Successfully navigating the valley of death: the importance of accelerators to support academic drug discovery and development.

Introduction: The drug discovery and development 'valley of death' remains a challenge for promising new therapies originating from academic research laboratories. Drug discovery support centers and accelerators have been established to provide monetary and scientific support, but limited available funding along with cultural and expertise gaps remain obstacles for many promising technologies.

Areas Covered: In this meta-opinion article, the authors summarize the literature around obstacles that academic drug discovery projects face, along with potential solutions and best practices.

Identification of Small Molecule Inhibitors of Human Cytochrome c Oxidase That Target Chemoresistant Glioma Cells.

The enzyme cytochrome c oxidase (CcO) or complex IV (EC 1.9.3.

Accelerating Drug Development: Antiviral Therapies for Emerging Viruses as a Model.

Drug discovery and development is a lengthy and expensive process. Although no one, simple, single solution can significantly accelerate this process, steps can be taken to avoid unnecessary delays. Using the development of antiviral therapies as a model, we describe options for acceleration that cover target selection, assay development and high-throughput screening, hit confirmation, lead identification and development, animal model evaluations, toxicity studies, regulatory issues, and the general drug discovery and development infrastructure.

Consortia's critical role in developing medical countermeasures for re-emerging viral infections: a USA perspective.

Viral infections, such as Ebola, severe acute respiratory syndrome/Middle East respiratory syndrome and West Nile virus have emerged as a serious health threat with no effective therapies. These infections have little commercial potential and are not a high priority for the pharmaceutical industry. However, the academic community has been active in this area for many years.

Academic medical product development: an emerging alliance of technology transfer organizations and the CTSA.

To bring the benefits of science more quickly to patient care, the NIH National Center Advancing Translational Sciences (NCATS) supports programs that enhance the development, testing, and implementation of new medical products and procedures. The NCATS clinical and translational science award (CTSA) program is central to that mission; creating an academic home for clinical and translational science and supporting those involved in the discovery and development of new health-related inventions. The technology transfer Offices (TTO) of CTSA-funded universities can be important partners in the development process; facilitating the transfer of medical research to the commercial sector for further development and ultimately, distribution to patients.

The Alabama Drug Discovery Alliance: a collaborative partnership to facilitate academic drug discovery.

The Alabama Drug Discovery Alliance is a collaboration between the University of Alabama at Birmingham and Southern Research Institute that aims to support the discovery and development of therapeutic molecules that address an unmet medical need. The alliance builds on the expertise present at both institutions and has the dedicated commitment of their respective technology transfer and intellectual property offices to guide any commercial opportunities that may arise from the supported efforts. Although most projects involve high throughput screening, projects at any stage in the drug discovery and development pathway are eligible for support.

An adenoviral vector expressing human adenovirus 5 and 3 fiber proteins for targeting heterogeneous cell populations.

Human adenovirus serotype 5 (HAdV-5) attaches to its primary receptor, the coxsackie and adenovirus receptor (CAR) as the first step of infection. However, CAR expression decreases as tumors progress, thereby diminishing the utility of HAdV-5-based vectors for cancer therapy. In contrast, many aggressive tumor cells highly express CD46, a cellular receptor for HAdV-3.

Chimeric adenoviral vectors incorporating a fiber of human adenovirus 3 efficiently mediate gene transfer into prostate cancer cells.

Background: We have developed a range of adenoviral (Ad) vectors based on human adenovirus serotype 5 (HAdV-5) displaying the fiber shaft and knob domains of species B viruses (HAdV-3, -11, or -35). These species B Ads utilize different cellular receptors than HAdV-5 for infection. We evaluated whether Ad vectors displaying species B fiber shaft and knob domains (Ad5F3Luc1, Ad5F11Luc1, and Ad5F35Luc1) would efficiently infect cancer cells of distinct origins, including prostate cancer.

Selective transduction of mature DC in human skin and lymph nodes by CD80/CD86-targeted fiber-modified adenovirus-5/3.

In vivo targeting of dendritic cells (DC) represents an attractive alternative to currently apply ex vivo DC-based genetic tumor vaccination protocols. Finding the optimal vector for in vivo targeting of DC is important for such strategies. We, therefore, tested a panel of subgroup C/B chimeric and fiber-modified adenoviruses (Ads) for their relative capacity to transduce human DC.

Combined transductional untargeting/retargeting and transcriptional restriction enhances adenovirus gene targeting and therapy for hepatic colorectal cancer tumors.

Unresectable hepatic colorectal cancer (CRC) metastases are a leading cause of cancer mortality. These tumors and other epithelial tumors often express both cyclooxygenase-2 (COX-2) and carcinoembryonic antigen (CEA). Because adenovirus (Ad) vectors infect the liver and lack tumor tropism, they cannot be used for systemic therapy of hepatic metastases.

Limitations of Adenoviral Vector-Mediated Delivery of Gold Nanoparticles to Tumors for Hyperthermia Induction.

Novel combinatorial treatment strategies are desired to achieve tumor eradication. In this regard, nanotechnology and gene therapy hold the potential to expand the available tumor treatment options. In particular, gold nanoparticles (AuNPs) have been utilized for hyperthermic tumor cell ablation.

Quantum dots as multimodal photoacoustic and photothermal contrast agents.

Quantum dots (QDs) have primarily been developed as fluorescent probes with unique optical properties. We herein demonstrate an extension of these QD utilities to photoacoustic (PA) and photothermal (PT) microscopy, using a nanosecond pulse laser excitation (420-900 nm, 8 ns, 10(-3)-10 J/cm(2)). The laser-induced PA, PT and accompanying bubble formation phenomena were studied with an advanced multifunctional microscope, which integrates fluorescence, PA, PT imaging, and PT thermolens modules.

An adenoviral platform for selective self-assembly and targeted delivery of nanoparticles.

Metallic nanoparticles (NPs) can be used for the diagnosis, imaging, and therapy of tumors and cardiovascular disease. However, targeted delivery of NPs to specific cells remains a major limitation for clinical realization of these potential treatment options. Herein, a novel strategy for the specific coupling of NPs to a targeted adenoviral (Ad) platform to deliver NPs to specific cells is defined.

Enhanced Gene Delivery to Human Primary Endothelial Cells Using Tropism-Modified Adenovirus Vectors.

Endothelial cells have been noted to have relatively low expression of the native receptor for adenovirus serotype 5 (Ad5), coxsackie and adenovirus receptor (CAR), and are thus refractory to Ad5 infection. In this study, we hypothesize that increases in the infectivity of Ad5 in primary human pulmonary artery (HPAEC), coronary artery (HCAEC) and umbilical vein endothelial cells (HUVEC) can be achieved through genetic capsid modification of Ad5 to bypass CAR-dependent infection. The modifications tested in this study include incorporation of an integrin-binding RGD peptide motif (Ad5.

Adenovirus tumor targeting and hepatic untargeting by a coxsackie/adenovirus receptor ectodomain anti-carcinoembryonic antigen bispecific adapter.

Adenovirus vectors have a number of advantages for gene therapy. However, because of their lack of tumor tropism and their preference for liver infection following systemic administration, they cannot be used for systemic attack on metastatic disease. Many epithelial tumors (e.

Thermal scalpel to target cancer.

Nanotechnology is increasingly applied to the field of medicine, particularly for the treatment of cancer. In this regard, gold nanoparticles can mediate hyperthermia induction and kill tumor cells upon laser irradiation, thereby functioning as a 'thermal scalpel'. Recent developments in gold nanoparticle design have resulted in their absorption of energy in the near-infrared wavelength spectrum, which is best suited to tissue penetration and, thus, clinical application.

Combination of viral biology and nanotechnology: new applications in nanomedicine.

Viruses are well known for their ability to cause disease, but their beneficial usefulness as vectors for gene therapy have been noted as well. As an extension of their use in a gene therapy context, their combination with nanotechnology is starting to benefit many areas of science and medicine. These include nanofabrication and medical diagnostics, to name a few, as well as viro-nanotherapy, here defined as the combination of viral biology with nanotechnology to create new therapeutic avenues to treat disease.

Self-assembling nanoclusters in living systems: application for integrated photothermal nanodiagnostics and nanotherapy.

Nanotechnologies represent an unprecedented recent advance that may revolutionize many areas of medicine and biology, including cancer diagnostics and treatment. Nanoparticle-based technologies have demonstrated especially high potential for medical purposes, ranging from diagnosing diseases to providing novel therapies. However, to be clinically relevant, the existing nanoparticle-based technologies must overcome several challenges, including selective nanoparticle delivery, potential cytotoxicity, imaging of nanoparticles, and real-time assessment of their therapeutic efficacy.

Effect of adenoviral mediated overexpression of fibromodulin on human dermal fibroblasts and scar formation in full-thickness incisional wounds.

Fibromodulin, a member of the small leucine-rich proteoglycan family, has been recently suggested as a biologically significant mediator of fetal scarless repair. To assess the role of fibromodulin in the tissue remodeling, we constructed an adenoviral vector expressing human fibromodulin cDNA. We evaluated the effect of adenovirus-mediated overexpression of fibromodulin in vitro on transforming growth factors and metalloproteinases in fibroblasts and in vivo on full-thickness incisional wounds in a rabbit model.

Covalently linked Au nanoparticles to a viral vector: potential for combined photothermal and gene cancer therapy.

Hyperthermia can be produced by near-infrared laser irradiation of gold nanoparticles present in tumors and thus induce tumor cell killing via a bystander effect. To be clinically relevant, however, several problems still need to be resolved. In particular, selective delivery and physical targeting of gold nanoparticles to tumor cells are necessary to improve therapeutic selectivity.

Preclinical evaluation of transcriptional targeting strategies for carcinoma of the breast in a tissue slice model system.

Introduction: In view of the limited success of available treatment modalities for metastatic breast cancer, alternative and complementary strategies need to be developed. Adenoviral vector mediated strategies for breast cancer gene therapy and virotherapy are a promising novel therapeutic platform for the treatment of breast cancer. However, the promiscuous tropism of adenoviruses (Ads) is a major concern.

The natural history of a novel, systemic, disseminated model of syngeneic mouse B-cell lymphoma.

Lymphomas and leukemias, neoplasms of hematopoetic lineage, pose unique challenges that require novel treatment paradigms. The inter-relationship between the immune system and the neoplastic lesion in these diseases dictates that, to evaluate novel therapies, models are needed that mimic human disease in an immunocompetent host. In the present study, we describe a disseminated, syngeneic model of B-cell lymphoma in the Balb/c mouse based upon the A20 cell line.

Gene transfer to carcinoma of the breast with fiber-modified adenoviral vectors in a tissue slice model system.

Successful adenoviral (Ad) vector-mediated strategies for breast cancer gene therapy and virotherapy have heretofore been hindered by low transduction efficiency. This has recently been understood to result from a relative paucity of expression of the primary adenovirus receptor, coxsackie-adenovirus-receptor (CAR), on primary tumor cells. To further investigate this issue, we evaluated the expression of CAR on breast cancer cell lines as well as primary breast cancer cells.

In vivo analysis of a genetically modified adenoviral vector targeted to human CD40 using a novel transient transgenic model.

Background: Retargeting is necessary to overcome the limitations of adenovirus (Ad)-based gene therapy vectors. To this end, we previously constructed an adenovirus with the fiber knob domain replaced by a fibritin trimerization motif fused to the CD40 ligand (Ad5Luc.FF/CD40L).