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Frank J. Hernandez

Bio: Frank J. Hernandez is an academic researcher from Linköping University. The author has contributed to research in topics: Aptamer & Nuclease. The author has an hindex of 11, co-authored 25 publications receiving 607 citations. Previous affiliations of Frank J. Hernandez include Integrated DNA Technologies & University of Iowa.

Papers
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TL;DR: A novel cell-based selection methodology is described that enables the identification of cell-internalizing RNA aptamers for targeting therapeutic siRNAs to HER2-expressing breast cancer cells, and it is demonstrated that, when applied to cells, the HER2 aptamer-Bcl-2 siRNA conjugates selectively internalize into HER2+-cells and silence Bcl- 2 gene expression.
Abstract: Human epidermal growth factor receptor 2 (HER2) expression in breast cancer is associated with an aggressive phenotype and poor prognosis, making it an appealing therapeutic target. Trastuzumab, an HER2 antibody-based inhibitor, is currently the leading targeted treatment for HER2(+)-breast cancers. Unfortunately, many patients inevitably develop resistance to the therapy, highlighting the need for alternative targeted therapeutic options. In this study, we used a novel, cell-based selection approach for isolating 'cell-type specific', 'cell-internalizing RNA ligands (aptamers)' capable of delivering therapeutic small interfering RNAs (siRNAs) to HER2-expressing breast cancer cells. RNA aptamers with the greatest specificity and internalization potential were covalently linked to siRNAs targeting the anti-apoptotic gene, Bcl-2. We demonstrate that, when applied to cells, the HER2 aptamer-Bcl-2 siRNA conjugates selectively internalize into HER2(+)-cells and silence Bcl-2 gene expression. Importantly, Bcl-2 silencing sensitizes these cells to chemotherapy (cisplatin) suggesting a potential new therapeutic approach for treating breast cancers with HER2(+)-status. In summary, we describe a novel cell-based selection methodology that enables the identification of cell-internalizing RNA aptamers for targeting therapeutic siRNAs to HER2-expressing breast cancer cells. The future refinement of this technology may promote the widespread use of RNA-based reagents for targeted therapeutic applications.

186 citations

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TL;DR: This work substantially truncates A9, an RNA aptamer to prostate-specific membrane antigen (PSMA), which retains binding activity, functionality, and is amenable to large-scale chemical synthesis for future clinical applications and highlights the utility of existing RNA structural prediction and protein docking techniques that may be generally applicable to developing RNA aptamers optimized for therapeutic use.
Abstract: RNA aptamers represent an emerging class of pharmaceuticals with great potential for targeted cancer diagnostics and therapy. Several RNA aptamers that bind cancer cell-surface antigens with high affinity and specificity have been described. However, their clinical potential has yet to be realized. A significant obstacle to the clinical adoption of RNA aptamers is the high cost of manufacturing long RNA sequences through chemical synthesis. Therapeutic aptamers are often truncated postselection by using a trial-and-error process, which is time consuming and inefficient. Here, we used a "rational truncation" approach guided by RNA structural prediction and protein/RNA docking algorithms that enabled us to substantially truncateA9, an RNA aptamer to prostate-specific membrane antigen (PSMA),with great potential for targeted therapeutics. This truncated PSMA aptamer (A9L; 41mer) retains binding activity, functionality, and is amenable to large-scale chemical synthesis for future clinical applications. In addition, the modeled RNA tertiary structure and protein/RNA docking predictions revealed key nucleotides within the aptamer critical for binding to PSMA and inhibiting its enzymatic activity. Finally, this work highlights the utility of existing RNA structural prediction and protein docking techniques that may be generally applicable to developing RNA aptamers optimized for therapeutic use.

113 citations

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TL;DR: The thorough preclinical characterization of an RNA aptamer (A9g) that functions as a smart drug for PC by inhibiting the enzymatic activity of prostate-specific membrane antigen (PSMA) is described and critical endpoints for the translation of a novel RNA smart drug are demonstrated.

91 citations

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TL;DR: A fast, specific and sensitive homogeneous assay for Staphylococcus aureus detection was developed by measuring the activity of secreted nuclease from the bacteria via a modified DNA oligonucleotide, formed by nucleic acid oligos and magnetic or mesoporous silica nanoparticles.

68 citations

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TL;DR: C4-3 is a potentially useful therapeutic agent for neurodegenerative diseases in which reduced TrkB activation has been implicated and it is anticipated that the cell-based aptamer selection approach used here will be broadly applicable to the identification of aptamer-based agonists for a variety of cell-surface signaling receptors.
Abstract: Many cell surface signaling receptors, such as the neurotrophin receptor, TrkB, have emerged as potential therapeutic targets for diverse diseases. Reduced activation of TrkB in particular is thought to contribute to neurodegenerative diseases. Unfortunately, development of therapeutic reagents that selectively activate particular cell surface receptors such as TrkB has proven challenging. Like many cell surface signaling receptors, TrkB is internalized upon activation; in this proof-of-concept study, we exploited this fact to isolate a pool of nuclease-stabilized RNA aptamers enriched for TrkB agonists. One of the selected aptamers, C4-3, was characterized with recombinant protein-binding assays, cell-based signaling and functional assays, and, in vivo in a seizure model in mice. C4-3 binds the extracellular domain of TrkB with high affinity (KD ∼2 nM) and exhibits potent TrkB partial agonistic activity and neuroprotective effects in cultured cortical neurons. In mice, C4-3 activates TrkB upon infusion into the hippocampus; systemic administration of C4-3 potentiates kainic acid-induced seizure development. We conclude that C4-3 is a potentially useful therapeutic agent for neurodegenerative diseases in which reduced TrkB activation has been implicated. We anticipate that the cell-based aptamer selection approach used here will be broadly applicable to the identification of aptamer-based agonists for a variety of cell-surface signaling receptors.

43 citations


Cited by
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3,326 citations

Journal ArticleDOI
TL;DR: This Review discusses challenges of clinical translation of therapeutic aptamers, highlighting recent clinical developments and technological advances that have revived the impetus for this promising class of therapeutics.
Abstract: Nucleic acid aptamers, often termed 'chemical antibodies', are functionally comparable to traditional antibodies, but offer several advantages, including their relatively small physical size, flexible structure, quick chemical production, versatile chemical modification, high stability and lack of immunogenicity. In addition, many aptamers are internalized upon binding to cellular receptors, making them useful targeted delivery agents for small interfering RNAs (siRNAs), microRNAs and conventional drugs. However, several crucial factors have delayed the clinical translation of therapeutic aptamers, such as their inherent physicochemical characteristics and lack of safety data. This Review discusses these challenges, highlighting recent clinical developments and technological advances that have revived the impetus for this promising class of therapeutics.

1,207 citations

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TL;DR: This Review highlights morphology-dependent properties of nonspherical noble metal nanoparticles with a focus on localized surface plasmon resonance and local field enhancement, as well as their applications in various fields including Raman spectroscopy, fluorescence enhancement, analytics and sensing, photothermal therapy, (bio-)diagnostics, and imaging.
Abstract: Nanoparticles of noble metals belong to the most extensively studied colloidal systems in the field of nanoscience and nanotechnology. Due to continuing progress in the synthesis of nanoparticles with controlled morphologies, the exploration of unique morphology-dependent properties has gained momentum. Anisotropic features in nonspherical nanoparticles make them ideal candidates for enhanced chemical, catalytic, and local field related applications. Nonspherical plasmon resonant nanoparticles offer favorable properties for their use as analytical tools, or as diagnostic and therapeutic agents. This Review highlights morphology-dependent properties of nonspherical noble metal nanoparticles with a focus on localized surface plasmon resonance and local field enhancement, as well as their applications in various fields including Raman spectroscopy, fluorescence enhancement, analytics and sensing, photothermal therapy, (bio-)diagnostics, and imaging.

922 citations

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TL;DR: A variety of current approaches for enhancing the delivery of oligonucleotides including molecular scale targeted ligand-oligonucleotide conjugates, lipid- and polymer-based nanoparticles, antibody conjugate and small molecules that improve oligon nucleotide delivery are examined.
Abstract: The oligonucleotide therapeutics field has seen remarkable progress over the last few years with the approval of the first antisense drug and with promising developments in late stage clinical trials using siRNA or splice switching oligonucleotides. However, effective delivery of oligonucleotides to their intracellular sites of action remains a major issue. This review will describe the biological basis of oligonucleotide delivery including the nature of various tissue barriers and the mechanisms of cellular uptake and intracellular trafficking of oligonucleotides. It will then examine a variety of current approaches for enhancing the delivery of oligonucleotides. This includes molecular scale targeted ligand-oligonucleotide conjugates, lipid- and polymer-based nanoparticles, antibody conjugates and small molecules that improve oligonucleotide delivery. The merits and liabilities of these approaches will be discussed in the context of the underlying basic biology.

609 citations

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TL;DR: The key issues in translating BDNF biology into synaptic repair therapies are reviewed, which pave the way for a 'synaptic repair' therapy for neurodegenerative diseases that targets pathophysiology rather than pathogenesis.
Abstract: Synaptic dysfunction is a key pathophysiological hallmark in several neurodegenerative disorders. In this Review, Lu and colleagues consider a 'synaptic repair'-based therapy for neurodegenerative diseases that targets pathophysiology rather than pathogenesis and discuss BDNF as a potential synaptic repair molecule.

589 citations