james wilson

EDUCATION

B.Tech

RESEARCH INTERESTS

Cencer, Heart, Physics, Chemistry

Scopus Publications

Branched endosomal disruptor (BEND) lipids mediate delivery of mRNA and CRISPR-Cas9 ribonucleoprotein complex for hepatic gene editing and T cell engineering
Marshall S. Padilla, Kaitlin Mrksich, Yiming Wang, Rebecca M. Haley, Jacqueline J. Li, Emily L. Han, Rakan El-Mayta, Emily H. Kim, Sofia Dias, Ningqiang Gong,et al.
Springer Science and Business Media LLC



In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors
Xuexiang Han, Junchao Xu, Ying Xu, Mohamad-Gabriel Alameh, Lulu Xue, Ningqiang Gong, Rakan El-Mayta, Rohan Palanki, Claude C. Warzecha, Gan Zhao,et al.
Springer Science and Business Media LLC
AbstractThe ionizable lipidoid is a key component of lipid nanoparticles (LNPs). Degradable lipidoids containing extended alkyl branches have received tremendous attention, yet their optimization and investigation are underappreciated. Here, we devise an in situ construction method for the combinatorial synthesis of degradable branched (DB) lipidoids. We find that appending branch tails to inefficacious lipidoids via degradable linkers boosts mRNA delivery efficiency up to three orders of magnitude. Combinatorial screening and systematic investigation of two libraries of DB-lipidoids reveal important structural criteria that govern their in vivo potency. The lead DB-LNP demonstrates robust delivery of mRNA therapeutics and gene editors into the liver. In a diet-induced obese mouse model, we show that repeated administration of DB-LNP encapsulating mRNA encoding human fibroblast growth factor 21 alleviates obesity and fatty liver. Together, we offer a construction strategy for high-throughput and cost-efficient synthesis of DB-lipidoids. This study provides insights into branched lipidoids for efficient mRNA delivery.


Optimization of the activity and biodegradability of ionizable lipids for mRNA delivery via directed chemical evolution
Xuexiang Han, Mohamad-Gabriel Alameh, Ying Xu, Rohan Palanki, Rakan El-Mayta, Garima Dwivedi, Kelsey L. Swingle, Junchao Xu, Ningqiang Gong, Lulu Xue,et al.
Springer Science and Business Media LLC



Fast and facile synthesis of amidine-incorporated degradable lipids for versatile mRNA delivery in vivo
Xuexiang Han, M. Alameh, Ningqiang Gong, Lulu Xue, Majed Ghattas, G. Bojja, Junchao Xu, Gan Zhao, C. C. Warzecha, Marshall S Padilla,et al.




Validation of high-sensitivity assays to quantitate cerebrospinal fluid and serum β-galactosidase activity in patients with GM1-gangliosidosis
Karen J. Quadrini, Catherine Vrentas, Christian Duke, Chris Wilson, Christian J. Hinderer, David A. Weinstein, Samiah A. Al-Zaidy, Susan E. Browne, James M. Wilson, and Yan G. Ni
Elsevier BV



Modulation of AAV9 Galactose Binding Yields Novel Gene Therapy Vectors and Predicts Cross-Species Differences in Glycan Avidity
Jacob A. Hoffman, Nathan Denton, Joshua J. Sims, Rosemary Meggersee, Zhe Zhang, Kanyin Olagbegi, and James M. Wilson
Mary Ann Liebert Inc
Effective use of adeno-associated viruses (AAVs) for clinical gene therapy is limited by their propensity to accumulate in and transduce the liver. This natural liver tropism is associated with severe adverse events at the high doses that can be necessary for achieving therapeutic transgene expression in extra-hepatic tissues. To improve the safety and cost of AAV gene therapy, capsid engineering efforts are underway to redirect in vivo AAV biodistribution away from the liver toward disease-relevant peripheral organs such as the heart. Building on previous work, we generated a series of AAV libraries containing variations at three residues (Y446, N470, and W503) of the galactose-binding pocket of the AAV9 VP1 protein. Screening of this library in mice identified the XRH family of variants (Y446X, N470R, and W503H), the strongest of which, HRH, exhibited a six-fold reduction in liver RNA expression and a ten-fold increase in cardiac RNA expression compared with wild-type AAV9 in the mouse. Screening of our library in a nonhuman primate (NHP) revealed reduced performance of AAV9 and two closely related vectors in the NHP liver compared with the mouse liver. Measurement of the galactose-binding capacity of our library further identified those same three vectors as the only strong galactose binders, suggesting an altered galactose presentation between the mouse and NHP liver. N-glycan profiling of these tissues revealed a 9% decrease in exposed galactose in the NHP liver compared with the mouse liver. In this work, we identified a novel family of AAV variants with desirable biodistribution properties that may be suitable for targeting extra-hepatic tissues such as the heart. These data also provide important insights regarding species- and tissue-specific differences in glycan presentation that may have implications for the development and translation of AAV gene therapies.


Lipid Nanoparticle mRNA Therapy Improves Survival and Reduces Serum Branched-Chain Amino Acids in Mouse Models of Maple Syrup Urine Disease
Jenny A. Greig, Matthew Jennis, Aditya Dandekar, Joanna K. Chorazeczewski, Nesteene Param, Meardey So, Mohamad Nayal, Peter Bell, Kimberly Coughlan, Minjung Choi,et al.
Mary Ann Liebert Inc
Maple syrup urine disease (MSUD) is a rare, inherited, metabolic disorder characterized by dysfunction of the multi-subunit, mitochondrial enzyme complex branched-chain alpha-keto acid dehydrogenase (BCKDH). BCKDH catalyzes the oxidative decarboxylation of branched-chain amino acids (BCAAs). BCAAs and their neurotoxic alpha-keto intermediates can accumulate in the blood and tissues in the absence of functional BCKDH. We evaluated a lipid nanoparticle (LNP)-based treatment approach to address all possible genetic mutations that can cause MSUD (BCKDHA, BCKDHB, and DBT). In the intermediate MSUD mouse model, which harbors a mutation in the dihydrolipoamide branched-chain transacylase E2 (DBT) subunit of BCKDH, repeated administration of LNP-encapsulated mRNA therapy significantly extended survival and reduced serum leucine levels. We also evaluated our LNP approach in several models of classic MSUD, namely DBT knockout (KO) mice and the new BCKDHA KO and BCKDHB KO mice. The latter two were generated by CRISPR/Cas9 gene editing and contain the highly prevalent classic MSUD-causing mutations seen in the Mennonite and Costa Rican populations. Intravenous LNP-encapsulated mRNA administration extended survival and increased body weight in the DBT KO and BCKDHA KO models of classic MSUD but was not effective in BCKDHB KO mice. Our data provide a promising proof-of-concept that a universal, mutation-independent approach to treating MSUD is possible and viable.


Integrated vector genomes may contribute to long-term expression in primate liver after AAV administration
Jenny A. Greig, Kelly M. Martins, Camilo Breton, R. Jason Lamontagne, Yanqing Zhu, Zhenning He, John White, Jing-Xu Zhu, Jessica A. Chichester, Qi Zheng,et al.
Springer Science and Business Media LLC
AbstractThe development of liver-based adeno-associated virus (AAV) gene therapies is facing concerns about limited efficiency and durability of transgene expression. We evaluated nonhuman primates following intravenous dosing of AAV8 and AAVrh10 vectors for over 2 years to better define the mechanism(s) of transduction that affect performance. High transduction of non-immunogenic transgenes was achieved, although expression declined over the first 90 days to reach a lower but stable steady state. More than 10% of hepatocytes contained single nuclear domains of vector DNA that persisted despite the loss of transgene expression. Greater reductions in vector DNA and RNA were observed with immunogenic transgenes. Genomic integration of vector sequences, including complex concatemeric structures, were detected in 1 out of 100 cells at broadly distributed loci that were not in proximity to genes associated with hepatocellular carcinoma. Our studies suggest that AAV-mediated transgene expression in primate hepatocytes occurs in two phases: high but short-lived expression from episomal genomes, followed by much lower but stable expression, likely from integrated vectors.


Magnetic Resonance Imaging-Guided Frameless Stereotactic Injections of the Bilateral Cerebellar Dentate Nuclei in Nonhuman Primates: Technical Note
Liming Qiu, Emily Xu, Sydney Chambule, Philip LaTourette, Cecilia D. Dyer, Chelsea K. Wallace, Rachel Donocoff, James M. Wilson, Timothy H. Lucas, and H. Isaac Chen
Ovid Technologies (Wolters Kluwer Health)
BACKGROUND AND OBJECTIVES: Nonhuman primates (NHPs) are important preclinical models for evaluating therapeutics because of their anatomophysiological similarities to humans, and can be especially useful for testing new delivery targets. With the growing promise of cell and gene therapies for the treatment of neurological diseases, it is important to ensure the accurate and safe delivery of these agents to target structures in the brain. However, a standard guideline or method has not been developed for stereotactic targeting in NHPs. In this article, we describe the safe use of a magnetic resonance imaging–guided frameless stereotactic system to target bilateral cerebellar dentate nuclei for accurate, real-time delivery of viral vector in NHPs. METHODS: Seventeen rhesus macaques (Macaca mulatta) underwent stereotactic surgery under real-time MRI guidance using the ClearPoint® system. Bilateral cerebellar dentate nuclei were targeted through a single parietal entry point with a transtentorial approach. Fifty microliters of contrast-impregnated infusate was delivered to each dentate nucleus, and adjustments were made as necessary according to real-time MRI monitoring of delivery. Perioperative clinical outcomes and postoperative volumes of distribution were recorded. RESULTS: All macaques underwent bilateral surgery successfully. Superficial pin site infection occurred in 4/17 (23.5%) subjects, which resolved with antibiotics. Two episodes of transient neurological deficit (anisocoria and unilateral weakness) were recorded, which did not require additional postoperative treatment and resolved over time. Volume of distribution of infusate achieved satisfactory coverage of target dentate nuclei, and only 1 incidence (2.9%) of cerebrospinal fluid penetration was recorded. Mean volume of distribution was 161.22 ± 39.61 mm3 (left, 173.65 ± 48.29; right, 148.80 ± 23.98). CONCLUSION: MRI-guided frameless stereotactic injection of bilateral cerebellar dentate nuclei in NHPs is safe and feasible. The use of this technique enables real-time modification of the surgical plan to achieve adequate target coverage and can be readily translated to clinical use.


Adeno-associated virus-mediated trastuzumab delivery to the central nervous system for human epidermal growth factor receptor 2+ brain metastasis
Marcela S. Werner, Shweta Aras, Ashleigh R. Morgan, Jillian Roamer, Nesteene J. Param, Kanyin Olagbegi, R. Jason Lamontagne, Jenny A. Greig, and James M. Wilson
Springer Science and Business Media LLC



High-dose systemic adeno-associated virus vector administration causes liver and sinusoidal endothelial cell injury
Juliette Hordeaux, R. Jason Lamontagne, Chunjuan Song, George Buchlis, Cecilia Dyer, Elizabeth L. Buza, Ali Ramezani, Erik Wielechowski, Jenny A. Greig, Jessica A. Chichester,et al.
Elsevier BV



Prednisolone and rapamycin reduce the plasma cell gene signature and may improve AAV gene therapy in cynomolgus macaques
Alexander Kistner, Jessica A. Chichester, Lili Wang, Roberto Calcedo, Jenny A. Greig, Leah N. Cardwell, Margaret C. Wright, Julien Couthouis, Sunjay Sethi, Brian E. McIntosh,et al.
Springer Science and Business Media LLC
AbstractAdeno-associated virus (AAV) vector gene therapy is a promising approach to treat rare genetic diseases; however, an ongoing challenge is how to best modulate host immunity to improve transduction efficiency and therapeutic outcomes. This report presents two studies characterizing multiple prophylactic immunosuppression regimens in male cynomolgus macaques receiving an AAVrh10 gene therapy vector expressing human coagulation factor VIII (hFVIII). In study 1, no immunosuppression was compared with prednisolone, rapamycin (or sirolimus), rapamycin and cyclosporin A in combination, and cyclosporin A and azathioprine in combination. Prednisolone alone demonstrated higher mean peripheral blood hFVIII expression; however, this was not sustained upon taper. Anti-capsid and anti-hFVIII antibody responses were robust, and vector genomes and transgene mRNA levels were similar to no immunosuppression at necropsy. Study 2 compared no immunosuppression with prednisolone alone or in combination with rapamycin or methotrexate. The prednisolone/rapamycin group demonstrated an increase in mean hFVIII expression and a mean delay in anti-capsid IgG development until after rapamycin taper. Additionally, a significant reduction in the plasma cell gene signature was observed with prednisolone/rapamycin, suggesting that rapamycin’s tolerogenic effects may include plasma cell differentiation blockade. Immunosuppression with prednisolone and rapamycin in combination could improve therapeutic outcomes in AAV vector gene therapy.


Combinatorial design of siloxane-incorporated lipid nanoparticles augments intracellular processing for tissue-specific mRNA therapeutic delivery
Lulu Xue, Gan Zhao, Ningqiang Gong, Xuexiang Han, Sarah J. Shepherd, Xinhong Xiong, Zebin Xiao, Rohan Palanki, Junchao Xu, Kelsey L. Swingle,et al.
Springer Science and Business Media LLC



Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy
Teerapat Rojsajjakul, Juliette J. Hordeaux, Gourav R. Choudhury, Christian J. Hinderer, Clementina Mesaros, James M. Wilson, and Ian A. Blair
Springer Science and Business Media LLC
AbstractDeficiency in human mature frataxin (hFXN-M) protein is responsible for the devastating neurodegenerative and cardiodegenerative disease of Friedreich’s ataxia (FRDA). It results primarily through epigenetic silencing of the FXN gene by GAA triplet repeats on intron 1 of both alleles. GAA repeat lengths are most commonly between 600 and 1200 but can reach 1700. A subset of approximately 3% of FRDA patients have GAA repeats on one allele and a mutation on the other. FRDA patients die most commonly in their 30s from heart disease. Therefore, increasing expression of heart hFXN-M using gene therapy offers a way to prevent early mortality in FRDA. We used rhesus macaque monkeys to test the pharmacology of an adeno-associated virus (AAV)hu68.CB7.hFXN therapy. The advantage of using non-human primates for hFXN-M gene therapy studies is that hFXN-M and monkey FXN-M (mFXN-M) are 98.5% identical, which limits potential immunologic side-effects. However, this presented a formidable bioanalytical challenge in quantification of proteins with almost identical sequences. This could be overcome by the development of a species-specific quantitative mass spectrometry-based method, which has revealed for the first time, robust transgene-specific human protein expression in monkey heart tissue. The dose response is non-linear resulting in a ten-fold increase in monkey heart hFXN-M protein expression with only a three-fold increase in dose of the vector.


Positron Emission Tomography Quantitative Assessment of Off-Target Whole-Body Biodistribution of I-124-Labeled Adeno-Associated Virus Capsids Administered to Cerebral Spinal Fluid
Jonathan B. Rosenberg, Edward K. Fung, Jonathan P. Dyke, Bishnu P. De, Howard Lou, James M. Kelly, Layla Reejhsinghani, Rodolfo J. Ricart Arbona, Dolan Sondhi, Stephen M. Kaminsky,et al.
Mary Ann Liebert Inc
Based on studies in experimental animals demonstrating that administration of adeno-associated virus (AAV) vectors to the cerebrospinal fluid (CSF) is an effective route to transfer genes to the nervous system, there are increasing number of clinical trials using the CSF route to treat nervous system disorders. With the knowledge that the CSF turns over 4 to 5 times daily, and evidence in experimental animals that at least some of CSF administered AAV vectors are distributed to systemic organs, we asked: with AAV administration to the CSF, what fraction of the total dose remains in the nervous system and what fraction goes off target and is delivered systemically? To quantify the biodistribution of AAV capsids immediately after administration, we covalently labeled AAV capsids with iodine 124 (I-124), a cyclotron generated positron emitter, enabling quantitative positron tomography (PET) scanning of capsid distribution for up to 96 hours after AAV vector administration. We assessed the biodistribution to nonhuman primates of I-124-labeled capsids from different AAV clades, including 9 (clade F), rh.10 (E), PHP.eB (F), hu68 (F) and rh91(A). The analysis demonstrated that 60 to 90% of AAV vectors administered to the CSF via either the intracisternal or intrathecal (lumbar) routes distributed systemically to major organs. These observations have potentially significant clinical implications regarding accuracy of AAV vector dosing to the nervous system, evoking systemic immunity at levels similar to that with systemic administration, and potential toxicity of genes designed to treat nervous system disorders being expressed in non-nervous system organs. Based on these data, individuals in clinical trials using AAV vectors administered to the CSF should be monitored for systemic as well as nervous system adverse events and CNS dosing considerations should account for a significant AAV systemic distribution.


Prevalent and Disseminated Recombinant and Wild-Type Adeno-Associated Virus Integration in Macaques and Humans
Kelly M. Martins, Camilo Breton, Qi Zheng, Zhe Zhang, Caitlin Latshaw, Jenny A. Greig, and James M. Wilson
Mary Ann Liebert Inc
Integration of naturally occurring adeno-associated viruses (AAV; wild-type AAV [wtAAV]) and those used in gene therapy (recombinant AAV [rAAV]) into host genomic DNA has been documented for over two decades. Results from mouse and dog studies have raised concerns of insertional mutagenesis and clonal expansion following AAV exposure, particularly in the context of gene therapy. This study aimed to characterize the genomic location, abundance, and expansion of wtAAV and rAAV integrations in macaque and human genomes. Using an unbiased, next-generation sequencing-based approach, we identified the genome-wide integration loci in tissue samples (primarily liver) in 168 nonhuman primates (NHPs) and 85 humans naïve to rAAV exposure and 86 NHPs treated with rAAV in preclinical studies. Our results suggest that rAAV and wtAAV integrations exhibit similar, broad distribution patterns across species, with a higher frequency in genomic regions highly vulnerable to DNA damage or close to highly transcribed genes. rAAV exhibited a higher abundance of unique integration loci, whereas wtAAV integration loci were associated with greater clonal expansion. This expansive and detailed characterization of AAV integration in NHPs and humans provides key translational insights, with important implications for the safety of rAAV as a gene therapy vector.


Adeno-associated virus-vectored erythropoietin gene therapy for anemia in cats with chronic kidney disease
Shelly L. Vaden, Allison R. Kendall, Jonathan D. Foster, Heidi L. New, Jane S. Eagleson, Jacky L. May, Anne M. Traas, Matthew J. Wilson, Beth H. McIntyre, Christian J. Hinderer,et al.
Wiley
AbstractBackgroundA treatment of chronic kidney disease (CKD)‐associated anemia in cats is needed. SB‐001 is an adeno‐associated virus‐vectored (AAV)‐based gene therapeutic agent that is administered intramuscularly, causing the expression of feline erythropoietin.Hypothesis/ObjectiveWe hypothesized that SB‐001 injection would lead to a sustained increase in PCV in cats with CKD‐associated anemia.AnimalsTwenty‐three cats with International Renal Interest Society (IRIS) Stage 2 to 4 CKD‐associated anemia were enrolled at 4 veterinary clinics.MethodsIn a prospective clinical trial, cats were treated with 1 of 3 regimens of SB‐001 (Lo 1.2 × 109 genome copies [GCs] on Day 0; Lo ± Hi [supplemental 2nd dose of 3.65 × 109 GC on Day 42]; Hi 3.65 × 109 GC IM on Day 0) and followed for 70 days.ResultsA response to SB‐001 at any time between Day 28 and Day 70 was seen in 86% (95% confidence interval 65, 97%) of all cats. There was a significant (P < .003) increase in PCV from Day 0 to Day 28 (mean increase 6 ± 6 percentage points [pp]; n = 21), Day 42 (8 ± 9 pp; n = 21), Day 56 (10 ± 11 pp; n = 17), and Day 70 (13 ± 14 pp, n = 14). Twelve cats were hypertensive at baseline, 4 of which developed encephalopathy during the study. An additional 6 cats became hypertensive during the study.Conclusions and Clinical ImportanceResults of this study suggest that SB‐001 therapy represents a suitable single injection treatment that can address nonregenerative anemia in cats with CKD. It was generally well tolerated; however, hypertension and encephalopathy developed in some cats as previously described in association with erythropoiesis‐stimulating agent therapy.


Significant Differences in Capsid Properties and Potency Between Adeno-Associated Virus Vectors Produced in Sf9 and HEK293 Cells
April Giles, Martin Lock, Shu-Jen Chen, Kevin Turner, Gregg Wesolowski, Andrew Prongay, Boris N. Petkov, Kanyin Olagbegi, Hanying Yan, and James M. Wilson
Mary Ann Liebert Inc
For successful vector-based gene therapy manufacturing, the selected adeno-associated virus (AAV) vector production system must produce vector at sufficient scale. However, concerns have arisen regarding the quality of vector produced using different systems. In this study, we compared AAV serotypes 1, 8, and 9 produced by two different systems (Sf9/baculovirus and HEK293/transfection) and purified by two separate processes. We evaluated capsid properties including protein composition, post-translational modification, particle content profiles, and in vitro and in vivo vector potency. Vectors produced in the Sf9/baculovirus system displayed reduced incorporation of viral protein 1 and 2 into the capsid, increased capsid protein deamidation, increased empty and partially packaged particles in vector preparations, and an overall reduced potency. The differences observed were largely independent of the harvest method and purification process. These findings illustrate the need for careful consideration when choosing an AAV vector production system for clinical production.


Neonatal Fc Receptor Inhibition Enables Adeno-Associated Virus Gene Therapy Despite Pre-Existing Humoral Immunity
Makoto Horiuchi, Christian J. Hinderer, Hailey N. Shankle, Peter M. Hayashi, Jessica A. Chichester, Casey Kissel, Peter Bell, Cecilia Dyer, and James M. Wilson
Mary Ann Liebert Inc
Advances in adeno-associated virus-based gene therapy are transforming our ability to treat rare genetic disorders and address other unmet medical needs. However, the natural prevalence of anti-adeno-associated virus neutralizing antibodies in humans currently limits the population who can benefit from adeno-associated virus-based gene therapies. Neonatal Fc receptor plays an essential role in the long half-life of IgG, a key neutralizing antibody. Researchers have developed several neonatal Fc receptor-inhibiting monoclonal antibodies to treat autoimmune diseases, as inhibiting the interaction between neonatal Fc receptor and IgG Fc can reduce circulating IgG levels to 20%-30% of the baseline. We evaluated the utility of one such monoclonal antibody, M281, to reduce pre-existing neutralizing antibody levels and to permit gene delivery to the liver and heart via systemic adeno-associated virus gene therapy in mice and nonhuman primates. M281 successfully reduced neutralizing antibody titers along with total IgG levels; it also enhanced gene delivery to the liver and other organs after intravenous administration of adeno-associated virus in neutralizing antibody-positive animals. These results indicate that mitigating pre-existing humoral immunity via disruption of the neonatal Fc receptor-IgG interaction may make adeno-associated virus-based gene therapies effective in neutralizing antibody-positive patients.


Vector Affinity and Receptor Distribution Define Tissue-Specific Targeting in an Engineered AAV Capsid
R. Alexander Martino, Qiang Wang, Hao Xu, Gui Hu, Peter Bell, Edgardo J. Arroyo, Joshua J. Sims, and James M. Wilson
American Society for Microbiology
Novel methods for measuring adeno-associated virus (AAV)-receptor affinities, especially in relation to vector performance in vivo , would be useful to capsid engineers as they develop AAV vectors for gene therapy applications and characterize their interactions with native or engineered receptors. Here, we use the AAV-PHP.B-Ly6a model system to assess the impact of receptor affinity on the systemic delivery and endothelial penetration properties of AAV-PHP.B vectors.


Lipid nanoparticle-encapsulated mRNA therapy corrects serum total bilirubin level in Crigler-Najjar syndrome mouse model
Jenny A. Greig, Joanna K. Chorazeczewski, Vivek Chowdhary, Melanie K. Smith, Matthew Jennis, James C. Tarrant, Elizabeth L. Buza, Kimberly Coughlan, Paolo G.V. Martini, and James M. Wilson
Elsevier BV



Immune transgene-dependent myocarditis in macaques after systemic administration of adeno-associated virus expressing human acid alpha-glucosidase
Juliette Hordeaux, Ali Ramezani, Steve Tuske, Nickita Mehta, Chunjuan Song, Anna Lynch, Katherine Lupino, Jessica A. Chichester, Elizabeth L. Buza, Cecilia Dyer,et al.
Frontiers Media SA
Immune responses to human non-self transgenes can present challenges in preclinical studies of adeno-associated virus (AAV) gene therapy candidates in nonhuman primates. Although anti-transgene immune responses are usually mild and non-adverse, they can confound pharmacological readouts and complicate translation of results between species. We developed a gene therapy candidate for Pompe disease consisting of AAVhu68, a clade F AAV closely related to AAV9, that expresses an engineered human acid-alpha glucosidase (hGAA) tagged with an insulin-like growth factor 2 variant (vIGF2) peptide for enhanced cell uptake. Rhesus macaques were administered an intravenous dose of 1x1013 genome copies (GC)/kg, 5x1013 GC/kg, or 1 x 1014 GC/kg of AAVhu68.vIGF2.hGAA. Some unusually severe adaptive immune responses to hGAA presented, albeit with a high degree of variability between animals. Anti-hGAA responses ranged from absent to severe cytotoxic T-cell-mediated myocarditis with elevated troponin I levels. Cardiac toxicity was not dose dependent and affected five out of eleven animals. Upon further investigation, we identified an association between toxicity and a major histocompatibility complex class I haplotype (Mamu-A002.01) in three of these animals. An immunodominant peptide located in the C-terminal region of hGAA was subsequently identified via enzyme-linked immunospot epitope mapping. Another notable observation in this preclinical safety study cohort pertained to the achievement of robust and safe gene transfer upon intravenous administration of 5x1013 GC/kg in one animal with a low pre-existing neutralizing anti-capsid antibodies titer (1:20). Collectively, these findings may have significant implications for gene therapy inclusion criteria.


Erratum: Intravenous immunoglobulin prevents peripheral liver transduction of intrathecally delivered AAV vectors (Molecular Therapy - Methods & Clinical Development (2022) 27 (272–280), (S2329050122001425), (10.1016/j.omtm.2022.09.017))
Makoto Horiuchi, Christian J. Hinderer, Jenny A. Greig, Cecilia Dyer, Elizabeth L. Buza, Peter Bell, Jessica A. Chichester, Peter M. Hayashi, Hanying Yan, Tamara Goode,et al.
Elsevier BV



Intravenous immunoglobulin prevents peripheral liver transduction of intrathecally delivered AAV vectors
Makoto Horiuchi, Christian J. Hinderer, Jenny A. Greig, Cecilia Dyer, Elizabeth L. Buza, Peter Bell, Jessica A. Chichester, Peter M. Hayashi, Hanying Yan, Tamara Goode,et al.
Elsevier BV



Treating Transthyretin Amyloidosis via Adeno-Associated Virus Vector Delivery of Meganucleases
J. Greig, C. Breton, Scott N. Ashley, Kelly M. Martins, Cassandra L. Gorsuch, Joanna K Chorazeczewski, Thomas Furmanak, Melanie K. Smith, Yanqing Zhu, P. Bell,et al.

Transthyretin amyloidosis (ATTR) is a progressive and fatal disease caused by transthyretin (TTR) amyloid fibril accumulation in tissues, which disrupts organ function. As the TTR protein is primarily synthesized by the liver, liver transplantation can cure familial ATTR but is not an option for the predominant age-related wild-type ATTR. Approved treatment approaches include TTR stabilizers and an RNA-interference therapeutic, but these require regular re-administration. Gene editing could represent an effective one-time treatment. We evaluated adeno-associated virus (AAV) vector-delivered, gene-editing meganucleases to reduce TTR levels. We used engineered meganucleases targeting two different sites within the TTR gene. AAV vectors expressing TTR meganuclease transgenes were first tested in immunodeficient mice expressing the human TTR sequence delivered using an AAV vector and then against the endogenous TTR gene in rhesus macaques. Following a dose of 3 × 1013 genome copies per kilogram, we detected on-target editing efficiency of up to 45% insertions and deletions (indels) in the TTR genomic DNA locus and >80% indels in TTR RNA, with a concomitant decrease in serum TTR levels of >95% in macaques. The significant reduction in serum TTR levels following TTR gene editing indicates that this approach could be an effective treatment for ATTR.

RECENT SCHOLAR PUBLICATIONS

225 Patient-centred approach to management of inflammatory arthritis was associated with improved satisfaction of care and perceived treatment benefit
L Attipoe, D Shah, J Greenan-Barrett, S Virdee, A Cotton, J Guinto, ...
Rheumatology 57 (suppl_3), key075. 449 2018



An AC coupled 10 Gb/s LVDS-compatible receiver with latched data biasing in 130 nm SiGe BiCMOS
B Mathieu, JJ McCue, B Dupaix, VJ Patel, S Dooley, J Wilson, ...
2017 IEEE Compound Semiconductor Integrated Circuit Symposium (CSICS), 1-4 2017



Low voltage differential signal receiver with fully integrated AC coupling and bias latching
J McCue, VJ Patel, W Khalil, B Dupaix, J Wilson, SR Dooley
US Patent 9,698,735 2017



Transformer winding resistance tester test probe and method
JC Wilson, R Ross
US Patent 9,151,788 2015



Rolling Stock Specification for an Auto-Transformer Electrification System
J Wilson
Railway Electrification, 9 2014



Toward millimeter-wave DACs: Challenges and opportunities
W Khalil, J Wilson, B Dupaix, S Balasubramanian, GL Creech
2012 IEEE Compound Semiconductor Integrated Circuit Symposium (CSICS), 1-4 2012



Ultimate transmission
S Balasubramanian, S Boumaiza, H Sarbishaei, T Quach, P Orlando, ...
IEEE Microwave Magazine 13 (1), 64-82 2012



终极传输
S Balasubramanian, S Boumaiza, H Sarbishaei, T Quach, P Orlando, ...
IEEE microwave magazine, 64 2012



Systematic analysis of interleaved digital-to-analog converters
S Balasubramanian, G Creech, J Wilson, SM Yoder, JJ McCue, ...
IEEE Transactions on Circuits and Systems II: Express Briefs 58 (12), 882-886 2011



Sensing and latching circuit for memory arrays
J Wilson, G Hoyer
US Patent 7,995,411 2011



Economy motors on after the crisis.
J Wilson
The Financial Times, 1-1 2011



Memory sensing and latching circuit
J Wilson, G Hoyer
US Patent 7,760,568 2010



Method for authenticating radio frequency identification
JC Wilson, G Andrechak
US Patent App. 12/216,456 2010



Key identification system and form fitting label and method of manufacture
JC Wilson
US Patent 7,587,848 2009



Input match and load tank digital calibration of an inductively degenerated CMOS LNA
J Wilson, M Ismail
Integration 42 (1), 3-9 2009



Method and apparatus for performing benefit transactions using a portable intergrated circuit device
B Lee, J Wilson
US Patent App. 11/767,919 2007



Method and apparatus for performing benefit transactions using a portable integrated circuit device
B Lee, JC Wilson
US Patent 7,234,638 2007



Identification card
J Wilson
US Patent App. 11/486,457 2007



Method, software and device for managing patient medical records in a universal format using USB flash drive and radio telephone auto dialer and siren
J Wilson
US Patent App. 11/450,151 2007



RFID: Item Level Management: a Practical Approach
G Andrechak, JC Wilson, C Zimmardi
Mullaney publishing group 2007

MOST CITED SCHOLAR PUBLICATIONS

Portable electronic data storage and retreival system for group data
J Wilson, B Lee
US Patent App. 10/760,172 2005
Citations: 302



A single-chip CMOS transceiver for 802.11 a/b/g wireless LANs
R Ahola, A Aktas, J Wilson, KR Rao, F Jonsson, I Hyyrylainen, A Brolin, ...
IEEE Journal of Solid-State Circuits 39 (12), 2250-2258 2004
Citations: 120



Internal protection circuit for electrically driven device
JR D'entremont, HH Fraser Jr, JC Wilson
US Patent 5,200,872 1993
Citations: 90



The chip-peak detectors for multistandard wireless receivers
SB Park, JE Wilson, M Ismail
IEEE Circuits and Devices Magazine 22 (6), 6-9 2006
Citations: 72



Systematic analysis of interleaved digital-to-analog converters
S Balasubramanian, G Creech, J Wilson, SM Yoder, JJ McCue, ...
IEEE Transactions on Circuits and Systems II: Express Briefs 58 (12), 882-886 2011
Citations: 70



Ultimate transmission
S Balasubramanian, S Boumaiza, H Sarbishaei, T Quach, P Orlando, ...
IEEE Microwave Magazine 13 (1), 64-82 2012
Citations: 69



A CMOS RF front-end for a multistandard WLAN receiver
KR Rao, J Wilson, M Ismail
IEEE Microwave and Wireless Components Letters 15 (5), 321-323 2005
Citations: 58



Ground fault protector with arcing fault indicator
JT Wilson, JC Wilson
US Patent 3,911,323 1975
Citations: 53



Methods and systems for improved integrated circuit functional simulation
J Wilson, K Imboden, D Gold
US Patent App. 10/927,810 2005
Citations: 49



Radio design in nanometer technologies
M Ismail, DR de Llera Gonzlez
Springer 2006
Citations: 45



A single chip CMOS transceiver for 802.11 a/b/g WLANs
R Ahola, A Aktas, J Wilson, KR Rao, F Jonsson, I Hyyrylainen, A Brolin, ...
2004 IEEE International Solid-State Circuits Conference (IEEE Cat. No 2004
Citations: 43



Method and apparatus for performing benefit transactions using a portable integrated circuit device
B Lee, JC Wilson
US Patent 7,234,638 2007
Citations: 42



Input match and load tank digital calibration of an inductively degenerated CMOS LNA
J Wilson, M Ismail
Integration 42 (1), 3-9 2009
Citations: 36



Method, software and device for managing patient medical records in a universal format using USB flash drive and radio telephone auto dialer and siren
J Wilson
US Patent App. 11/450,151 2007
Citations: 29



Multi standard transceiver architecture for wlan
A Aktas, K Rama, J Wilson
US Patent App. 10/478,467 2004
Citations: 28



Containment device for retaining semiconductor wafers
L Lewis, KT Hirose, J Wilson, J Dove, M Hayden
US Patent 6,193,068 2001
Citations: 25



End-winding leakage of high-speed alternators by three-dimensional field determination
MS Sarma, JC Wilson, PJ Lawrenson, AL Jokl
IEEE Transactions on Power Apparatus and Systems, 465-477 1971
Citations: 24



Aerospace composite-rotor induction motors
JC Wilson, EA Erdelyi, RE Hopkins
IEEE Transactions on Aerospace, 18-23 1965
Citations: 24



Toward millimeter-wave DACs: Challenges and opportunities
W Khalil, J Wilson, B Dupaix, S Balasubramanian, GL Creech
2012 IEEE Compound Semiconductor Integrated Circuit Symposium (CSICS), 1-4 2012
Citations: 18



A low-voltage CMOS 5-bit 600 MHz 30 mW SAR ADC for UWB wireless receivers
SY Ng, B Jalali, P Zhang, J Wilson, M Ismail
48th Midwest Symposium on Circuits and Systems, 2005., 187-190 2005
Citations: 17

RESEARCH OUTPUTS (PATENTS, SOFTWARE, PUBLICATIONS, PRODUCTS)

A single-chip CMOS transceiver for 802.11 a/b/g wireless LANs
Portable electronic data storage and retreival system for group data