Category Archives: Genetic medicine

PITTSBURGH--(BUSINESS WIRE)--ElevateBio, LLC (ElevateBio) and the University of Pittsburgh today announced that they have entered into a long-term strategic partnership to accelerate the development of highly innovative cell and gene therapies. Through this agreement, ElevateBio will locate one of its next BaseCamp process development and Good Manufacturing Practice (GMP) manufacturing facilities in Pittsburgh, fully equipped with its enabling technologies, including gene editing, induced pluripotent stem cell (iPSC) and cell, vector, and protein engineering capabilities. The University of Pittsburgh has long been a research powerhouse and is consistently among the top U.S. institutions in National Institutes of Health research funding.

The Richard King Mellon Foundation announced a $100 million grant to the University of Pittsburgh in November 2021 to create the Pitt BioForge BioManufacturing Center at Hazelwood Green. The grant was the largest single-project grant in the Foundation's 75-year history. The University of Pittsburgh and ElevateBio BaseCamp intend to locate the new technology-enabled process development and GMP manufacturing facility at Pitt BioForge at Hazelwood Green to further innovation in the Pittsburgh region. The new facility is expected to generate more than 170 permanent full-time jobs, 900 construction jobs, and 360 off-site support jobs.

This announcement supports the region's rise as a leader in cell and gene therapy and advances our vision of bringing an entirely new commercial manufacturing sector to the area," says Patrick Gallagher, Chancellor of the University of Pittsburgh. "The University of Pittsburgh is proud to partner with ElevateBio in this work, which will see us leveraging lessons from the labin new and exciting waysfor the benefit of human health.

To realize our vision of transforming the cell and gene therapy field for decades to come, broadening our footprint across metropolitan areas is a key priority for us, and we are thrilled that the University of Pittsburgh will be home to one of our BaseCamp facilities, said David Hallal, Chairman and Chief Executive Officer of ElevateBio. Weve identified Pittsburgh as an ideal location to extend our BaseCamp presence as it sits at the intersection of science, technology, and talent. We are grateful for the support of the Governor and County Executive as we bring the first-of-its-kind offering we have built at ElevateBio BaseCamp to advance the work of the entire biopharmaceutical industry.

Pitt Senior Vice Chancellor for the Health Sciences, Dr. Anantha Shekhar, continued by saying, We have some exceptional emerging research coming out of the University of Pittsburgh. However, the missing ingredient has been access to high-quality process science and manufacturing capabilities. As we position ourselves to become the next global hub for life sciences and biotech, we were in search of the right partner to help us realize our vision, and ElevateBios expertise and reputation in cell and gene therapy made them the perfect partner to accelerate our ability to build our biomanufacturing center of excellence.

This partnership between two national life-science powerhouses the University of Pittsburgh and ElevateBio - is a consequential step forward in realizing our shared vision to make Pittsburgh a national and international biomanufacturing destination, said Sam Reiman, Director of the Richard King Mellon Foundation. Pitt BioForge is a generational opportunity to bring extraordinary economic-development benefits to our region, and life-changing cell and gene therapies to patients - distribution that will be accelerated and enhanced by Pitts partnership with UPMC. ElevateBio could have chosen to locate its next biomanufacturing hub anywhere in the world; the fact they are choosing to come to Pittsburgh is another powerful validation of our region, and the Pitt BioForge project at Hazelwood Green.

We are excited that Pitt, working with UPMC Enterprises, has attracted ElevateBio to this region, said Leslie Davis, President and Chief Executive Officer of UPMC (University of Pittsburgh Medical Center). The companys expertise and manufacturing capabilities, combined with Pitt research and UPMCs clinical excellence, are essential to delivering the life-changing therapies that people depend on UPMC to deliver.

In addition, the Commonwealth of Pennsylvania and the County of Allegheny have provided incentive grants to ElevateBio in support of this partnership to build a biomanufacturing center and establish Pittsburgh as a premier biomanufacturing destination.

This announcement is continued verification of Pittsburgh's ability to attract new and emerging companies that provide economic opportunities in the life sciences field. The University of Pittsburgh and its medical school are a magnet for that ecosystem and along with this region's quality of life and investment in innovation, we continue to see businesses choosing Pittsburgh, said County Executive Rich Fitzgerald. The creation of the Innovation District, and the many companies that call it home, continue to provide great opportunities for talent to fill jobs across the ecosystem's pipeline. We welcome ElevateBio to our region and look forward to all that you will do here as part of this great ecosystem.

About ElevateBio:

ElevateBio is a technology-driven company built to power the development of transformative cell and gene therapies today and for many decades to come. The company has assembled industry-leading talent, built state-of-the-art facilities, and integrated diverse technology platforms, including gene editing, induced pluripotent stem cells (iPSCs), and protein, vector, and cellular engineering, necessary to drive innovation and commercialization of cellular and genetic medicines. In addition, BaseCamp in Waltham, MA, is a purpose-built facility offering process innovation, process sciences, and current Good Manufacturing Practice (cGMP) manufacturing capabilities. It was designed to support diverse cell and gene therapy products, including autologous, allogeneic, and regenerative medicine cell products such as induced pluripotent stem cells, or iPSC, and viral vector manufacturing capabilities.

Through BaseCamp and its enabling technologies, ElevateBio is focused on growing its collaborations with industry partners while also developing its own portfolio of cellular and genetic medicines. ElevateBio's team of scientists, drug developers, and company builders are redefining what it means to be a technology company in the world of drug development, blurring the line between technology and healthcare.

For more information, visit us at http://www.elevate.bio, or follow ElevateBio on LinkedIn, Twitter, or Instagram.

About the University of Pittsburgh:

Founded in 1787, the University of Pittsburgh is an internationally renowned leader in health sciences learning and research. A top 10 recipient of NIH funding since 1998, Pitt has repeatedly been ranked as the best public university in the Northeast, per The Wall Street Journal/Times Higher Education. Pitt consists of a campus in Pittsburghhome to 16 undergraduate, graduate and professional schools and four regional campuses located throughout Western Pennsylvania. Pitt offers nearly 500 distinct degree programs, serves more than 33,000 students, employs more than 14,000 faculty and staff, and awards 9,000 degrees systemwide.

For more information, please visit http://www.pitt.edu and http://www.health.pitt.edu.

About the Richard King Mellon Foundation:

Founded in 1947, the Richard King Mellon Foundation is the largest foundation in Southwestern Pennsylvania, and one of the 50 largest in the world. The Foundations 2021 year-end net assets were $3.4 billion, and its Trustees in 2021 disbursed $152 million in grants and Program-Related Investments. The Foundation focuses its funding on six primary program areas, delineated in its 2021-2030 Strategic Plan.

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ElevateBio and the University of Pittsburgh Announce Creation of Pitt BioForge BioManufacturing Center at Hazelwood Green to Accelerate Cell and Gene...

Introduction

Sepsis is a lethal critical disease, identified as a main health concern across the world. In the past 10 years, hospital mortalities from sepsis and septic shock every year registered 17% and 26%, separately, causing about 8 million deaths each year.1,2 Cardiac function disorder induced by sepsis, often referred to as SIC, is commonly seen and has long been an intriguing topic.3 As a pathophysiological syndrome caused by infection rather than a specific disease, the specific identification of targeted SIC is essential for minimizing the mortality and morbidity in this regard. Despite the fact that the indications for supervising and healing SIC are clinical and directed toward restoring tissue perfusion, a deeper comprehension of the important gene signatures and underlying pathogenesis of SIC can assist in optimizing treatments and ameliorating clinical results.47

Gram-negative bacterial endotoxin (lipopolysaccharide, LPS) serves as a key sepsis mediator for septicemia-associated multiple organ dysfunction or mortality.8 After undergoing LPS insult, both macrophages and cardiomyocytes can release substantial inflammatory mediators, such as MCP-1, GM-CSF, IL-1, IL-1, IL-6, IL-7, IL-8, and IL-12.9,10 These inflammatory cytokines could give rise to the imbalance of calcium homeostasis,11 disturbance of energy metabolism,12 impairment of adrenergic signaling, and excess production of nitric oxide,13 all of which facilitate decreased contractility, diastolic dysfunction, impaired ejection fraction and reduced cardiac index. Cytokines, especially IL1, IL6, and TNF, are major contributors in the initiation of SIC.14

RA is a powerful derivant of vitamin A, and is pivotal for body developmental process and organ genesis via regulating cellular proliferative and differentiative activities. Substantial researches on animal models and clinic tests have verified its capability of preventing infections and enhance immunosystems.15,16 Austenaa et al demonstrated that RA inhibited LPS-triggered stimulation in mice and mankind monoblasts.17 In addition, Martire-Greco D et al displayed that all-trans retinoic acid (ATRA), which could improve functional immunoresponses in LPS-exposed mice, could serve as a novel underlying method for the healing of the immune suppressive status of sepsis.18 Considering the increasing evidence that RA can improve immune function and reduce inflammation, we speculated that RA might exert a beneficial effect on LPS-induced heart function disorder. The present research aimed to determine the roles of RA in LPS-induced cardiac dysfunction and explore its underlying mechanisms.

Currently, the network pharmacological approach can be employed to forecast the correlation between targets and diseases.19,20 The network pharmacological approach was deemed as a new method of medicine design.21,22 Network pharmacology methods are developing rapidly and have been leveraged to find new treatment methods, ameliorating the approved drugs and expanding the application scenarios of clinical medicines. They can also be utilized to effectively search for undeveloped targets for compounds or natural products.23 The purpose of network construction was to reveal the interaction between bioactive compounds and target proteins as well as the interaction between various target proteins. We identified and verified key nodes through network analysis and verification.21 Systematic or network pharmacology combined with multiomics analysis showed unique advantages in predicting and explaining the pharmacological principles of drugs and mechanisms of action in treating various diseases.24,25 For that reason, herein, network pharmacological approach was employed to discover treatment targets and associated signaling pathways of RA against SIC.

The primary aims of our research were 1) to select the underlying targets of Retinoic acid and DEGs in SIC heart tissues; 2) to study the potential causal links of Retinoic acid against SIC via bioinformatic analysis; 3) to confirm the anti-inflammation, antioxidant levels and potential signaling pathways of Retinoic acid in LPS-induced cardiac dysfunction. Our research might offer a novel treatment method for improving sepsis-induced cardiomyopathy.

Male C57BL/6 mice (810 weeks) were kept at the Experiment Animal Center of Wenzhou Medical University. Those animals were kept at 231 with a 12-hour light/dark period in a specially disinfected environment with free access to bacteria-free water and food. Every animal assay, with a minimum sacrificed mice according to our design, was accepted by the Animal Assay Ethical Board of our university (ID: WYYY-AEC-2021-301). All experiment procedures were completed blindly, such as the animal models and following assays. The animals were stochastically separated into these groups: (1) Saline (i.p., n= 6), (2) LPS(10mg/kg i.p., n= 6), (3) LPS(10mg/kg) plus RA(1mg/kg, i.p., n= 6), (4) LPS(10mg/kg) plus RA(3mg/kg, i.p., n= 6), (5) LPS(10mg/kg) plus Dexamethasone (DEX)(2.5mg/kg, i.p., n= 6). The administration of RA was arranged 60 min prior to LPS injections. Subsequently, after 24 hours of supervision, the animals were euthanised via exsanguination with overdosage of sodium pentobarbital and all our efforts aimed to minimise pains of the animals. Meanwhile, all heart samples were collected for histology analyses or immediately frozen in liquid nitrogen, preserved under 80 for future biochemistry examination. Lipopolysaccharide (LPS), Retinoic Acid (RA) and Dexamethasone (Dex) were bought from Sigma (St Louis, MO, USA).

The gene expression dataset GSE44363 related to endotoxemic myocarditis was acquired from the GEO database.26 The GSE44363 data collection, which involved 4 normal and 4 endotoxemic myocardium that were treated for 24 hours with either saline or LPS, was based on wild-type mice. All RNA information of the chosen specimens was acquired for future analysis. The limma package27 was employed to calculate the difference between two groups of patients, and gene screening conditions with p.adj<0.05 and | Log2FC | > 1 were used for filtering DEGs in SIC.

The chemistry structure and SMILES of Retinoic acid was acquired from PubChem web site.28 The target forecast of Retinoic acid was completed via the STITCH data base (http://stitch.embl.de/),29 while the species was limited to Mus musculus.

GO function analysis (CC, BP, and MF) was a potent biological information method to categorize genetic expressing and its performances,30,31 while KEGG pathway analysis was adopted to determine which cellular pathway may participate in the variations of DEGs.32,33 The visualization of GO enriching assay (p.adj<0.05) and KEGG pathway assay (p.adj<0.05) was realized via the R ggplot2 package.

The PPI net of targeted genes was acquired via from STRING 11.0 database,34 with minimal needed interactive score 0.7. The visualization of the PPI net was realized via Cytoscape 3.7.2.35 In the net, nodal points denoted targeted protein, and edges denoted the forecasted or verified mutual effect between protein. Topology analyses of targeted genes were completed via the Cytohubba plug-in of Cytoscape. Targeted protein was subjected to filtration, respectively, as per the BottleNeck, Betweenness, Stress and Radiality subnetworks, which were computed via Cytohubba plug-in. Top 10 genes of every sub-net were searched, and overlapping genes were chosen as critical targets herein.

Another 50 mice were stochastically separated into the following groups: (1) Saline (i.p., n = 10), (2) LPS (10 mg/kg i.p., n = 10), (3) LPS (10 mg/kg) plus RA (1 mg/kg, i.p., n = 10), (4) LPS (10 mg/kg) plus RA (3 mg/kg, i.p., n = 10), (5) LPS (10 mg/kg) plus Dexamethasone (DEX) (2.5 mg/kg, i.p., n = 10). Administration of saline, RA, or DEX was scheduled 60 minutes before LPS injection. The intervention and modeling methods of mice in each group were the same as before. After modeling, the 7-day survival rates of the five groups of mice were observed.

CK-MB (MEIMIAN, China) and LDH (LEAGENE, China) levels in serum were quantified using kits according to the manufacturer's instructions.

Our team prepared samples according to the test kit specifications. The levels of catalase (CAT),36 superoxide dismutase (SOD)37 and GSH/GSSG38 in the heart samples were determined by colorimetry according to the kits in previous studies mentioned above. The results of CAT and SOD were expressed in units of protein per mg (U/mg prot).

Echocardiography was implemented by a Vevo 3100 ultrasonic equipment with a 10-MHz linear array ultrasonic transducer (Fujifilm, VisualSonics, USA) after mice were anesthetized by 1.5% isoflurane. As medial echocardiographic readings were collected from 35 heart cycles, heart function indexes, such as fractional shortening (FS), ejection fraction (EF), etc., were documented.

Overall RNA from all frozen cardiac tissues was abstracted via TRIzol reagent (Invitrogen). Overall RNA (2 g) was converted to cDNA through reverse transcription by cDNA synthesis kit (Takara Clontech, Dalian, Japan). qPCR was completed by toroivd SYBR Green qPCR Master Mix (20 L). The cycling status were stated below: denaturalization under 95 for 60s, 40 cycles under 95 for 10s, 60 for 30s, and 72 for 45s. The RNA quantity was computed via the comparative threshold cycle approach, with every primer customized by Sangon Biotechnology Co., Ltd. (Shanghai, China). Eventually, each primer sequence is presented in Table 1.

Table 1 Primers Used for qPCR of Genes from Mouse

Proteins were abstracted from the entire frozen cardiac tissues via RIPA lysis buffering solution with 1% protease suppressor mixture. The BCA approach was employed to compute the protein level. Equal amounts of proteins were separated by 1015% SDS-PAGE. Samples were moved onto PVDF films, subjected to blockade via 5% dry skimmed milk, and incubated with primary antibodies including anti-ITGAM (Abcam, Ab133357, 1:1000), anti-VCAM1 (Abcam, Ab134047, 1:1000), anti-PPARA (Abcam, Ab61182, 1:1000), anti-IGF1 (Abcam, Ab9572, 1:1000), anti-IL-6 (Abcam, Ab259341, 1:1000), anti-GAPDH (Abcam, Ab181602, 1:2000), anti-phospho-Akt S473 (Cell Signaling Technology, 4060, 1:1000) and anti-Akt (Cell Signaling Technology, 4691, 1:1000) separately, at 4 nightlong. Posterior to the cleaning in TBST, the blots were cultivated with antirabbit or antimouse second antisubstances for 60 min under ambient temperature. Afterwards, the outcomes were identified via the ECL identification reagents. Proteins in Western blot were quantified via Image Lab software. All assays were completed in triplicate.

Cardiac specimens were subjected to 4% neutral PFA fixation, paraffin embedment, and sectioning. For H&E dyeing (Solarbio, Beijing, China), 5 m slices were dyed in hematoxylin for 600 s, and afterwards cleaned and dyed in 0.5% eosin for 300 s. Posterior to the cleaning in water, the samples were subjected to dehydration in 70%, 85%, 95%, and 100% ethyl alcohol and afterwards in xylene. Heart injuries were analyzed by microscopic fields of every tissular specimen, which was stochastically chosen. The morphological status of myofilament and inflammation cell infiltration were evaluated as standard.

For IHC, paraffin slices were subjected to deparaffinization via xylene and subjected to rehydration via the concentration gradient of ethyl alcohol. Subsequently, antigen repair was completed and the specimens were cultivated with anti-CD68 (CST, D4B9C, 1:200) nightlong at 4 . Eventually, the slices were cultivated by an antirabbit EnVisionTM +/HRP reagent for sixty minutes at 37 for the observation via a light microscopy (Nikon, H550L, Tokyo, Japan).

By virtue of the TUNEL approach, heart slices were dyed for identifying DNA fragmentation, which could reflect cell apoptosis. Slices were cultivated in TdT-reaction liquor and the visualization of nuclei was realized via TUNEL reagents (Promega, America) and DAPI nuclear dye. Fluorescent pictures were captured via a Nikon microscopic device. Quantitation of TUNEL-positive cells was completed via identifying the corresponding proportion (%) (green) in several high-power fields (n = 3 slices every mouse strain and treatment group).

The experiment data were studied via GraphPad Prism 8.0. The entire experiment data were described as average SD. Students t-test was used for comparison between the two groups, and the diversities between the groups were compared by two-way ANOVA and corrected by Bonferroni. P < 0.05 had significance on statistics. Survival rate was evaluated by KaplanMeier analysis.

The 2D structure of RA was acquired from PubChem (Figure 1A). An overall 500 genes were identified as targeted genes of RA from the STITCH database. In addition, 1035 DEGs were selected from GSE44363 dataset, and 547 genes were regulated upward, with 488 regulated downward (Figure 1B). By pairing DEGs with RA targets (Figure 1C), 54 genes were chosen as underlying targeted genes in septic cardiac dysfunction. The thermograph of those 54 genes was presented by Figure 1D.

Figure 1 Target genes of RA and DEGs in GSE44363. (A) Chemical structure of Retinoic acid; (B) DEGs in GSE44363 (Upregulated genes were marked in red and downregulated genes were marked in blue). (C) Venn diagram of Retinoic acid target genes and DEGs. (D) Clustered heat map of overlapped genes .

GO analyses of the 54 underlying treatment target genes were completed via the DAVID database. Targeted genes were primarily enriched in the regulation of ossification, myeloid leukocyte differentiation and epithelial cell proliferation in BP enrichment analysis, and they were also enriched in extracellular matrix, collagen-containing extracellular matrix and membrane raft in CC analysis. In MF analysis, they were enriched in glycosaminoglycan binding, heparin binding, and cytokine activity (Figure 2A). The outcome of KEGG pathway enriching analyses revealed that targeted genes were remarkably enriched in the PI3K-Akt signaling pathway, transcriptional misregulation in cancer, and TNF signaling pathway, etc. (Figure 2B and C).

Figure 2 Enrichment Analysis of Overlapped Target. (A) Gene ontology (GO) enrichment analysis for key targets (Top 10 were listed). (B) KEGG pathway enrichment analysis of key targets (Top 10 were listed); the abscissa label represents GeneRatio. (C) KEGG pathway analysis and related genes (Top ten were listed).

The PPI net of aforesaid targeted proteins was established via STRING and the visualization of the network was realized via Cytoscape. The PPI net comprised 54 nodal points and 266 edges (Figure 3A). BottleNeck, Betweenness, Stress and Radiality of targeted protein were computed via topology analyses (Figure 3BE). Top 10 hub nodes of BottleNeck, Betweenness, Stress and Radiality sub-nets were searched, and we discovered 5 overlapping genes: Peroxisome proliferator activated receptor alpha (PPARA), Integrin Subunit Alpha M (ITGAM), Vascular cell adhesion molecule-1 (VCAM1), Insulin-like growth factor 1 (IGF-1), and Interleukin-6 (IL-6) (Figure 3F).

Figure 3 PPI network construction. (A) PPI network construction of overlapped genes (Retinoic acid target genes and DEGs). (BE) Top 10 genes with the highest BottleNeck, Betweenness, Stress and Radiality. (F) Venn diagram summarizing overlapped genes in four sections.

Our team studied the role of RA in survival condition by intraperitoneally injecting male C57BL/6 mice with LPS (10mg/kg), LPS (10 mg/kg) plus RA (1 mg/kg), LPS (10 mg/kg) plus RA (3 mg/kg), LPS (10 mg/kg) plus DEX (2.5 mg/kg) or an equal volume of saline for 7 days. As presented in Figure 4A, our team computed the 7-day survival rate in the five groups below: the Sham group, LPS group, LPS + RA (1 mg/kg) group, LPS + RA (3 mg/kg) group, LPS + DEX (2.5 mg/kg) group. The 7-day survival rate in the Sham group was nearly a hundred percent, whereas 7 days posterior to LPS treatment, the survival rate of LPS group dropped notably to 40%. RA (1 mg/kg) pretreatment enhanced the survival rate to 50% in LPS-exposed animals. RA (3 mg/kg) pretreatment elevated the survival rate to 70% in LPS-exposed animals. DEX (2.5 mg/kg) pretreatment elevated the survival rate to 60% in LPS-exposed animals.

Figure 4 Determine the effective concentration of RA. (A) Survival curve of mice treated with saline, LPS (10 mg/kg), LPS (10 mg/kg) plus RA (1 mg/kg), LPS (10 mg/kg) plus RA (3 mg/kg), LPS (10 mg/kg) plus DEX (2.5 mg/kg). Observe and record the mortality of mice within 1 week (n = 10) .(B and C) The serum levels of CK-MB and LDH in mice treated with saline, LPS (10 mg/kg), LPS (10 mg/kg) plus RA (1 mg/kg), LPS (10 mg/kg) plus RA (3 mg/kg), LPS (10 mg/kg) plus DEX (2.5 mg/kg) for 24h were determined. *P<0.05, **P < 0.01, ***P < 0.001 vs LPS. ns: no significant difference.

Since LDH and CK-MB are sensitive biomarkers of cardiac injury, our team measured LDH and CK-MB levels in serum. We found that using RA (1 mg/kg), RA (3 mg/kg) and DEX (2.5 mg/kg) significantly reduced the level of CK-MB in LPS-injected mice, and the administration of RA (3 mg/kg) displayed the most significant effect (Figure 4B). Meanwhile, the administration of RA (3 mg/kg) and DEX (2.5 mg/kg) significantly reduced LDH levels in LPS-injected mice. However, the administration of RA (1 mg/kg) also reduced LDH in LPS-injected mice, whereas it was not statistically significant (Figure 4C). As high-dose group showed a more significant efficacy when it came to the improvement of mortality and myocardial injury in mice, the dose of RA was 3 mg/kg in the subsequent experiments.

As shown in Figure 5AC, after LPS treatment, SOD, CAT, GSH/GSSG in the heart tissue of mice in the model group were significantly lower than those in the Sham group (P < 0.05), while SOD, CAT, GSH/GSSG in the heart tissue of the RA group were significantly higher than those in the model group (P < 0.05). The activation of inflammatory response marks one of the most essential pathology variations in sepsis-caused cardiac muscle injury. Hence, our team studied the inflammatory cell infiltration and the mRNA expression of proinflammatory cytokines in all groups. As shown in Figure 5DF, qRT-PCR results displayed the favorable effect of RA on heart inflammatory events induced by LPS, as proven by the reduced mRNA contents of TNF-, IL-1 and IL-6 in myocardium tissues. By virtue of the echocardiographic method, our team explored heart functions in 3 groups. RA pretreatment reinforced ejection fraction and fraction shortening in LPS-exposed animals (Figure 5G and 5H).

Figure 5 RA suppressed oxidative stress, cardiac inflammation, and cardiac injury in LPS-treated mice. (AC) SOD, CAT, GSH/GSSG levels in myocardial tissue of each group. (n = 6). *P < 0.05, **P < 0.01, ***P < 0.001 vs LPS. (DF) The mRNA levels of IL-1, IL-6 and TNF- in myocardial tissues of each group (n = 6). *P < 0.05, **P < 0.01, ***P < 0.001 vs LPS. (G and H) Effects of saline, LPS and LPS+RA on left ventricle fractional shortening and left ventricle ejection fraction (n = 6). (IJ) Representative images of the morphological analysis and inflammatory cells infiltration as reflected by the H&E staining, and immunohistochemistry staining for CD68 protein.(K) TUNEL assay was used to detect apoptosis of cardiac tissue in each group.

The myocardium slices were dyed by H&E to evaluate the heart muscle injury and inflammatory cell infiltration. Histological features of heart damage, such as evident capillary congestion, interstitial tissue oedema, and infiltration of massive inflammation cells, were identified in the LPS group. However, in the LPS + RA group, the myocardium fibers registered obvious striation and little inflammatory infiltration was detected in heart muscle tissues (Figure 5I). IHC dyeing revealed that the infiltrative activities of CD68-labeled macrophages, which were caused by LPS, were inhibited by Retinoic acid (Figure 5J). Furthermore, the cardiac injury was evaluated in 3 groups. Tunel dyeing outcomes revealed that the LPS + RA group exhibited less programmed cell death in contrast to the LPS group (Figure 5K). Taken together, those data revealed that Retinoic acid could ameliorate oxidative stress, cardiac inflammation, cardiac injury and heart functions in septic mice.

To verify the network pharmacological forecast of Retinoic acid in LPS-treated mice, we performed qRT-PCR and WB observation to calculate the PPARA, ITGAM, VCAM-1, IGF-1, and IL-6 levels in healthy cardiac samples and cardiac samples from the LPS group and LPS + RA group. Posterior to the normalization with GAPDH, the expressing levels of ITGAM, VCAM-1, and IL-6 were remarkably elevated in the LPS group in contrast to the Sham group, whereas the expressing levels of those biomarkers were remarkably decreased (P< 0.05) in the RA-exposed group in contrast to the LPS group. Meanwhile, the expression levels of PPARA and IGF-1 were remarkably reduced in the LPS group in contrast to the Sham group, whereas the expressing levels of them were remarkably increased (P < 0.05) in the RA-exposed group (Figures 5E and 6A). Then, Western blot analyses verified that Retinoic acid markedly diminished the ITGAM, VCAM-1, and IL-6 protein levels compared with the LPS group, and LPS markedly decreased the protein levels of PPARA and IGF-1. In addition, RA reversed LPS-induced PPARA and IGF-1 inhibition as expected (Figure 6BF). Therefore, those outcomes revealed that RA might suppress the stimulation of inflammation reactions and engage in the progress of SIC by means of the aforementioned molecules.

Figure 6 RA modulated PPARA, ITGAM, VCAM-1, and IGF-1 in hearts of LPS-treated mice. (A) The mRNA levels of ITGAM, VCAM-1, PPARA and IGF-1 in myocardial tissues of each group (n = 6). *P < 0.05, **P < 0.01, ***P < 0.001 vs LPS. (BF) The protein levels of ITGAM, VCAM-1, PPARA, IGF-1, and IL-6 in myocardial tissues of each group (n = 6). *P < 0.05, **P < 0.01, ***P < 0.001 vs LPS.

In order to further verify the network pharmacological prediction of RA in lipopolysaccharide-induced cardiac dysfunction, Western blot analysis was performed to detect the phosphorylation level of Akt. The results showed that RA could restore the expression of P-Akt in LPS-treated mouse heart tissues (P < 0.05) (Figure 7).

Figure 7 RA affects the expression of p-Akt in hearts of LPS treated mice. (A) Representative Western blot images of p-Akt, Akt. (B) Densitometric quantification analysis of the protein expression levels of p-Akt and Akt in mice. **P < 0.01, ***P < 0.001 vs LPS.

The definition for sepsis from the third international consensus states that sepsis is a lethal organ function disorder induced by an aberrant reaction to infections.39 Cytokines, especially IL1, IL6, and TNF, are major contributors in the initiation of SIC.40 It has been demonstrated that when endotoxin like LPS binds to the receptor TLR4 expressed on cardiomyocytes and macrophages, these cells can release massive inflammatory mediators, such as MCP-1, GM-CSF, IL-1, IL-1, IL-6, IL-7, IL-8, and IL-12.41

Retinoic acid (RA) has been reported to reduce the levels of circulation endotoxin and ameliorate survival in endotoxaemic rats.42 Furthermore, RA was a powerful derivant of vitamin A. In previous studies, administrating vitamin A to infants and minors could decrease the risks of septic diseases, immune deficiencies and inflammatory events in endemic regions with deficient vitamin.17,43,44 Eriksson et al also demonstrated that vitamin A administered before a E. coli endotoxin infusion modified the harmful events on heart-lung systems which was caused by such LPS.45 Pretreating with vitamin A counteracted the role of endotoxin in mean arterial pressure (MAP) and cardiac index (CI). Therefore, exploring the mechanism by which RA fights against SIC is quite pregnant.

Network pharmacology method is a comparatively new way to investigate the treatment potency and potential causal links of medicines on the foundation of the net of medicines and targets.46 Herein, our team utilized network pharmacology method to explore the treatment targets participating in the RA healing of SIC. We revealed that RA exposure could elevate survival rate and heart functions of LPS-induced mice while inhibiting inflammatory cytokines and oxidative stress of cardiac muscles. Furthermore, the treatment of RA reversed the production of PPARA, ITGAM, VCAM-1, IGF-1, and IL-6 in LPS-induced SIC.

PPARs are vital targets for approved and experiment medicines in substantial clinical indications, such as metabolism and inflammation illnesses.4749 The expression of PPARA is extensive in our bodies (particularly in hearts, kidneys, and livers), as an important regulator in the heart after LPS administration.50 Described that heart PPARA expression was imperative for protecting against sepsis-triggered heart damage.51 The 3 PPAR sub-groups, PPAR, PPAR, and PPAR/ generate heterodimers with their obligatory dimer partner RXR,52 and RA modulates genetic expression straightly via binding to a heterodimer of the RARs and RXRs, which are capable of binding to RAREs in the modulatory area of the targeted genes.17 These results suggest that altered RA-mediated PPARA expression might be vital for sepsis-associated end-organ damage and function disorder, particularly in cardiac tissues.

Integrin subunit alpha M (ITGAM) was discovered to be highly expressed in adults and sepsis of the newborn.53,54 A past research unraveled that ITGAM primarily facilitated septic development via fostering the nucleus, cytoplasm movement and stimulating the releasing of HMGB1.55 ITGAM block antibodies or suppressors could defend mice against the fatalness related to LPS and microbe sepsis.56 ITGAM, namely CD11b, regulates the activation, adhesion, and migration of leucocytes from blood to injury sites.57 Vitamin A and its active metabolite retinoic acid (RA) are essential for the development and function of the immune system. Recent studies have also indicated that vitamin A stimulates the development of CD11b+ dendritic cells, and affects the generation of a specific niche that drives CD11b+ dendritic cells (CD11b+ DC) differentiation.5861 Thus, we speculated that RA might exert an anti-SIC effect via preventing the ITGAM-associated leukocyte recruitment to inflamed tissues.

The vascular cell adhesion molecule (VCAM-1), a heterodimeric molecule expressed on the surface of leukocytes, is induced in inflammatory stimulation.46,6264 Mice deficient of endothelial selectins exhibited increased survival in an animal model of sepsis.65,66 Furthermore, increased serum content of VCAM1 was a superior predicting factor for sepsis-induced brain diseases in adult community-onset sepsis on admission.67 Recently, Moser J et al have identified that RIG-I, a new modulator of endothelium pro-inflammation stimulation functioning in parallel with TLR4, can regulate the expressing of VCAM-1 in reaction to LPS exposure.68 Gille et al reported that pretreatment with all-trans-retinoic acid prevented the TNFa-mediated VCAM-1 induction.69 In the present study, the experiment outcomes revealed the suppressive role of RA in VCAM-1 generation.

The insulin-like growth factor-1 (IGF-1), a hormone with an insulin-alike architecture, is the main mediating factor of growing hormone.70 Additionally, studies have demonstrated that oxidative stress regulates the level of IGF-1, which is reduced in the acute phase of critical patients blood samples,71,72 and that IGF-1 can facilitate the growth and repairment of hearts.73 Furthermore, IGF-1 may defend our hearts against sepsis-triggered myocarditis.7476 In another study, the researchers found that RA increased the production of THREE-DIMENSIONAL human dermal equivalents (HDEs) IGF1 and IGF2.77 The WB outcome revealed that RA restored the expressing of IGF1 in LPS-induced cardiac dysfunction.

The Phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway is a classic signaling pathway. It plays an important role in regulating cell growth, proliferation, differentiation, metabolism, cytoskeletal reorganization, autophagy and apoptosis.7880 Various growth factors and cytokines activate the PI3K/Akt signaling pathway, which ultimately phosphorylates Akt. Substantial studies have revealed that activated Akt1 has cardioprotective effects.8183 A number of studies have found that the apoptosis of myocardial cells in Akt2 knockout mice is more serious than that in normal mice during myocardial ischemia, which reveals that Akt2 can also reduce the apoptosis of myocardial cells and protect the heart.84 Therefore, the activation of the PI3K/Akt signaling pathway can reduce cardiac injury and protect cardiac function through various ways. By analyzing the potential target of RA-treated lipopolysaccharide-induced cardiac dysfunction, we discovered that the PI3K/Akt signaling pathway was the key pathway in the RA treatment of lipopolysaccharide-induced cardiac dysfunction. After experimental verification, we found that RA could restore the activation of the PI3K/Akt signaling pathway in the heart tissues of LPS-treated mice.

Hence, our team estimate that RA might be an anti-inflammation agent in SIC. Nevertheless, there were certain deficiencies in our research. First, as the experimental subjects were merely mice, future researches have to investigate the roles of lipopolysaccharide-induced cardiac dysfunction in human. Furthermore, the effects of the 5 key targets of RA on LPS-induced cardiac dysfunction in mice require further exploration so as to unravel the corresponding mechanisms underneath.

In the present research, we analyzed the cellular components, biological processes, functions, and relevant pathways of retinoic acid, as well as its molecular effects on lipopolysaccharide-induced cardiac dysfunction in mice through extensive bioinformatics analysis. Using the Cytohubba software, we successfully identified five potential key therapeutic targets. In addition, by regulating 5 survival-related key therapeutic targets and a key pathway, PI3K-Akt signaling pathway, our team confirmed that Retinoic acid could be a potential therapeutic drug for lipopolysaccharide-induced cardiac dysfunction.

SIC, sepsis-induced cardiomyopathy; CC, cellular component; DEGs, differentially expressed genes; LPS, lipopolysaccharide; RA, retinoic acid; MF, molecular function; FS, fractional shortening; IHC, immunohistochemistry; TdT, terminal deoxynucleotidyl transferase; RAREs, RA response elements; MAP, Mean Arterial Pressure; PPI, proteinprotein interaction; BP, biological process; CI, cardiac index; PPARs, peroxisome proliferator-activated receptors; RXR, retinoid X receptor; ATRA, all-trans retinoic acid; EF, ejection fraction; RXRs, retinoid X receptors; ITGAM, integrin subunit alpha M; HDEs, human Dermal equivalents; LN, liquid nitrogen; SMILES, simplified molecular input line entry specification; H&E, hematoxylin and eosin; WB, Western blot; RIG-I, retinoic acid inducible gene-I; RARs, RA nuclear receptors.

The datasets used and/or analyzed during the current study are available from the corresponding author and GEO database (https://www.ncbi.nlm.nih.gov/geo).

According to the Regulations and Rules of Guidelines for Ethical Review of the Welfare in Laboratory Animals (2018), each animal assay was accepted by the Animal Experimentation Ethics Committee of Wenzhou Medical University (Approval Ethical Inspection ID: WYYY-AEC-2021-301).

We are grateful for the experimental instruments provided by the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Xi Wang and Chang Kong share first authorship. X. Wang and H. Tang conceived and designed the experiments. Ch. Kong, X. Wang and P. Liu executed the experiments and analyzed the samples. X. Wang, B. Zhou and W. Geng analyzed the data. X. Wang and Ch. Kong wrote the first version of the manuscript. All authors interpreted the data, critically revised the manuscript, and approved the final version of the manuscript. All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

We acknowledge the funding received from the Natural Science Foundation of China (Grant No. 81774109 and 81973620) and Wenzhou Municipal Science and Technology Bureau (ZY2019015).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Therapeutic Effects of Tretinoin | JIR - Dove Medical Press

Newswise Previous research has shown that low physical activity and greater time spent sitting are associated with a higher risk of death. Does risk change if a person is genetically predisposed to live a long life?

That is the question researchers at the Herbert Wertheim School of Public Health and Human Longevity Science at University of California San Diego set out to answer in a study published in the August 24, 2022 online edition of the Journal of Aging and Physical Activity.

The goal of this research was to understand whether associations between physical activity and sedentary time with death varied based on different levels of genetic predisposition for longevity, said lead author Alexander Posis, M.P.H., a fourth-year doctoral student in the San Diego State University/UC San Diego Joint Doctoral Program in Public Health.

In 2012, as part of the Womens Health Initiative Objective Physical Activity and Cardiovascular Health study (OPACH), researchers began measuring the physical activity of 5,446 women in the United States who were 63 and older, following them through 2020 to determine mortality. Participants wore a research-grade accelerometer for up to seven days to measure how much time they spent moving, the intensity of physical activity, and sedentary time.

The prospective study found that higher levels of light physical activity and moderate-to-vigorous physical activity were associated with lower risk of death. Higher sedentary time was associated with higher risk of mortality. These associations were consistent among women who had different levels of genetic predisposition for longevity.

"Our study showed that, even if you aren't likely to live long based on your genes, you can still extend your lifespan by engaging in positive lifestyle behaviors such as regular exercise and sitting less," said senior author Aladdin H. Shadyab, Ph.D., assistant professor at the Herbert Wertheim School of Public Health and Human Longevity Science at UC San Diego. Conversely, even if your genes predispose you to a long life, remaining physically active is still important to achieve longevity.

Given the aging adult population in the United States, and longer time spent engaging in lower intensity activities, the study findings support recommendations that older women should participate in physical activity of any intensity to reduce the risk of disease and premature death, wrote the authors.

The OPACH Study is funded by the National Heart, Lung, and Blood Institute (RO1 HL105065). Funding also came from the National Institute on Aging (P01 AG052352) and a T32 Predoctoral Training Fellowship (T32 AG058529). The Womens Health Initiative was funded by the National Heart, Lung, and Blood Institute (75N92021-D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005).

Co-authors include: John Bellettiere, Rany M. Salem and Andrea Z. LaCroix, all of UC San Diego; Michael J. LaMonte, State University of New York at Buffalo; JoAnn E. Manson, Brigham and Womens Hospital, and Harvard Medical School; and Ramon Casanova, Wake Forest School of Medicine.

Disclosures: The authors report no conflicts of interest.

DOI: 10.1123/japa.2022-0067

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Physical Activity May Have a Stronger Role than Genes in Longevity - Newswise

Commercial-stage biopharmaceutical company BridgeBio Pharma and Baylor College of Medicine announced the two will enter an academic collaboration that will seek to translate research findings into new therapies to treat genetic diseases.

BridgeBio has adopted a strategy of identifying cutting-edge research in academia and finding way to leverage this information as part of the drug development process.

In these challenging times, we believe it is more important than ever to be a stalwart partner to academic institutions working to serve patient populations big and small, said Neil Kumar, Ph.D., BridgeBio founder and CEO in a press release announcing the collaboration. We look forward to developing a close partnership with scientists at Baylor College of Medicine, which is known for its productive research engine, in the hope of translating innovations into meaningful medicines for patients with unmet medical needs.

Baylor College of Medicine is known as one of the leading academic medical institutions in the U.S. that is looking to unlock the molecular underpinnings of genetic diseases and cancer using an approach that integrates basic scientific research with translational and clinical sciences. In this case, BridgeBio and Baylor will work together to identify and translate promising research findings into potential therapeutics for genetically driven diseases.

Together with BridgeBios drug development team, we are optimistic that our interdisciplinary team of scientists and physicians will be able to develop new therapeutics for patients in need and further our mission to identify and develop drugs for a wide variety of diseases, said Joseph Petrosino, Ph.D., chief scientific innovation officer and chair and professor of molecular virology & microbiology at Baylor.

To date, BridgeBio has forged nearly a dozen-and-a-half similar research-drug development collaborations with academic institutions, a strategy the company says will move it beyond the typical one-off approach that most companies take with academia and into more lasting, comprehensive creative partnerships.

Far too often strong scientific research that could benefit patients is left on the shelves of academia because it cant get the funding needed to move it forward, the company notes on its website. At BridgeBio, we are focused on forging meaningful partnerships with academic institutions to support and accelerate the work of researchers who are on the front lines of understanding how genetic diseases may be treated.

We feel privileged to partner with top academic and research institutions that share our commitment to discover, create, test ,and deliver life-changing medicines for patients with genetic diseases and cancers with clear genetic drivers.

In a similar vein, BridgeBio also announced on Thursday a founding affiliation with Bakar Labs, the incubator at UC Berkeleys Bakar BioEnginuity Hub. Bakar Labs was established by the University of California (UC), Berkeley and QB3, UCs research institute for innovation and entrepreneurship in the life sciences. Bakar labs is available to academic researchers from around the world and plans to provide research facilities for as many as up to 50 life science start-up companies seeking to commercialize promising research.

Partnering with UC Berkeley and QB3 to launch Bakar Labs is a natural extension of our mission to discover, create, test, and deliver transformative medicines to as many patients as possible. Through this collaboration, we aim to strengthen the Bay Area biotech ecosystem and potentially unlock new therapies for patients with unmet needs, Kumar said.

BridgeBios participation in the incubator will provide it with the opportunity to review discoveries made by resident researchers, provide support to entrepreneurs, and consider possible partnership opportunities with startups focused on potential therapies for patients with genetically-driven diseases and cancers.

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BridgeBio, Baylor College of Medicine to Collaborate on Genetic Disease ...

The US Food and Drug Administration (FDA) has approved the first ever cell-based gene therapy, a one-off treatment for patients with a rare genetic blood disease. The single treatment will cost US$2.8 million, making it the most expensive medicine in history.

Called Zynteglo, the gene therapy is designed to treat beta-thalassemia, a rare disease with patients often requiring life-long blood transfusions. The gene therapy is personalized to each patient.

Bone marrow stem cells are harvested from the patient and then genetically modified to insert working copies of a gene that can effectively produce functional red blood cells. The modified stem cells are then infused back into the patient, with the positive effects of the one-off treatment expected to last a lifetime.

Clinical trials have found 89% of patients become transfusion independent following the treatment but this kind of gene therapy is not without risk. Although no serious adverse events were detected in Zynteglos clinical trials, other trials testing similar kinds of gene therapies have reported cases of cancer.

In approving Zynteglo the FDA noted a potential risk for cancer and recommends monitoring patients for 15 years following treatment with the gene therapy. In June, when the therapy was evaluated by a panel of independent experts for the FDA, the cancer risks were noted but the benefits of the treatment were found to outweigh any potential harms.

The approval of Zynteglo is somewhat historic as it's only the third gene therapy to reach the market in the United States. It is also the first cell-based gene therapy to ever be approved in the US, meaning it's the first authorized therapy where stem cells are removed, genetically modified, and then returned to a patient.

But Zynteglo may become most notorious for setting a new benchmark in medicine costs. The company behind the medicine, bluebird bio, has set Zynteglos initial wholesale cost at $2.8 million, making it the most expensive medicine to ever reach the US market. The previous record was set by a gene therapy in 2019 called Zolgensma, with its one-off cost sitting around $2 million.

Addressing the high price of the treatment, bluebird bio has argued the cost must be considered as relative to the lifetime healthcare costs for patients with beta-thalassemia. The company said this single gene therapy treatment is essentially a cure that removes the need for decades of ongoing medical care.

The lifetime cost of medical care for a patient with transfusion-dependent beta-thalassemia can reach up to $6.4 million in the U.S. and the average total health care cost per patient per year is 23 times higher than the general population, the company explained in a statement. bluebird estimates that there are approximately 1,300-1,500 individuals with transfusion-dependent beta-thalassemia in the U.S.

The cost of one-time gene therapies has been a thorny topic for health insurers over the past few years. The nature of single-dose curative treatments means pharmaceutical companies are likely to set incredibly high prices as their only way to recoup the development costs that go into producing these therapies. However, insurance companies have unsurprisingly balked at the huge price tags.

Zolgensmas $2 million price tag has been the source of extensive negotiation with health insurers over the past couple of years. Its manufacturer Novartis has tried to break its cost down into annual installments for insurers, spreading the price over three or four years.

Although bluebird bio has indicated it will reimburse insurers up to 80 percent of the treatment cost if Zynteglo fails in a given patient within two years, that still may not be enough some insurance companies.

Zynteglo was initially approved for use in the European Union back in 2019 but bluebird bio struggled to come to arrangements with health insurers over the treatments cost. The gene therapy was subsequently withdrawn from several markets in Europe after insurers refused to foot the multi-million-dollar bill.

Source: FDA

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New $2.8-million gene therapy becomes most expensive medicine in history - New Atlas

By The ASCO Post StaffPosted: 8/16/2022 2:43:00 PM Last Updated: 8/16/2022 3:15:33 PM

A newly constructed map of the landscape of genetic changes in chronic lymphocytic leukemia (CLL) may provide a better understanding of this complex malignancy that could lead to more accurate prognoses for patients, improved diagnostics, and novel treatments. These research findings were published by Knisbacher et al in Nature Genetics, and the study was conducted by an international collaboration of investigators, including teams from the Mass General Cancer Center, the Dana-Farber Cancer Institute, and the Broad Institute of MIT and Harvard.

CLL exists as either a slowly or rapidly growing cancer and has been linked to certain genetic mutations, but it has yet to be fully characterized. Previous analyses have provided only fragments of a CLL map, each focusing on particular types of patients or limited data. To provide a more thorough understanding of the biological underpinnings of CLL and its molecular subtypes, scientists set out to construct a map from the largest CLL data set to date. To build the CLL map, the team analyzed variations in genetic sequences, gene-expression patterns, and chemical modifications to DNAor genomic, transcriptomic, and epigenomic datafrom 1,148 patients.

Such a CLL map could eventually be leveraged in the clinic, wherein the genomic features of new patients can be compared with the treatments and outcomes of patients with similar genetic profiles, said co-senior and co-corresponding author Catherine Wu, MD, Chief of the Division of Stem Cell Transplantation and Cellular Therapies at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School. This profiling could potentially help more accurately tailor prognosis and treatment of a new patient based on their particular molecular features, getting closer to precision medicine.

Key Findings

The scientists identified 202 genes109 of which were novelthat when mutated, could potentially drive CLL, and they refined the characterization of subtypes of CLL with distinct genomic characteristics and prognoses. Beyond genetic sequences, the expression patterns of certain genes further subcategorized CLL and provided valuable prognostic information.

Our study has revealed that the genetic and biologic landscape of CLL is more complex than previously appreciated, said co-senior and co-corresponding author Gad Getz, PhD, Director of Bioinformatics at the Mass General Cancer Center and Director of the Cancer Genome Computational Analysis group at the Broad Institute. Patients clinical outcomes were associated with a combination of genomic, transcriptomic, and epigenomic featuresintegrating these data could predict a patients likelihood of experiencing remission vs developing more advanced cancer.

We are releasing a CLL map portal that is based on the CLL map and will be an interactive website for translational researchers to use as a resource for further investigationsuch as learning more about the different drivers and subtypes of CLL, said Dr. Getz.

Disclosure: This work was supported by the National Institutes of Health and the Broad/IBM Cancer Resistance Research Project. For full disclosures of the study authors, visit nature.com.

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Molecular Map Reveals Insights Into the Genetic Drivers of CLL - The ASCO Post

The Dindot Lab team. Front row (L to R): Research scientist Dr. Sarah Christian and Dr. Scott Dindot. Back row (L to R): Dr. Johnathan Ballard (Texas A&M Institute for Genomic Medicine) and biomedical sciences doctoral students Tom Jepp and Luke Myers

A treatment for a rare disease that was researched and developed in the laboratory of Texas A&M School of Veterinary Medicine & Biomedical Sciences (VMBS) associate professor Scott Dindot has not only produced encouraging interim data from a phase 1/2 clinical trial in the United States, United Kingdom, and Canada but has become the subject of a $75 million acquisition by Ultragenyx Pharmaceutical, Inc., which will continue to develop the treatment.

In an update last month, Ultragenyx announced that GTX-102, the drug originating in Dindots lab, had demonstrated meaningful improvement in pediatric patients afflicted with a genetic disorder called Angelman Syndrome (AS) and that the company is expanding patient enrollment in its ongoing phase 1/2 study of the drug.

AS is a rare genetic disorder that affects approximately one in 15,000 live births per year; the disorder is caused by a loss of function of the UBE3A gene, which leads to developmental delay, speech impairment, movement or balance disorder, and seizures.

Currently, there is no cure for AS. Available treatments for the disorder focus solely on behavioral therapy and controlling the symptoms, specifically the seizures that often affect patients with AS.

However, researchers have reported improvements in measurements of disease severity and quality of life for AS patients in the phase 1/2 study of GTX-102, leading Ultragenyx to believe that the novel, targeted therapeutic could be a promising treatment for the disorder.

This groundbreaking work not only highlights the strong science being conducted in our school but also demonstrates how researchers in the School of Veterinary Medicine & Biomedical Sciences are finding novel solutions to real-world problems that can improve the lives of both animals and human beings, said Dr. John R. August, the Carl B. King Dean of Veterinary Medicine at Texas A&M.

In developing the drug, Dindot and his Texas A&M research team identified a region on the UBE3A antisense (UBE3A-AS) transcript, which regulates the expression of the paternally inherited allele of the UBE3A gene. The drug an antisense oligonucleotide (ASO) inhibits UBE3A-AS and reactivates expression of the paternal UBE3A allele, restoring UBE3A protein in the brain.

We targeted a very specific region on the UBE3A-AS transcript that we believe is important for regulating its expression, said Dindot, who also is a Texas A&M University System Chancellors Enhancing Development and Generating Excellence in Scholarship (EDGES) Fellow. In theory, this treatmentgoes after the heart of the condition.

In natural conditions, only the copy of UBE3A inherited from the mother is expressed in the brain. Individuals living with AS have a mutation or deletion in the maternal copy of the gene, and thus, they lack the UBE3A protein in the brain.

Dindots drug, the first molecular therapeutic for AS to advance into clinical development, works by reactivating the paternal copy of UBE3A so it can compensate for the loss of function in the maternal copy.

After the initial discovery, which was supported by funding from the Foundation for Angelman Syndrome Therapeutics (FAST), Dindot continued the research and development of the drug in collaboration with the newly-formed biotech company GeneTx Biotherapeutics, LLC, (GeneTx) and later, Ultragenyx which conducted investigational-new-drug-enabling studies on the therapeutic as it moved into clinical trials in the US, UK and Canada.

That the drug made it to a clinical trial is an enormous milestone and now it is just amazing to hear the interim data suggesting that kids conditions are improving in multiple areas, Dindot said. Over the past decade, there have been probably over a dozen people who have worked on this in my lab undergraduate and graduate students and scientists and I really want to recognize them for the hard work they put into the research and development of this drug; it takes a lot of people to do this and Im proud of what we have accomplished together.

With the acquisition of GeneTx by Ultragenyx, Ultragenyx will now take the lead on advancing GTX-102 into late-stage development for AS by testing the effectiveness of the therapeutic at higher monthly doses.

This is a really great example of the successful commercialization of a technology from the research stage to the clinical development of a promising therapeutic with a company, said Janie Hurley, program director atTexas A&M AgriLifeResearch Intellectual Property & Commercialization, who oversees the development of commercialization and intellectual property protection strategies for technologies created by researchers affiliated with Texas A&M AgriLife and the CVMBS. We strive to ensure that new discoveries such as this one have the best chance possible to reach those in society who could benefit. Working with companies like GeneTx and Ultragenyx is how we accomplish this goal.

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Biopharmaceutical Company Expands Clinical Trials On Texas A&M-Developed Angelman Syndrome Treatment - Texas A&M University Today

During a pregnancy, women are offered prenatal genetic screening and diagnostic testing to determine whether a fetus is healthy or has certain genetic disorders or anomalies.

This information can help patients and their doctors prepare for the pregnancy. But some opt out of such testing, believing that babies should be born regardless of potential abnormalities.

For those who do choose to undergo such testing, maternal-fetal medicine specialists and genetic counselors usually work closely with the pregnant person or couple to explain in detail what the results mean for a birth, for mother and child, if a genetic disorder or fetal anomaly is detected. These health care providers can also provide the pregnant person or couple with guidance on what options are available to them after a diagnosis, which can include aborting apregnancy. That option, however, is limited or no longer available to women in many U.S. states.

Prenatal tests cant diagnose a genetic condition before 6 weeks

Without the protection of Roe v. Wade, the 1973 Supreme Court decision that legalized abortion nationwideand was overturnedin June, the procedure has become illegal or heavily restricted in at least 14 states. Six states Mississippi, Missouri, Tennessee, North Dakota, South Dakota and Ohio prohibit abortions when the fetus may have a genetic anomaly, and infive of those states, its now nearly impossible, because it is banned at about six weeks. This is so early in a pregnancy that many women at that point dont even know they are carrying a child.

A person's first [doctors] appointment in pregnancy doesn't usually happen until eight or 10 weeks, so never mind the rest of the story. That's when obstetric care begins, said Philip D. Connors, lead genetic counselor at Boston Medical Center.

Three [percent] to 4% of all pregnancies are going to be affected by some sort of complication related to a difference in fetal or embryonic development, a genetic condition. And essentially none of those can be screened for or diagnosed until after the gestational age limits that are being placed by some of these really discriminatory laws, Connors added.

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Dr. Tani Malhotra, a maternal-fetal medicine specialist in Cleveland,Ohio, a state where abortions are now illegal after six weeks and where there are no exceptions for cases of rape, incest or fatal fetal anomalies, said it is impossible to assess whether there are any issues with the fetus at such an early point in pregnancy.

The size of the embryo at six weeks is somewhere between 6 to 7 millimeters. It's less than 1 centimeter, and that centimeter is like the size of my finger, right? So it's just impossible for us to be able to detect abnormal findings on an ultrasound at that point, Malhotra said.

KatieSagaser, director of genetic counseling at Juno Diagnostics, a women's health company, told Yahoo News: Theres no genetic testing or screening that can be done prior to six weeks.

One method of testing which she said has revolutionized the landscape of prenatal chromosome screening and is mostly used today is a noninvasive prenatal screening technology known as NIPT or NIPS. This can detect genetic variations as early as nine weeks into pregnancy, using a blood sample from the mother. But the test, Sagaser said, can only indicate if there is a potential problem, and does not replace diagnostic testing, such as chorionic villus sampling (CVS) or amniocentesis, which study the cells from the fetus or placenta and can confirm a diagnosis.

The earliest a CVS diagnostic test can be performed is at the 10th week of pregnancy. Amniocentesisis usually conducted at between 15 and 20 weeks of pregnancy, but can technically be done up until a person gives birth, according to the American College of Obstetricians and Gynecologists.

WASHINGTON, DC - JUNE 24: Abortion-rights activists gather in front of the Supreme Court building following the announcement to the Dobbs v Jackson Women's Health Organization ruling on June 24, 2022 in Washington, DC. (Photo by Nathan Howard/Getty Images)

Aborting a pregnancy because of genetic anomalies

As prenatal screening testing like NIPS has become more common, selective terminations involving genetic conditions have too. Some studies have shown that parents often decide to terminate a pregnancy, even after finding a mild form of a genetic condition, including Turner and Klinefelter syndromes.

Down syndrome is the most common chromosomal disorder in the U.S., and about 6,000 babies are born with it in the U.S. each year, according to the Centers for Disease Control and Prevention.

A published review of studies, which included 24 publications studying pregnancy terminations after a prenatal diagnosis of Down syndrome in the U.S., found that 67% ofthose pregnancies end in abortion.

Terminating a pregnancy after the 2nd trimester because of medical complications

Its notable, however, that the majority of abortions in the U.S.(91%) occur at or before 13 weeks of gestation. Abortions late in pregnancy are rare,butMalhotra said some of the main reasons why they do happen include delays and other barriers in obtaining abortion care, or after discovering medical complications. Those complications often include the discovery of lethal fetal anomalies, which can be detected during a fetal anatomy scan that is usually performed at around 20 weeks of pregnancy. Terminations at this stage, Malhotra said, are difficult and traumatic, because these pregnancies are often desired.

It's really tragic, as you're telling these patients who have been continuing their pregnancy. They're at 20 weeks. They're excited about the pregnancy. They're planning their baby showers. They come to that ultrasound hoping to be able to find out the sex of the baby and you tell them this devastating news, that there is an abnormality that is either not compatible with life, or is going to have significant impact on the quality of life after birth, the Ohio doctor said.

Malhotra told Yahoo News that Ohios new abortion law has made her job even tougher, because she also has to tell patients in these situations who wish to terminate the pregnancy that they cannot receive such care in their state.

It is just horrible, because not only are you giving them this tragic, heartbreaking news, but you're stigmatizing their care, because you're saying, Oh, this thing is illegal here, but you could go to another state. So they have to travel to another state to do something that's illegal, which is a part of medical care, Malhotra said. If they're not able to go out of the state, then we're asking them to take on risks associated with a pregnancy, which we know inherently, pregnancy is not risk-free.

In addition, she explained, she needs to inform these patients that they must act rapidly. Abortions later in a pregnancy are more complex and also more expensive. Medication abortion, which can be taken at home, can only be safely used in the first 70 days, or 10 weeks of pregnancy. After that, women need a surgical abortion, which typically takes about two days and requires inpatient care. A patient who needs to go out of state to receive care must therefore also take into account additional costs related to travel and lodging.

Because of the abortion bans that have gone into effect in the Midwest, surrounding states where the procedure is protected have seen an increase in patients, Malhotra said. They are really backed up, currently complicating the scheduling of an abortion, she said.

Another important reason to act quickly in these situations, according to Malhotra, is because most states do not permit abortions after 24 weeks when a fetus has reached viability and can survive outside the uterus. According to the Guttmacher Institute, a research group focused on reproductive health, 17 states impose a ban at viability.

Little research has been conducted on what happens to women who are unable to terminate a pregnancy because of a fetal genetic condition or anomaly. However, one study conducted by the University of California, San Francisco, that tracked 1,000 women unable to get an abortion because they had passed the gestational limits, found they were more likely to fall into poverty, as well as have worse financial, health and family outcomes, than those who had terminated their pregnancies.

Opponents of abortions conducted as a result of screening for disabilities believe that such procedures are unjust, because all human beings have inherent value from the moment of conception. Malhotra, on the other hand, told Yahoo News that she finds it absolutely horrible to put patients in a position where they dont have a choice anymore.

There are multiple reasons women may choose to terminate a pregnancy because of a genetic condition or anomaly, ranging from the emotional and financial cost of raising a disabled child to the effect that this may have on the existing children in a family, as well as the feeling that it is cruel to give birth to a child who may need a lifetime of constant medical intervention.

Connors said that terminations due to genetic or fetal anomalies are comparatively rare, but are often emphasized unduly in conversations on abortion and abortion care. It inadvertently leads to a narrative about what makes a good or a bad abortion, he said.

Sagaser agreed, saying:There's no benefit to us as a society to say, Oh, there's this one population that really needs access to abortion care more so than other people.'

Everyone deserves to be able to make the choices that are right for them and their family in that unique situation, she added.

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Restrictive abortion laws are limiting the options parents have after receiving genetic test results, experts say - Yahoo News

The field of precision medicine blends molecular biology and systems biology to understand better and treat disease.

FREMONT, CA: The precision medicine industry integrates molecular biology and systems biology to identify illness prevention and treatment methods. It enables clinicians to select tailored treatments based on a genetic understanding of a patient's ailment and environmental and lifestyle factors. It uses big data technologies to help more precise and individualized therapy by finding correlations in vast data sets. This decreases the impacts of an overly comprehensive therapeutic approach, which may have unwanted side effects, and reduces treatment costs for physicians. It is especially crucial to discover medicines for neurological illnesses as life expectancy and population increase. It is also essential to better understand and treat cancer individually. Here are some precision medicine market trends to watch in 2022:

Oncology Will Continue to Hold the Largest Market Share: Oncological illnesses will likely continue to focus on precision medicine's efforts to develop new treatments. The United States is one of the primary locations where precision medicine and research oncological applications are conducted. It is utilized 30 percent more frequently as a treatment for oncological disorders than the next highest application of precision medicine. State funding is anticipated to accelerate the precision medicine sector's expansion to treat oncological disorders.

Increased Non-Oncology Therapeutic Research: As genetic research has expanded, there are indications that the emphasis on precision medicine may shift from oncology to non-oncology fields. Two-thirds of phase three pipelines are focused on non-oncology sectors, per Diaceutics Group. This gives researchers in precision medicine strong motivation to identify applications outside of oncology. Infectious disorders, central nervous system diseases, and cardiovascular diseases are where such uses may be found. Alzheimer's disease and Parkinson's disease, which have substantial genetic links, have been suggested as potential prospects for additional research within the precision medicine business.

The precision medicine market will continue to be competitive: The precision medicine market is neither competitive, with significant enterprises competing, nor monopolistic, with one or a few major corporations, dominating. Several major corporations, including Pfizer and Novartis, and mid-sized and smaller firms, are entering the market and introducing innovative technology. A competitive economy is more likely to produce lower-cost solutions without government intervention, which is beneficial for transmitting precision medicine advancements.

Better Diagnoses: In oncology, precision medicine can determine whether breast cancer patients have estrogen or progesterone receptors. By sequencing blood and detecting tumor DNA, researchers in precision medicine are now developing a blood test that might detect cancer in any part of the body. Physicians will also have a clearer understanding of whether the patient responds to treatment or is simply in remission. According to the medical community, the FDA is likely to approve additional precision medicine treatments that can detect the existence of cancer-based on genetic changes.

Read more:
Marketing and Industry Trends Influencing Precision Medicine in 2022 - Healthcare Tech Outlook

August 18, 2022

A study published in the British Journal of Cancer looks at the use of a genetic risk score to predict prostate cancer diagnosis in men with lower urinary tract symptoms.

Dr Chantal Babb de Villiers, PHG Foundation, said:

This paper looked at if genomic information can predict which men would develop prostate cancer after presenting at a GP with lower urinary tract symptoms. The study researchers found that, using age as well as a genetic risk score, they could stratify which men were most, and least, likely to develop prostate cancer after having symptoms. There are limitations to the study, notably that only men of European ancestry were included, which is a major limitation as black men are twice as likely to be diagnosed with prostate cancer, and have worse outcomes. The findings support the idea that accurate risk prediction using a genetic risk score along with other risk factors could improve symptomatic patient triaging in primary care, to determine which men could have further investigationto find out their possibility of prostate cancer. The PHG Foundation is following developments in these areas carefully to understand their implications for healthcare policy and delivery.

Dr James Ware, Cardiologist, Reader in Genomic Medicine at Imperial College London and MRC Investigator, MRC London Institute of Medical Sciences, said:

Overall I think this is an interesting study. I think the press release reflects the science in most important respects. I have reservations on one element: the press release emphasises that genetic risk scores (GRS) could identify people at highest risk, for fast-track referral. In fact in the paper they emphasise that the principle utility is in identifying low risk individuals who can avoid referral. The press release says that Only one in three men with a positive PSA test have cancer, but from this perspective the GRS arguably performs even worse figure 2 and table 2 shows that about 1 in 12 men with symptoms (8%) with a high genetic risk develop cancer in the next 2 years. Perhaps this difference is not hugely important for a lay audience, since there is potential utility either way, but I would emphasise that the real value is likely to be through reducing unnecessary invasive tests in low risk individuals. It does not have a high precision (positive predictive value) in this context. (Here the evaluation was done in men with symptoms, with an overall cancer risk of 3.7% in 2 years)

I did not identify any particular methodological problems. The authors acknowledge important limitations. An important limitation (in common with much similar work) is that the work was done in individuals with European ancestry, and utility is likely to be limited to this group.

My expertise is in genomic medicine more broadly I am not particularly expert in prostate cancer. The authors cite a previous high profile study in Nature Genetics (Conti et al, 2021) which showed how a GRS could be predictive of prostate cancer in the UK biobank population. So some of what is reported here is already known. The main advance here seems to be in assessing risk stratification in symptomatic men which simulates a real-world clinical problem, and the authors present specific data on utility in context

A Genetic Risk Score (GRS) that identifies low risk individuals who can avoid an invasive biopsy would likely be of clinical value.

At the moment the genetic data needed to calculate a GRS is not generally available in patients health records. If a sample needs to be sent for genetic testing then this would take some time so in the short term you would need to take this into account when designing a clinical referral pathway for patients with symptoms suggestive of possible prostate disease, and factor in the additional cost of this test.

Again I highlight that I am not a cancer expert specifically, but I note that prostate cancer represents a wide spectrum of disease, some of which is not clinically significant. The prior work from Conti et al. found that the GRS identified prostate cancer, but did not discriminate between aggressive and non-aggressive disease. Other studies have also found that GRS do not select for clinically-significant disease. So while the test may help to identify individuals with cancer, other approaches may be needed to discriminate which of the men with prostate cancer need active treatment.

Prof Shirley Hodgson, Emeritus Professor of Cancer Genetics, St Georges, University of London (SGUL), said:

This is a very interesting study of a cohort of men who attended their general practice because of urinary symptoms. The researchers used genetic profiling with 260 common genetic variants known to influence prostate cancer risk, and other data including self-reported family history of prostate cancer, BMI and smoking status. Nearly 5,000 men with symptoms that could indicate prostate cancer were enrolled in the study, and 400 were diagnosed with prostate cancer within 2 years of enrolment. The study outcome was diagnosis of prostate cancer within 2 years of the index date of interview.

The genetic risk score (GRS) appeared to be very useful for predicting the diagnosis of cancer, where the highest risk score quintile was highly predictive of cancer with an incidence rate of 8.1%, and the lowest score quintile with a risk of less than 1%.

This pilot study suggests that if this was implemented in general practice, it could mean that men with the highest risk scores could be targeted for increased screening by referral to secondary care, whereas those in the lowest quintile could be managed in primary care, thus saving anxiety and costs.

The study is limited by being biased to younger men and mostly white individuals, meaning that the outcomes could be different in the groups who were not included.

Prof Dusko Ilic, Professor of Stem Cell Science, Kings College London, said:

This is an interesting research paper. However, a much simpler and significantly cheaper blood test for prostate-specific antigen (PSA), that is already in place, has more value as a biomarker in diagnosis of prostate cancer. When PSA is moderately increased, it may not be easy to differentiate benign prostatic hyperplasia from cancer and in such cases, a genetic risk score might have potential application to improve diagnostic the pathway.

Applying a genetic risk score for prostate cancer to men with lower urinary tract symptoms in primary care to predict prostate cancer diagnosis, as implicated in the paper, would be an unnecessary waste of the NHS funds.

Applying a genetic risk score for prostate cancer to men with lower urinary tract symptoms in primary care to predict prostate cancer diagnosis: a cohort study in the UK Biobank by Harry D. Green et al. was published in British Journal of Cancer at 01:00 UK time on Thursday 18 August.

Declared interests

Dr James Ware: None directly relevant to this work. I have acted as a consultant for and/or received research funding from Pfizer, MyoKardia, Bristol-Myers Squibb, and Foresite Labs, related to work on genetic disease and/or genome-based risk stratification.

Prof Shirley Hodgson: No conflicts of interest.

Prof Dusko Ilic: I declare no conflict of interest.

For all other experts, no reply to our request for DOIs was received.

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expert reaction to study investigating use of genetic risk score for prostate cancer in men with lower urinary tract symptoms to predict diagnosis -...