Abstract: If those of us privileged enough to have the opportunity to work towards curing human diseases had the power to design the ideal therapeutic molecule, the question would be what selection criteria would we choose? Arguably, at the top of the list would be four mandatory properties: specificity, potency, tolerability, and universality. So it should come as no surprise the momentum associated with the field of small interfering RNA (siRNA)-induced RNA Interference (RNAi) therapeutics has gained strength, as these molecules have shown exceptional promise in fulfilling all of these requirements. Unfortunately, siRNAs are too large, too charged, and too rigid to passively diffuse across the cellular membrane and thereby require a delivery system to enter cells. Thus, since its conception of working in human cells, siRNA delivery remains THE 800 Pound Gorilla in the room. The main complication yet to overcome is engineering delivery systems that are safe and efficient in systemically delivering siRNA molecules to the diseased tissue and across the cellular membrane of target cells. Currently, encapsulating the siRNA in nanoparticle and liposomal systems has risen to become the standard of delivery approaches. While generally speaking these delivery platforms offer significant advancements, our laboratory is committed to generating alternative siRNA delivery technologies that avoid nanoparticle packaging and allow siRNA molecules to be delivered as single, soluble entities. This brief review discusses the first of these technologies, a Peptide Transduction Domain-dsRNA Binding Domain (PTD-DRBD) fusion protein that avidly binds to the siRNA backbone to mask the negative charge and uses the PTD for macromolecular cellular delivery. ... Read more

Abstract: Treatment outcome for advanced-stage non-small cell lung cancer (NSCLC) is limited by empiric administration of cytotoxic chemotherapy. Recent advances in molecular genomics have revolutionized cancer management and, specifically, epidermal growth factor receptor (EGFR) mutation has become a potent biomarker for lung cancer, which predicts tumor response to and prolonged duration of disease control by EGFR tyrosine kinase inhibitors (TKI). The Iressa Pan-Asia Study (IPASS) is a randomized phase III study comparing gefitinib (EGFR TKI) with paclitaxel/carboplatin (standard chemotherapy) in Asian non-/light smokers with adenocarcinoma. Progression-free survival (PFS) in EGFR mutation-positive patients was longer with gefitinib than with chemotherapy (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.36-0.64; p<0.0001); in EGFR mutation-negative patients, PFS was longer with chemotherapy than with gefitinib (HR 2.85; 95% CI 2.05-3.98; p<0.0001). The findings are confirmed by one single-arm study and three other randomized studies. It has become clear that personalized medicine for NSCLC is feasible. This small step towards personalized medicine represents a paradigm shift in the management of NSCLC. ... Read more

Abstract: Certain mutations in the epidermal growth factor receptor (EGFR) gene confer hypersensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib in patients with advanced non-small cell lung cancer. Large-scale screening for EGFR mutations in such patients is feasible for predicting response to TKIs and thus guiding treatment. ... Read more

Abstract: Gene therapy for inherited retinal degeneration has made major advances toward the ultimate goal of reversing blindness in human patients. With significant advances in recombinant viral vector design, safety and efficacy profiles have greatly improved. Although these recent advances have been applied to many different retinal diseases, one retinal degenerative disease, Leber congenital amaurosis, appears to have the greatest potential for reversing blindness. In pre-clinical animal studies, gene therapy for Leber congenital amaurosis has demonstrated visual recovery. Recently, in landmark clinical trials, preliminary results have indicated safety and efficacy for the use of gene therapy in Leber congenital amaurosis, thus laying the foundation for continued use of gene therapy in other forms of inherited blinding disease. ... Read more

Abstract: The new mantra for delivering optimal cancer treatment is "personalized care." This extends beyond the holistic to using germline and somatic tumoral mutations to link a specific therapy to some prognostic or predictive factor which defines a particularly responsive patient subgroup who might benefit most from treatment. Furthermore, inherited polymorphisms have the potential to greatly modulate the side effects of treatment, especially for chemotherapy which has a notoriously narrow therapeutic window (Walther et al., 2009). ... Read more

Abstract: Gene-directed enzyme prodrug therapy offers a new approach to treating some cancers. Clinical trials have been completed for brain and prostate cancers and the first product for post-surgical treatment of some brain tumors is awaiting marketing approval. Recent innovations provide a glimpse into the possible future evolution of a new gene medicine. ... Read more

Abstract: Prostate cancer is the most common cancer seen in aging males in the Western world, and is a major clinical challenge in uro-oncology due to biological heterogeneity. Recent advances in molecular medicine suggest that the genetic composition of a prostate tumor contributes significantly to the complexity of the disease. An important genetic mechanism underlying biological diversity is alternative pre-mRNA splicing, which is thought to affect ~95% of transcripts derived from protein-encoding genes. During alternative splicing, coding (exons) and non-coding (introns) regions of pre-messenger RNA (pre-mRNA) transcripts derived from a single gene are rearranged to generate several mRNAs species, which are translated into distinct protein isoforms with differing biological functions. Recent emerging evidence suggests that prostate cancer-specific aberrant and alternative splicing may contribute to the biological heterogeneity of the disease. Furthermore, identification of prostate cancer-specific splice variants may yield novel biomarkers and targets for therapy to improve patient care and clinical outcome. ... Read more

Abstract: Despite the social stigma and manufacturing hurdles that come with using viruses as therapeutic tools, the molecular specificity offered by these bugs makes them too attractive to ignore. Still largely based on vaccines, viral vectors offer exciting tools to treat cancer or deliver specific genetic payloads to a desired tissue. Unfortunately, early clinical trials utilizing such vectors have been plagued with poor performance or even clinical toxicity most commonly associated with spurious genetic regulation and/or replication of the vector. Past efforts to control for unwanted toxicity have focused on modification of the receptor or use of tissue-specific genetic elements that added specificity to the transcriptional induction of the gene(s) of interest. While this has had some success, engineering receptors to control viral tropism often fails or results in a loss of replicative fitness. In addition, the use of tissue-specific promoter elements not only restricts the vector that can be used, bona fide small promoter elements are often not available for the desired target. With the caveats of viral vector-based therapeutics largely centered on a lack of in vivo control, the recent success of exploiting microRNA expression to limit viral tropism may breathe new life into the field. ... Read more

Abstract: Most drugs don't work optimally in most patients. The same drug can exert a significant overall therapeutic benefit in some patients while post a pronounced overall toxicity risk in others with the same disease. Pharmacogenomics has progressively received attention in the drug development process. But genetics is not the only factor that contributes to the differences that individual patients respond to drugs. Enter global systems biology. ... Read more

Abstract: Comparisons of gene and protein profiling between sickness and health offer tremendous opportunities for finding new drug targets and aiding clinical trial design, in addition to fueling promising expansion of advanced diagnostics. ... Read more