ORCID Profile
0000-0001-8577-3915
Current Organisations
Foundation for Innovative New Diagnostics
,
Military Institute of Medicine
,
Children's Medical Research Institute
,
University of Sydney
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Publisher: Cold Spring Harbor Laboratory
Date: 09-11-2020
DOI: 10.1101/2020.11.09.359968
Abstract: While direct allorecognition underpins both solid organ allograft rejection and tolerance induction, the specific molecular targets of most directly-alloreactive CD8 + T cells have not been defined. In this study, we used a combination of genetically-engineered MHC class I (MHC I) constructs, mice with a hepatocyte-specific mutation in the class I antigen-presentation pathway and immunopeptidomic analysis to provide definitive evidence for the contribution of the peptide cargo of allogeneic MHC I molecules to transplant tolerance induction. We established a systematic approach for the discovery of directly-recognised pMHC epitopes, and identified 17 strongly immunogenic H-2K b -associated peptides recognised by CD8 + T cells from B10.BR (H-2 k ) mice, 13 of which were also recognised by BALB/c (H-2 d ) mice. As few as five different tetramers used together were able to identify a high proportion of alloreactive T cells within a polyclonal population, suggesting that there are immunodominant allogeneic MHC-peptide complexes that can account for a large component of the alloresponse.
Publisher: Elsevier BV
Date: 03-2023
Publisher: Springer Science and Business Media LLC
Date: 25-09-2020
DOI: 10.1038/S41467-020-18715-Y
Abstract: Precision genome engineering has dramatically advanced with the development of CRISPR/Cas base editing systems that include cytosine base editors and adenine base editors (ABEs). Herein, we compare the editing profile of circularly permuted and domain-inlaid Cas9 base editors, and find that on-target editing is largely maintained following their intradomain insertion, but that structural permutation of the ABE can affect differing RNA off-target events. With this insight, structure-guided design was used to engineer an SaCas9 ABE variant (microABE I744) that has dramatically improved on-target editing efficiency and a reduced RNA-off target footprint compared to current N-terminal linked SaCas9 ABE variants. This represents one of the smallest AAV-deliverable Cas9-ABEs available, which has been optimized for robust on-target activity and RNA-fidelity based upon its stereochemistry.
Publisher: Oxford University Press (OUP)
Date: 30-07-2020
DOI: 10.1093/CID/CIAA1742
Abstract: Tuberculosis (TB) continues to account for significant morbidity and mortality annually. Household contacts (HHCs) of persons with TB are a key population for targeting prevention and control interventions. We aimed to identify risk factors associated with developing TB among HHCs. We conducted a nested case-control study among HHCs in 8 provinces in Vietnam enrolled in a randomized controlled trial of active case finding for TB. Cases were any HHCs diagnosed and registered with TB within the Vietnam National TB Program during 2 years of follow-up. Controls were selected by simple random s ling from the remaining HHCs. Risk factor data were collected at enrollment and during follow-up. A logistic regression model was developed to determine predictors of TB among HHCs. We selected 1254 HHCs for the analysis: 214 cases and 1040 controls. Underlying characteristics varied between both groups cases were older, more likely to be male, with a higher proportion of reported previous TB and diabetes. Risk factors associated with a TB diagnosis included being male (adjusted odds ratio [aOR], 1.4 95% confidence interval [CI], 1.03–2.0), residing in an urban setting (aOR, 1.8 1.3–2.5), prior TB (aOR, 4.6 2.5–8.7), history of diabetes (aOR, 3.1 1.7–5.8), current smoking (aOR, 3.1 2.2–4.4), and prolonged history of coughing in the index case at enrollment (OR , 1.6 1.1–2.3). Household contacts remain an important key population for TB prevention and control. TB programs should ensure effective contact investigations are implemented for household contacts, particularly those with additional risk factors for developing TB.
Publisher: BMJ
Date: 2020
DOI: 10.1136/BMJOPEN-2019-033945
Abstract: Treatment of latent tuberculosis infection (LTBI) plays a substantial role in the prevention of drug-susceptible tuberculosis (TB). However, clinical trials to evaluate the efficacy of preventive therapy for presumed multidrug-resistant (MDR) LTBI are lacking. This trial aims to evaluate the efficacy of the antibiotic levofloxacin in preventing the development of active TB among latently infected contacts of index patients with MDR-TB. A double-blind placebo-controlled parallel group randomised controlled trial will be conducted in 10 provinces of Vietnam. Household contacts living with patients with bacteriologically confirmed rif icin-resistant or MDR-TB will be eligible for recruitment if they have a positive tuberculin skin test or are known to be immunosuppressed, and do not have active TB. Participants will be randomised to receive either levofloxacin or placebo tablets once per day for 6 months. Screening for incident TB will be performed at 6 months intervals. The primary study outcome is the incidence of bacteriologically confirmed TB within 30 months after randomisation. Analysis will be by intention to treat, using Poisson regression. Ethical approval from the University of Sydney Human Research Ethics Committee was obtained on 29 April 2015 (2014/929), and from the Vietnam Ministry of Health Institutional Review Board on 30 September 2015 (4040/QD-BYT). Findings of the study will be published in peer-reviewed publications and conference presentations. ACTRN12616000215426.
Publisher: BMJ
Date: 05-09-2023
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 07-2021
Publisher: Elsevier BV
Date: 03-2022
Publisher: Wiley
Date: 14-12-2020
DOI: 10.1111/XEN.12669
Abstract: Neonatal porcine islets (NPIs) can restore glucose control in mice, pigs, and non‐human primates, representing a potential abundant alternative islet supply for clinical beta cell replacement therapy. However, NPIs are vulnerable to inflammatory insults that could be overcome with genetic modifications. Here, we demonstrate in a series of proof‐of‐concept experiments the potential of the cytoplasmic ubiquitin‐editing protein A20, encoded by the TNFAIP3 gene, as an NPI cytoprotective gene. We forced A20 expression in NPI grafts using a recombinant adenovirus 5 (Ad5) vector and looked for impact on TNF‐stimulated NF‐κB activation and NPI graft function. As adeno‐associated vectors (AAV) are clinically preferred vectors but exhibit poor transduction efficacy in NPIs, we next screened a series of AAV serotypes under different transduction protocols for their ability achieve high transduction efficiency and suppress NPI inflammation without impacting NPI maturation. Forcing the expression of A20 in NPI with Ad5 vector blocked NF‐κB activation by inhibiting IκBα phosphorylation and degradation, and reduced the induction of pro‐inflammatory genes Cxcl10 and Icam1 . A20‐expressing NPIs also exhibited superior functional capacity when transplanted into diabetic immunodeficient recipient mice, evidenced by a more rapid return to euglycemia and improved GTT compared to unmodified NPI grafts. We found AAV2 combined with a 14‐day culture period maximized NPI transduction efficiency ( % transduction rate), and suppressed NF‐κB‐dependent gene expression without adverse impact upon NPI maturation. We report a new protocol that allows for high‐efficiency genetic modification of NPIs, which can be utilized to introduce candidate genes without the need for germline engineering. This approach would be suitable for preclinical and clinical testing of beneficial molecules. We also report for the first time that A20 is cytoprotective for NPI, such that A20 gene therapy could aid the clinical development of NPIs for beta cell replacement.
Publisher: Elsevier BV
Date: 10-2018
Publisher: Research Square Platform LLC
Date: 24-07-2023
DOI: 10.21203/RS.3.RS-3158964/V1
Abstract: Developing clinically predictive model systems for evaluating gene transfer and gene editing technologies has become increasingly important in the era of personalized medicine. Liver-directed gene therapies present a unique challenge due to the complexity of the human liver. In this work, we describe the application of whole human liver explants in an ex situ normothermic perfusion system to evaluate a set of fourteen natural and bioengineered adeno-associated viral (AAV) vectors directly in human liver, in the presence and absence of neutralizing human sera. Under non-neutralizing conditions, the recently developed AAV variants, AAV-SYD12 and AAV-LK03, emerged as the most functional variants in terms of cellular uptake and transgene expression. However, when assessed in the presence of human plasma containing anti-AAV neutralizing antibodies (NAbs), vectors of human origin, specifically those derived from AAV2/AAV3b, were extensively neutralized, whereas AAV8- derived variants performed efficiently. This study establishes the use of normothermic liver perfusion as an invaluable preclinical model for evaluating liver-targeted gene therapies and providing guidance for making essential decisions that promote the most effective translational programs.
Publisher: Elsevier BV
Date: 11-2018
Publisher: Springer Science and Business Media LLC
Date: 19-06-2017
DOI: 10.1038/NG.3893
Abstract: Vectors based on adeno-associated virus type 2 (AAV2) are powerful tools for gene transfer and genome editing applications. The level of interest in this system has recently surged in response to reports of therapeutic efficacy in human clinical trials, most notably for those in patients with hemophilia B (ref. 3). Understandably, a recent report drawing an association between AAV2 integration events and human hepatocellular carcinoma (HCC) has generated controversy about the causal or incidental nature of this association and the implications for AAV vector safety. Here we describe and functionally characterize a previously unknown liver-specific enhancer-promoter element in the wild-type AAV2 genome that is found between the stop codon of the cap gene, which encodes proteins that form the capsid, and the right-hand inverted terminal repeat. This 124-nt sequence is within the 163-nt common insertion region of the AAV genome, which has been implicated in the dysregulation of known HCC driver genes and thus offers added insight into the possible link between AAV integration events and the multifactorial pathogenesis of HCC.
Publisher: Microbiology Society
Date: 11-2022
DOI: 10.1099/JGV.0.001812
Abstract: The devil facial tumour disease (DFTD) has led to a massive decline in the wild Tasmanian devil ( Sarcophilus harrisii ) population. The disease is caused by two independent devil facial tumours (DFT1 and DFT2). These transmissible cancers have a mortality rate of nearly 100 %. An adenoviral vector-based vaccine has been proposed as a conservation strategy for the Tasmanian devil. This study aimed to determine if a human adenovirus serotype 5 could express functional transgenes in devil cells. As DFT1 cells do not constitutively express major histocompatibility complex class I (MHC-I), we developed a replication-deficient adenoviral vector that encodes devil interferon gamma (IFN-γ) fused to a fluorescent protein reporter. Our results show that adenoviral-expressed IFN-γ was able to stimulate upregulation of beta-2 microglobulin, a component of MHC-I, on DFT1, DFT2 and devil fibroblast cell lines. This work suggests that human adenoviruses can serve as a vaccine platform for devils and potentially other marsupials.
Publisher: Elsevier BV
Date: 03-2019
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 02-2021
Abstract: BACKGROUND: Exposure to people with TB substantially elevates a person's risk of tuberculous infection and TB disease. Systematic screening of TB contacts enables the early detection and treatment of co‐prevalent disease, and the opportunity to prevent future TB disease. However, scale‐up of contact investigation in high TB transmission settings remains limited. METHODS: We undertook a narrative review to evaluate the evidence for contact investigation and identify strategies that TB programmes may consider when introducing contact investigation and management. RESULTS: Selection of contacts for priority screening depends upon their proximity and duration of exposure, along with their susceptibility to develop TB. Screening algorithms can be tailored to the target population, the availability of diagnostic tests and preventive therapy, and healthcare worker expertise. Contact investigation may be performed in the household or at communal locations. Local contact investigation policies should support vulnerable patients, and ensure that drop‐out during screening can be mitigated. Ethical issues should be anticipated and addressed in each setting. CONCLUSION: Contact investigation is an important strategy for TB elimination. While its epidemiological impact will be greatest in lower‐transmission settings, the early detection and prevention of TB have important benefits for contacts and their communities.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.IJID.2021.02.094
Abstract: Latent tuberculosis infection affects one quarter of the world's population, and effective therapies are available. However, scale-up of tuberculosis preventive treatment (TPT) remains limited. We describe strategies to support scale-up of TPT in high-prevalence settings, where the potential benefit for affected in iduals is considerable. Patients must be at the centre of policies to scale-up TPT. Addressing the health system requirements for scale-up will ensure that programs can deliver treatment safely, efficiently and sustainably. Further research is required to adapt TPT to local contexts, and develop new shorter treatments that will be suitable for wide-scale deployment.
Publisher: American Society for Clinical Investigation
Date: 11-2021
DOI: 10.1172/JCI146771
Publisher: Elsevier BV
Date: 05-2023
Publisher: Springer Science and Business Media LLC
Date: 20-01-1919
DOI: 10.1186/S12879-021-06992-X
Abstract: Improving treatment outcomes for multidrug-resistant tuberculosis (MDR-TB) is a leading priority for global TB control. This retrospective cohort study evaluated the factors associated with treatment success among patients treated for MDR-TB in two provinces in Vietnam. Treatment outcomes were evaluated for adult patients treated in Hanoi and Thanh Hoa provinces between 2014 and 2016. The primary outcome was the proportion of patients with treatment success, defined as cure or treatment completion. Logistic regression analysis was used to evaluate the relationship between patient clinical and microbiological characteristics and treatment success. Treatment outcomes were reported in 612 of 662 patients of these, 401 (65.5)% were successfully treated. The odds of treatment success were lower for male patients (aOR 0.56, 95% CI 0.34–0.90), for people living with HIV (aOR 0.44, 95% CI 0.20–1.00), and for patients treated for extensive antibiotic resistance (pre-XDR-/XDT-TB) (aOR 0.53, 95% CI 0.29–0.97), compared with others. Patients who achieved culture conversion in the first 4 months of treatment had increased odds (aOR 2.93, 95% CI 1.33–6.45) of treatment success. In addition, loss to follow-up was less common among patients covered by social health insurance compared to those who paid for treatment out-of-pocket (aOR 0.55, 95% CI 0.32–0.95). Among patients with MDR-TB, males, people living with HIV, and those with more extensive antibiotic resistance at diagnosis are at greatest risk of an unsuccessful treatment outcome. Efforts to optimise the management of co-morbidities (such as HIV), ensure rapid bacteriological conversion, and provide financial support for patients promise to improve treatment outcomes.
Publisher: Springer Science and Business Media LLC
Date: 25-12-2013
DOI: 10.1038/NATURE12875
Publisher: Elsevier BV
Date: 03-2021
DOI: 10.1053/J.GASTRO.2020.11.011
Abstract: Cancer-associated fibroblasts (CAFs), key constituents of the tumor microenvironment, either promote or restrain tumor growth. Attempts to therapeutically target CAFs have been h ered by our incomplete understanding of these functionally heterogeneous cells. Key growth factors in the intestinal epithelial niche, bone morphogenetic proteins (BMPs), also play a critical role in colorectal cancer (CRC) progression. However, the crucial proteins regulating stromal BMP balance and the potential application of BMP signaling to manage CRC remain largely unexplored. Using human CRC RNA expression data, we identified CAF-specific factors involved in BMP signaling, then verified and characterized their expression in the CRC stroma by in situ hybridization. CRC tumoroids and a mouse model of CRC hepatic metastasis were used to test approaches to modify BMP signaling and treat CRC. We identified Grem1 and Islr as CAF-specific genes involved in BMP signaling. Functionally, GREM1 and ISLR acted to inhibit and promote BMP signaling, respectively. Grem1 and Islr marked distinct fibroblast subpopulations and were differentially regulated by transforming growth factor β and FOXL1, providing an underlying mechanism to explain fibroblast biological dichotomy. In patients with CRC, high GREM1 and ISLR expression levels were associated with poor and favorable survival, respectively. A GREM1-neutralizing antibody or fibroblast Islr overexpression reduced CRC tumoroid growth and promoted Lgr5 Stromal BMP signaling predicts and modifies CRC progression and survival, and it can be therapeutically targeted by novel AAV-directed gene delivery to the liver.
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 05-2014
Publisher: Elsevier BV
Date: 2018
Publisher: Elsevier BV
Date: 02-2020
Publisher: European Respiratory Society (ERS)
Date: 07-2021
DOI: 10.1183/23120541.00149-2021
Abstract: Contacts of an in idual with active tuberculosis (TB) disease have a higher risk of developing latent TB infection (LTBI) or active TB disease. Contact tracing is a public health measure that seeks to identify exposed contacts, screen them for co-prevalent TB and consider prophylactic treatment to prevent progression from LTBI to active TB disease. The investigators sought to determine the prevalence of LTBI and active TB disease among contacts of patients with multidrug-resistant (MDR)-TB in New South Wales, Australia. A retrospective cohort study was performed among the contacts of patients diagnosed with MDR-TB between 2000 and 2016, inclusive, at seven chest clinics. Medical records were used to identify eligible contacts. Outcomes of screening and prophylactic treatment regimens offered to MDR-TB contacts with LTBI were characterised. Collected data included demographic information, screening tests results and initial management. In total, 247 contacts of 55 MDR-TB patients were identified. LTBI was identified in 105 contacts (42.5%). Preventive treatment was received by 20 contacts with LTBI (32.3%) in the form of various regimens, ranging from one to three antimicrobials, with various doses and durations. One contact with LTBI who was untreated progressed to active TB disease during the study period, according to clinic notes. Contacts of MDR-TB patients have a high prevalence of LTBI. Management of these contacts varies substantially in New South Wales, reflecting a lack of definitive evidence for preventive therapy. Further research is required to determine the optimal management of this population.
Publisher: Mary Ann Liebert Inc
Date: 2019
DOI: 10.1089/HUM.2018.098
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.COPH.2015.07.006
Abstract: Gene transfer vectors based on adeno-associated virus (AAV) are showing exciting therapeutic promise in early phase clinical trials. The ability to cross-package the prototypic AAV2 vector genome into different capsids is a powerful way of conferring novel tropism and biology, with evolving capsid engineering technologies and directed evolution approaches further enhancing the utility and flexibility of these vectors. Novel properties of specific capsids show unpredictable species and cell-type specificity. Therefore, full realisation of the therapeutic potential of AAV vectors requires the development of more therapeutically predictive preclinical methods for evaluating capsid performance. This will strongly complement an iterative approach to the evaluation of capsid variants in the clinic and, should wherever possible, include the determination of gene transfer efficiencies.
Publisher: BMJ
Date: 06-2022
DOI: 10.1136/BMJOPEN-2021-052633
Abstract: Multidrug-resistant tuberculosis (MDR-TB) remains a major public health problem globally. Long, complex treatment regimens coupled with frequent adverse events have resulted in poor treatment adherence and patient outcomes. Smartphone-based mobile health (mHealth) technologies offer national TB programmes an appealing platform to improve patient care and management however, clinical trial evidence to support their use is lacking. This trial will test the hypothesis that an mHealth intervention can improve treatment success among patients with MDR-TB and is cost-effective compared with standard practice. A community-based, open-label, parallel-group randomised controlled trial will be conducted among patients treated for MDR-TB in seven provinces of Vietnam. Patients commencing therapy for microbiologically confirmed rif icin-resistant or multidrug-resistant tuberculosis within the past 30 days will be recruited to the study. Participants will be in idually randomised to an intervention arm, comprising use of an mHealth application for treatment support, or a ‘standard care’ arm. In both arms, patients will be managed by the national TB programme according to current national treatment guidelines. The primary outcome measure of effectiveness will be the proportion of patients with treatment success (defined as treatment completion and/or bacteriological cure) after 24 months. A marginal Poisson regression model estimated via a generalised estimating equation will be used to test the effect of the intervention on treatment success. A prospective microcosting of the intervention and within-trial cost-effectiveness analysis will also be undertaken from a societal perspective. Cost-effectiveness will be presented as an incremental cost per patient successfully treated and an incremental cost per quality-adjusted life-year gained. Ethical approval for the study was granted by The University of Sydney Human Research Ethics Committee (2019/676). Study findings will be disseminated to participants and published in peer-reviewed journals and conference proceedings. ACTRN12620000681954.
Publisher: Cold Spring Harbor Laboratory
Date: 10-07-2023
DOI: 10.1101/2023.07.10.548299
Abstract: Developing clinically predictive model systems for evaluating gene transfer and gene editing technologies has become increasingly important in the era of personalized medicine. Liver-directed gene therapies present a unique challenge due to the complexity of the human liver. In this work, we describe the application of whole human liver explants in an ex situ normothermic perfusion system to evaluate a set of fourteen natural and bioengineered adeno-associated viral (AAV) vectors directly in human liver, in the presence and absence of neutralizing human sera. Under non-neutralizing conditions, the recently developed AAV variants, AAV-SYD12 and AAV-LK03, emerged as the most functional variants in terms of cellular uptake and transgene expression. However, when assessed in the presence of human plasma containing anti-AAV neutralizing antibodies (NAbs), vectors of human origin, specifically those derived from AAV2/AAV3b, were extensively neutralized, whereas AAV8-derived variants performed efficiently. This study establishes the use of normothermic liver perfusion as an invaluable preclinical model for evaluating liver-targeted gene therapies and providing guidance for making essential decisions that promote the most effective translational programs.
Publisher: Cold Spring Harbor Laboratory
Date: 30-09-2022
DOI: 10.1101/2022.09.28.510021
Abstract: The liver is a prime target for in vivo gene therapies using recombinant adeno-associated viral vectors (rAAV). Multiple clinical trials have been undertaken for this target in the past 15 years, however we are still to see market approval of the first liver-targeted AAV-based gene therapy. Inefficient expression of the therapeutic transgene, vector-induced liver toxicity and capsid, and/or transgene-mediated immune responses reported at high vector doses are the main challenges to date. One of the contributing factors to the insufficient clinical outcomes, despite highly encouraging preclinical data, is the lack of robust, biologically- and clinically-predictive preclinical models. To this end, this study reports findings of a functional evaluation of six AAV vectors in twelve preclinical models of the human liver, with the aim to uncover which model is the most relevant for the selection of AAV capsid variant for safe and efficient transgene delivery to primary human hepatocytes. The results, generated by studies in models ranging from immortalized cells, iPSC-derived and primary hepatocytes, and primary human hepatic organoids to in vivo models, increased our understanding of the strengths and weaknesses of each system. This should allow the development of novel gene therapies targeting the human liver.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 09-09-2020
DOI: 10.1126/SCITRANSLMED.ABA3312
Abstract: AAVs isolated from human liver are tropic for human hepatocytes in vivo, but this phenotype becomes attenuated after passage in culture.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.EXER.2018.09.003
Abstract: Inherited retinal disease (IRD) affects about 1 in 3000 to 1 in 5000 in iduals and is now believed to be the most common cause of blindness registration in developed countries. Until recently, the management of such conditions had been exclusively supportive. However, advances in molecular biology and medical engineering have now seen the rise of a variety of approaches to restore vision in patients with IRDs. Optogenetic approaches are primarily aimed at rendering secondary and tertiary neurons of the retina light-sensitive in order to replace degenerate or dysfunctional photoreceptors. Such approaches are attractive because they provide a "causative gene-independent" strategy, which may prove suitable for a variety of patients with IRD. We discuss theoretical and practical considerations in the selection of optogenetic molecules, vectors, surgical approaches and review previous trials of optogenetics for vision restoration. Optogenetic approaches to vision restoration have yielded promising results in pre-clinical trials and a phase I/II clinical trial is currently underway (ClinicalTrials.gov NCT02556736). Despite the significant inroads made in recent years, the ideal optogenetic molecule, vector and surgical approach have yet to be established.
Location: United States of America
Location: United States of America
Location: United States of America
No related grants have been discovered for Kavindhran Velen.