, and metastasis. EGFR is overexpressed or dysregulated in many solid tumors and high levels are expressed in 33-98% of all epithelial ovarian cancers. Their high expression is believed to mitigate the effectiveness of taxane chemotherapy alone. Targeted cancer therapy by RNAi is a relatively new approach, and silencing EGFR by RNAi would show promising results. The method is based on core/shell hydrogel nanoparticle (nanogel) siRNA carriers, which represent a convenient and versatile structure for targeted drug delivery.
Results published in the January 11, 2010, online edition of the journal BMC Cancer revealed that treatment of EphA2 positive Hey cells with siRNA-loaded, peptide-targeted nanogels decreased EGFR expression levels and significantly increased the sensitivity of this cell line to docetaxel [2].
CALAA-01 Calando's leading drug candidate (combination of RONDEL™ and a patented siRNA) [3] carried out Phase I trial which was completed on March 2011 for evaluating safety, toxicity and maximum tolerated dose when administered intravenously to patients with relapsed or refractory cancer. Results revealed that 15 patients with a variety of solid cancers have been treated with CALAA-01. Importantly, the safety profile shows that it is well tolerated, including at the highest dose tested so far, and therefore confirms the pre-clinical results [4]. Non-viral carrier systems, especially nanoparticles, have been investigated extensively for siRNA delivery, and may be utilized in clinical applications in the future. So far, a few preliminary clinical trials of nanoparticles have produced promising results. However, further research is still required to pave the way to successful clinical applications. The most important issues that need to be focused on include encapsulation efficiency, formulation stability of siRNA, degradation in circulation, endosomal escape and delivery efficiency, targeting, toxicity and off-target effects. Pharmacology and pharmacokinetic studies also present another great challenge for nanoparticle delivery systems, owing to the unique nature of siRNA oligonucleotides compared with small molecules.
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[1] BMC Cancer; Jan 2010
[2] Expert Opinion on Drug Delivery; Vol. 8(4); Apr 2011
[3] ClinicalTrials.gov Identifier: NCT00689065
[4] Calando Pharmaceuticals News
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