Systemic Toxicity of Recombinant Adeno-Associated Virus Gene Therapy Vectors.

Recombinant adeno-associated virus (rAAV) vectors have emerged as a promising tool for gene therapy. However, the systemic administration of rAAV vectors is not without risks, particularly for dose levels >1 × 10 viral genome per kilogram of body weight (vg/kg). rAAV-associated toxicities can variably manifest either acutely or in a delayed manner.

Endovascular Conversion of a Failed Nellix AAA-Repair by a Custom-Made Branched Device.

Purpose: This technical note presents a case of a patient with a failed Nellix device (Endologix, Irvine, Calif) who was not deemed fit for open conversion. Our planned approach for repair involved an endovascular procedure utilizing a custom-made branched device.

Technique: An endovascular repair was performed via a custom-made four outer branched device in conjunction with a custom-made bifurcated graft featuring inverted limbs (Cook Inc.

Scientific and Regulatory Policy Committee Technical Review: Biology and Pathology of Ganglia in Animal Species Used for Nonclinical Safety Testing.

Dorsal root ganglia (DRG), trigeminal ganglia (TG), other sensory ganglia, and autonomic ganglia may be injured by some test article classes, including anti-neoplastic chemotherapeutics, adeno-associated virus-based gene therapies, antisense oligonucleotides, nerve growth factor inhibitors, and aminoglycoside antibiotics. This article reviews ganglion anatomy, cytology, and pathology (emphasizing sensory ganglia) among common nonclinical species used in assessing product safety for such test articles (TAs). Principal histopathologic findings associated with sensory ganglion injury include neuron degeneration, necrosis, and/or loss; increased satellite glial cell and/or Schwann cell numbers; and leukocyte infiltration and/or inflammation.

CBFA2T3-GLIS2-dependent pediatric acute megakaryoblastic leukemia is driven by GLIS2 and sensitive to navitoclax.

Pediatric acute megakaryoblastic leukemia (AMKL) is an aggressive blood cancer associated with poor therapeutic response and high mortality. Here we describe the development of CBFA2T3-GLIS2-driven mouse models of AMKL that recapitulate the phenotypic and transcriptional signatures of the human disease. We show that an activating Ras mutation that occurs in human AMKL increases the penetrance and decreases the latency of CBF2AT3-GLIS2-driven AMKL.

Scientific and Regulatory Policy Committee Points to Consider: Sampling, Processing, Evaluation, Interpretation, and Reporting of Test Article-Related Ganglion Pathology for Nonclinical Toxicity Studies.

Certain biopharmaceutical products consistently affect dorsal root ganglia, trigeminal ganglia, and/or autonomic ganglia. Product classes targeting ganglia include antineoplastic chemotherapeutics, adeno-associated virus-based gene therapies, antisense oligonucleotides, and anti-nerve growth factor agents. This article outlines "points to consider" for sample collection, processing, evaluation, interpretation, and reporting of ganglion findings; these points are consistent with published best practices for peripheral nervous system evaluation in nonclinical toxicity studies.

M-STAR: Magnetism second target advanced reflectometer at the Spallation Neutron Source.

M-STAR is a next generation polarized neutron reflectometer with advanced capabilities. A new focusing guide concept is optimized for samples with dimensions down to a millimeter range. A proposed hybrid pulse-skipping chopper will enable experiments at constant geometry at one incident angle in a broad range of wavevector transfer Q up to 0.

overexpression of frataxin causes toxicity mediated by iron-sulfur cluster deficiency.

Friedreich's ataxia is a rare disorder resulting from deficiency of frataxin, a mitochondrial protein implicated in the synthesis of iron-sulfur clusters. Preclinical studies in mice have shown that gene therapy is a promising approach to treat individuals with Friedreich's ataxia. However, a recent report provided evidence that AAVrh10-mediated overexpression of frataxin could lead to cardiotoxicity associated with mitochondrial dysfunction.

Observation of Coexisting Weak Localization and Superconducting Fluctuations in Strained SnInTe Thin Films.

Topological superconductors have attracted tremendous excitement as they are predicted to host Majorana zero modes that can be utilized for topological quantum computing. Candidate topological superconductor SnInTe thin films (0 < < 0.3) grown by molecular beam epitaxy and strained in the (111) plane are shown to host quantum interference effects in the conductivity coexisting with superconducting fluctuations above the critical temperature .

Scientific and Regulatory Policy Committee Points to Consider: Nonclinical Research and Development of In Vivo Gene Therapy Products, Emphasizing Adeno-Associated Virus Vectors.

Sequencing of the human genome and numerous advances in molecular techniques have launched the era of genetic medicine. Increasingly precise technologies for genetic modification, manufacturing, and administration of pharmaceutical-grade biologics have proved the viability of in vivo gene therapy (GTx) as a therapeutic modality as shown in several thousand clinical trials and recent approval of several GTx products for treating rare diseases and cancers. In recognition of the rapidly advancing knowledge in this field, the regulatory landscape has evolved considerably to maintain appropriate monitoring of safety concerns associated with this modality.

Considerations for Preclinical Safety Assessment of Adeno-Associated Virus Gene Therapy Products.

Progress in understanding the molecular bases of human health and disease in recent decades has flourished making it possible for the field of gene therapy (GT) to offer new possibilities for treating, and even curing, a plethora of medical conditions such as monogenic disorders and metabolic diseases. GT is a therapeutic intervention to genetically alter or modify living cells by means of gene delivery achieved using either viral vectors or nonviral vectors, with adeno-associated virus (AAV) vectors constituting market-share majority. Although GT is conceptually attractive, adverse and even fatal iatrogenic complications have marred the initial enthusiasm of clinical successes.

Interplay of orbital effects and nanoscale strain in topological crystalline insulators.

Orbital degrees of freedom can have pronounced effects on the fundamental properties of electrons in solids. In addition to influencing bandwidths, gaps, correlation strength and dispersion, orbital effects have been implicated in generating novel electronic and structural phases. Here we show how the orbital nature of bands can result in non-trivial effects of strain on band structure.

Negative Longitudinal Magnetoresistance from the Anomalous N=0 Landau Level in Topological Materials.

Negative longitudinal magnetoresistance (NLMR) is shown to occur in topological materials in the extreme quantum limit, when a magnetic field is applied parallel to the excitation current. We perform pulsed and dc field measurements on Pb_{1-x}Sn_{x}Se epilayers where the topological state can be chemically tuned. The NLMR is observed in the topological state, but is suppressed and becomes positive when the system becomes trivial.

Cytomegaloviral hypophysitis in a simian immunodeficiency virus-infected rhesus macaque (Macacca mulatta).

Rhesus macaques experimentally infected with Simian Immunodeficiency Virus (SIV) experience immunosuppression and often opportunistic infection. Among the most common opportunistic infections are rhesus cytomegalovirus (RhCMV), a ubiquitous betaherpesvirus that undergoes continuous low-level replication in immunocompetent monkeys. Upon SIV-mediated immunodeficiency, RhCMV reactivates and results in lesions in numerous organ systems including the nervous and reproductive systems.

A high-temperature ferromagnetic topological insulating phase by proximity coupling.

Topological insulators are insulating materials that display conducting surface states protected by time-reversal symmetry, wherein electron spins are locked to their momentum. This unique property opens up new opportunities for creating next-generation electronic, spintronic and quantum computation devices. Introducing ferromagnetic order into a topological insulator system without compromising its distinctive quantum coherent features could lead to the realization of several predicted physical phenomena.

Massive and massless Dirac fermions in Pb1-xSnxTe topological crystalline insulator probed by magneto-optical absorption.

Dirac fermions in condensed matter physics hold great promise for novel fundamental physics, quantum devices and data storage applications. IV-VI semiconductors, in the inverted regime, have been recently shown to exhibit massless topological surface Dirac fermions protected by crystalline symmetry, as well as massive bulk Dirac fermions. Under a strong magnetic field (B), both surface and bulk states are quantized into Landau levels that disperse as B(1/2), and are thus difficult to distinguish.

Strain engineering Dirac surface states in heteroepitaxial topological crystalline insulator thin films.

The unique crystalline protection of the surface states in topological crystalline insulators has led to a series of predictions of strain-generated phenomena, from the appearance of pseudo-magnetic fields and helical flat bands to the tunability of Dirac surface states by strain that may be used to construct 'straintronic' nanoswitches. However, the practical realization of this exotic phenomenology via strain engineering is experimentally challenging and is yet to be achieved. Here, we have designed an experiment to not only generate and measure strain locally, but also to directly measure the resulting effects on Dirac surface states.

High-precision realization of robust quantum anomalous Hall state in a hard ferromagnetic topological insulator.

The discovery of the quantum Hall (QH) effect led to the realization of a topological electronic state with dissipationless currents circulating in one direction along the edge of a two-dimensional electron layer under a strong magnetic field. The quantum anomalous Hall (QAH) effect shares a similar physical phenomenon to that of the QH effect, whereas its physical origin relies on the intrinsic spin-orbit coupling and ferromagnetism. Here, we report the experimental observation of the QAH state in V-doped (Bi,Sb)2Te3 films with the zero-field longitudinal resistance down to 0.

Preclinical biosafety evaluation of cell-based therapies: emerging global paradigms.

Cell-based therapies have the potential to treat a diversity of disease conditions, many representing significant and long-standing unmet medical needs. Certain properties of cell-based therapies, such as differentiation potential and proliferative potential, present safety concerns uniquely distinct from those of small molecule drugs and other macromolecule biologics. These cellular products carry risks associated with localized host tissue response, long-term persistence, ectopic tissue formation, differentiation to undesirable cell and tissue types, uncontrollable biodistribution, tumorigenicity, and immunogenicity.

Preclinical study design for evaluation of stem cell-derived cellular therapy products: a pathologist's perspective.

Despite-or perhaps because of-the rapid expansion of interest in stem cell-derived cellular therapy products, relatively few guidelines have been published to assist in the design of scientifically sound preclinical studies. The field is complex and wide ranging, and of necessity regulators tend to treat each project on a case by case basis. One of the core tenets remains the need to retain all tissues from the study, thereby allowing for further analysis of tissues should unexpected effects be seen in clinical studies; attempts to comply with this may result in an unmanageable financial burden.

Limited dissemination and shedding of the UL128 complex-intact, UL/b'-defective rhesus cytomegalovirus strain 180.92.

Unlabelled: The UL128 complex of human cytomegalovirus (CMV) is a major determinant of viral entry into epithelial and endothelial cells and a target for vaccine development. The UL/b' region of rhesus CMV contains several open reading frames, including orthologs of the UL128 complex. We recently showed that the coding content of the rhesus CMV (RhCMV) UL/b' region predicts acute endothelial tropism and long-term shedding in vivo in the rhesus macaque model of CMV infection.

Spin regulation in composite spin-filter barrier devices.

Magnetic insulators are known to provide large effective Zeeman fields that are confined at an interface, making them especially powerful in modifying adjacent one- or two-dimensional electronic structures. Utilizing this phenomenon and the other important property of magnetic insulators--spin filtering--here we report the generation and subsequent detection of a large interface field, as large as tens of tesla in EuS/Al/EuS heterostructures with metallic coulomb islands confined within a magnetic insulator barrier. The unique energy profile across this sandwich structure produces spin-assisted charge transfer across the device, generating a spontaneous spin current and voltage.

rhesus cytomegalovirus (macacine herpesvirus 3)-associated facial neuritis in simian immunodeficiency virus-infected rhesus macaques (Macaca mulatta).

Peripheral neuropathies are common sequelae to human immunodeficiency virus (HIV) infection in humans and are due to a variety of mechanisms, including direct antiretroviral toxicity, HIV-mediated damage, immune-mediated disorders, and opportunistic viral infections. Rhesus macaques (Macaca mulatta) infected with simian immunodeficiency virus (SIV) remain the most consistent animal model for unraveling the pathogenesis of lentiviral-associated disease and its associated opportunistic infections. Rhesus cytomegalovirus (RhCMV) is the most common opportunistic viral infection in rhesus macaques infected with SIV and causes multiorgan pathology; however, its role in peripheral nerve pathology has not been explored.

Quantification of strain and charge co-mediated magnetoelectric coupling on ultra-thin Permalloy/PMN-PT interface.

Strain and charge co-mediated magnetoelectric coupling are expected in ultra-thin ferromagnetic/ferroelectric multiferroic heterostructures, which could lead to significantly enhanced magnetoelectric coupling. It is however challenging to observe the combined strain charge mediated magnetoelectric coupling, and difficult in quantitatively distinguish these two magnetoelectric coupling mechanisms. We demonstrated in this work, the quantification of the coexistence of strain and surface charge mediated magnetoelectric coupling on ultra-thin Ni0.

Exchange-coupling-induced symmetry breaking in topological insulators.

An exchange gap in the Dirac surface states of a topological insulator (TI) is necessary for observing the predicted unique features such as the topological magnetoelectric effect as well as to confine Majorana fermions. We experimentally demonstrate proximity-induced ferromagnetism in a TI, combining a ferromagnetic insulator EuS layer with Bi(2)Se(3), without introducing defects. By magnetic and magnetotransport studies, including anomalous Hall effect and magnetoresistance measurements, we show the emergence of a ferromagnetic phase in TI, a step forward in unveiling their exotic properties.