Kaylin M McMahon

Northwestern University, Evanston, IL, United States

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Publications (6)39.02 Total impact

  • Kaylin Marie McMahon, Colby Shad Thaxton
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    ABSTRACT: Introduction: RNA interference (RNAi) is a powerful mechanism for gene silencing with the potential to greatly impact the development of new therapies for many human diseases. Short interfering RNAs (siRNAs) may be the ideal molecules for therapeutic RNAi. However, therapeutic siRNAs face significant challenges that must be overcome prior to widespread clinical use. Many efforts have been made to overcome the hurdles associated with systemic administration of siRNA; however, current approaches are still limited. As such, there is an urgent need to develop new strategies for siRNA delivery that have the potential to impact a broad spectrum of systemic diseases. Areas covered: This review focuses on the promise of siRNA therapies and highlights current siRNA delivery methods. With an eye toward new strategies, this review first introduces high-density lipoprotein (HDL) and describes its natural biological functions, and then transitions into how HDLs may provide significant opportunities as next-generation siRNA delivery vehicles. Importantly, this review describes how synthetic HDLs leverage the natural ability of HDL to stabilize and deliver siRNAs. Expert opinion: HDLs are natural nanoparticles that are critical to understanding the systemic delivery of therapeutic nucleic acids, like siRNA. Methods to synthesize biomimetic HDLs are being explored, and data demonstrate that this type of delivery vehicle may be highly beneficial for targeted and efficacious systemic delivery of siRNAs.
    Expert Opinion on Drug Delivery 12/2013; · 4.87 Impact Factor
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    ABSTRACT: The efficiency of islet graft survival after intraportal implantation is compromised by host innate immune responses and the production of proinflammatory cytokines that cause acute cellular injury. This reaction activates intraislet nuclear factor-κB (NF-κB), causing production of gene products that have detrimental effects on β-cell survival and function. We hypothesized that small interfering RNA targeting of IKKβ, a crucial kinase in the NF-κB activation pathway, in islets before transplantation would ameliorate the detrimental effects of cytokines and improve islet survival after transplantation. To test this hypothesis, we prepared small interfering RNA-based spherical nucleic acid nanoparticle conjugates targeting IKKβ IKKβ SNA-NCs). We treated isolated islets with IKKβ SNA-NCs and assessed the functional consequences of IKKβ knockdown in vitro and after intraportal transplantation in mice. Treatment of freshly isolated mouse islets with IKKβ SNA-NCs reduced constitutive IKKβ expression and protected against proinflammatory cytokine-induced NF-κB activation, resulting in improved cell viability and decreased expression of gene products associated with β-cell dysfunction. Intraportal transplantation of a marginal mass (50 islets) of syngeneic islets treated with nanoparticle conjugates targeting IKKβ resulted in reversion to normoglycemia in 50% of streptozotocin-induced diabetic recipients (n=12) compared with 0% of controls (n=12). Histologic analyses showed reduced CD11b cellular infiltration and decreased islet apoptosis. These results are consistent with the hypothesis that inhibition of intraislet NF-κB activation ameliorates the detrimental effects of host cytokines and demonstrates that preconditioning freshly isolated islets in culture with IKKβ SNA-NCs may be a promising therapy to enhance islet graft function and survival after transplantation.
    Transplantation 11/2013; 96(10):877-84. · 3.78 Impact Factor
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    ABSTRACT: High density lipoproteins (HDLs) are dynamic natural nanoparticles best known for their role in cholesterol transport and the inverse correlation that exists between blood HDL levels and the risk of developing coronary heart disease. In addition, enhanced HDL-cholesterol uptake has been demonstrated in several human cancers. As such, the use of HDL as a therapeutic and as a vehicle for systemic delivery of drugs and as imaging agents is increasingly important. HDLs exist on a continuum from the secreted HDL-scaffolding protein, apolipoprotein A-1 (Apo A1), to complex, spherical "mature" HDLs. Aspects of HDL particles including their size, shape, and surface chemical composition are being recognized as critical to their diverse biological functions. Here we review HDL biology; strategies for synthesizing HDLs; data supporting the clinical use and benefit of directly administered HDL; a rationale for developing synthetic methods for spherical, mature HDLs; and, the potential to employ HDLs as therapies, imaging agents, and drug delivery vehicles. Importantly, methods that utilize nanoparticle templates to control synthetic HDL size, shape, and surface chemistry are highlighted.
    Advanced drug delivery reviews 08/2012; · 11.96 Impact Factor
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    ABSTRACT: We report a gold nanoparticle-templated high density lipoprotein (HDL AuNP) platform for gene therapy that combines lipid-based nucleic acid transfection strategies with HDL biomimicry. For proof-of-concept, HDL AuNPs are shown to adsorb antisense cholesterylated DNA. The conjugates are internalized by human cells, can be tracked within cells using transmission electron microscopy, and regulate target gene expression. Overall, the ability to directly image the AuNP core within cells, the chemical tailorability of the HDL AuNP platform, and the potential for cell-specific targeting afforded by HDL biomimicry make this platform appealing for nucleic acid delivery.
    Nano Letters 02/2011; 11(3):1208-14. · 13.03 Impact Factor
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    ABSTRACT: Transplantation of pancreatic islets is an effective treatment for select patients with type 1 diabetes. Improved cellular therapy results may be realized by altering the gene expression profile of transplanted islets. Current viral and nonviral vectors used to introduce nucleic acids for gene regulation hold promise, but safety and efficacy shortcomings motivate the development of new transfection strategies. Polyvalent gold nanoparticles (AuNPs) densely functionalized with covalently immobilized DNA oligonucleotides (AuNP-DNA) are new single entity transfection and gene regulating agents (ie, not requiring lipids, polymers, or viral vectors for cell entry) able to enter cells with high efficiency and no evidence of toxicity. We hypothesize that AuNP-DNA conjugates can efficiently transfect pancreatic islets with no impact on viability or functionality, and can function to regulate targeted gene expression. AuNPs were surface-functionalized with control and antisense DNA oligonucleotides. Purified murine and human islets were exposed to AuNP-DNA conjugates for 24 hours. Islet AuNP-DNA uptake, cell viability, and functionality were measured. Furthermore, the ability of antisense AuNP-DNA conjugates to regulate gene expression was measured using murine islets expressing eGFP. Collectively, fluorescent confocal microscopy, transmission electron microscopy, mass spectrometry, and flow cytometry revealed substantial penetration of the AuNP-DNA conjugates into the inner core of the islets and within islet cells. No change in cellular viability occurred and the insulin stimulation index was unchanged in treated versus untreated islets. Transplantation of AuNP-DNA treated islets cured diabetic nude mice. Functionally, antisense eGFP AuNP-DNA conjugates reduced eGFP expression in MIP-eGFP islets. Polyvalent AuNP-DNA conjugates may represent the next generation of nucleic acid-based therapeutic agents for improving pancreatic islet engraftment, survival, and long-term function.
    Surgery 08/2010; 148(2):335-45. · 3.37 Impact Factor
  • Journal of Surgical Research 02/2010; 158(2):202-3. · 2.02 Impact Factor