Category Archives: Gene Medicine

Scientists strive to have a better understanding of the complex biological processes involved in health and disease, and what they can learn usually goes hand-in-hand with the number, quality and type of measurements techniques provide.

Cancer, for instance, usually originates through changes on many different genes and pathways, not just one, but currently most cell-based screening assays conduct single measurements, said Dr. Koen Venken, assistant professor of biochemistry and molecular biology, and pharmacology and chemical biology at Baylor. We thought that if we could see what happens to more than one cellular pathway at once, we could have a more complete picture of what goes on inside a cancer cell.

To get a more detailed picture of the cellular processes that differentiate normal versus cancer cells, researchers resort to conduct several independent screening assays at the expense of time and additional cost.

In his lab at Baylor College of Medicine, Venken and his colleagues apply state-of-the-art synthetic biology, cell biology, genetics, genome engineering and transgenic technologies to have a better understanding of the processes involved in cancer.

Our goal in this study was to measure multiple cellular pathways at once in a single biological sample, which would also minimize experimental errors resulting from conducting multiple separate assays using different samples, said Venken, a McNair Scholar and member of the Dan L Duncan Comprehensive Cancer Center at Baylor.

Dr. Alejandro Sarrion-Perdigones, first author of the paper, wanted to develop an experimental assay that would expand the number of molecular pathways that can be studied simultaneously in a cell sample.

He focused on developing a multiplexed method a method for simultaneously detecting many signals from complex systems, such as living cells. He developed a sensitive assay using luciferases, enzymes that produce bioluminescence. The assay includes six luciferases, each one emitting bioluminescence that can be distinguished from the others. Each luciferase was engineered to reveal the activity of a particular pathway by emitting bioluminescence.

To engineer and deliver the luciferase system to cells, we used a molecular Lego approach, said co-author Dr. Lyra Chang, post-doctoral researchers at the Center for Drug Discovery at Baylor. This consists of connecting the DNA fragments encoding all the biological and technological information necessary to express each luciferase gene together sequentially forming a single DNA chain called vector. This single vector enters the cells where each luciferase enzyme is produced separately.

Treating the cells with a single multi-luciferase gene vector instead of using six individual vectors, decreased variability between biological replicates and provided an additional level of experimental control, Chang explained. This approach allowed for simultaneous readout of the activity of five different pathways (a control makes number six), compared to just one using traditional approaches, providing a much deeper understanding of cellular pathways of interest.

The new assay is sensitive, saves time and expense when compared to traditional approaches, reduces experimental error and can be adapted to any research field where the dual luciferase assay is already implemented, and beyond.

In addition to applications in cancer research, as we have shown in this work, our multiplex luciferase assay can be used to study other cellular pathways or complex diseases across different research fields, Venken said. For instance, the assay can be adapted to study the effect of drugs on insulin sensitivity in different cell types, the immune response to viral infections or any other combinations of pathways.

Interested in this new technology? Find all the details in the journal Nature Communications.

Other contributors to this work include Yezabel Gonzalez, Tatiana Gallego-Flores and Damian W. Young, all at Baylor.

This work was supported by start-up funds provided by Baylor College of Medicine, the Albert and Margaret Alkek Foundation and the McNair Medical Institute at The Robert and Janice McNair Foundation. Additional support was provided by March of Dimes Foundation grant #1-FY14-315, the Foundation For Angelman Syndrome Therapeutics grant FT2016-002, the Cancer Prevention and Research Institute of Texas grants R1313 and R1314 and the National Institutes of Health grants 1R21GM110190, 1R21OD022981 and R01GM109938.

The authors dedicate this work to the memory of Dr. Alejandro Sarrion-Perdigones, who passed away before the paper was published.

By Ana Mara Rodrguez, Ph.D.

Original post:
Six is better than two: assay assesses multiple cellular pathways at once - Baylor College of Medicine News

The first symposium of the South West Brain Tumour Centre was held on Thursday at Derriford Hospital in Plymouth. During a fascinating and very well attended event, topics covered included the mechanism of tumour development, new drug targets, new biomarkers and brain tumour imaging. The South West Brain Tumour centre is of course one of the UK Centres of Excellence funded by Brain Tumour Research.

A really big cancer wide story this week is here Immune discovery 'may treat all cancer' applicable to some solid tumours but not yet brain it really shows the direction of travel toward immunotherapy I have recommended this book before but if interested please do read The Breakthrough by Charles Graeber it is available on Amazon and you can read reviews here - http://www.charlesgraeber.com.Researchers uncover novel drug target for glioblastoma by revealing a cellular pathway that appears to contribute to glioma stem cell spread and proliferation. This pathway shows that glioma stem cells ability to access key nutrients in their surrounding microenvironment is integral for their maintenance and spread. Finding a way to interrupt this feedback loop will be important for treating glioblastoma.

An intelligent molecule could significantly extend the lives of patients with glioblastoma, research finds. The molecule, called ZR2002, which can be administered orally and is capable of penetrating the blood-brain barrier, could delay the multiplication of glioblastoma stem cells resistant to standard treatment. According to scientists in the Metabolic Disorders and Complications Program at the Research Institute of the McGill University Health Centre (RI-MUHC) the ZR2002 molecule is designed to kill two birds with one stone: on top of attacking the tumour, it destroys its defence system.

Researchers find clues to drug resistance in medulloblastoma subtype.US scientists have identified specific types of cells that cause targeted treatment to fail in a subtype of medulloblastoma. They found while the majority of cells responded to treatment, diverse populations within the tumour continue to grow leadingto treatment resistance. They concluded that the diversity of cells within tumours allow them to become rapidly resistant to precisely targeted treatments," and that due to this tumour cell diversity, molecularly precise therapies should be used in combinations to be effective."

Nanoparticles deliver 'suicide gene' therapy to paediatric brain tumours growing in mice So-called "suicide genes" have been studied and used in cancer treatments for more than 25 years. Researchers report here that a type of biodegradable, lab-engineered nanoparticle they fashioned can successfully deliver a ''suicide gene'' to paediatric brain tumour cells implanted in the brains of mice.

According to a study that uncovers an unexpected connection between gliomas and neurodegenerative diseases a protein typically associated with neurodegenerative diseases like Alzheimers might help scientists explore how gliomas become so aggressive. The new study, in mouse models and human brain tumour tissues, was published in Science Translational Medicine and found a significant expression of the protein TAU in glioma cells, especially in those patients with better prognoses. Patients with glioma are given a better prognosis when their tumour expresses a mutation in a gene called isocitrate dehydrogenase 1 (IDH1). In this international collaborative study led by the Instituto de Salud Carlos III-UFIEC in Madrid, Spain, those IDHI mutations stimulated the expression of TAU. Then, the presence of TAU acted as a brake for the formation of new blood vessels, which are necessary for the aggressive behaviour of the tumours.

'Innovative research award' helps Colorado scientists block brain cancer escape routes Cancers used to be defined by where they grow in the body - lung cancer, skin cancer, brain cancer, etc. But work in recent decades has shown that cancers sharing specific genetic changes may have more in common than cancers that happen to grow in an area of the body. For example, lung cancers, skin cancers, and brain cancers may all be caused by mutation in a gene called BRAF. Drugs targeting BRAF have changed the treatment landscape for melanoma, an aggressive form of skin cancer, and are also in use against lung cancers and brain cancers with BRAF mutations. It is really worth clicking through to read more on this and the ultimate goal of identifying new potential targets for combination therapy and new agents that could be added to BRAF inhibiting drugs in brain cancer to keep the cancer from developing resistance.

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Weekly pick of brain tumour research news from around the world - Brain Tumour Research

A team of investigators from Case Western Reserve School of Medicine, say they have identified a gene and associated protein that previously had not been associated with Alzheimers disease (AD), which could potentially be suppressed to slow the progression of Alzheimers disease.

The research was published this month by the journal Nature Communications, and supported by grants from the National Institutes of Health (NIH) and the Alzheimers Association.

For the research led by Xinglong Wang, an associate professor of pathology at the School of Medicine, the team correlated roughly 1 million single nucleotide polymorphisms (SNPs) with brain images obtained from the Alzheimers Disease Neuroimaging Initiative, an NIH-supported project. Using this method, a specific SNP in the FAM222 gene was identified that was linked to a variety of different patterns of regional brain atrophy.

Upon further investigation, the investigators found evidence that the protein encoded by the gene FAM222A is associated with AD patient-related beta-amyloid plaques, regional brain atrophy, and the protein the team dubbed aggregatinwhich attaches to amyloid beta peptide and accumulates in the center of plaque in AD patients.

Based on the data we have, this protein can be an unrecognized new risk factor for Alzheimers disease (AD), said Xinglong Wang, an associate professor of pathology at the School of Medicine in a press release. We also see this as a potential novel therapeutic target for this devastating disease.

Wang noted that additional research would be required to confirm the function and role aggregatin plays in the development of AD, he is optimistic this discovery could one day lead to clinical trials of targeting the protein. With an eye toward this possibility, Wang, his colleague Xiaofeng Zhu, a professor of Population and Quantitative Health Sciences at the School of Medicine and the research team have filed for a patent via Case Westerns Office of Research and Technology Management for novel Alzheimers disease treatments and diagnosis based on this and related study.

After identifying aggregatin, the research team then injected mouse models with the protein it had made from the FAM222A gene. They discovered that plaque (amyloid deposits) formation accelerated in the brain of the mice injected with aggregatin, resulting in more neuroinflammation and cognitive dysfunction due to the protein binding directly to the amyloid beta peptide, which facilitated aggregation and plaque formation.

Conversely, when the protein was suppressed plaques were reduced and neuroinflammation and cognitive impairment alleviated. Their findings indicate that reducing levels of this protein and inhibition of its interaction with amyloid beta peptide could potentially be therapeuticnot necessarily to prevent Alzheimers but to slow its progression.

Were very excited about this because our study is likely the first systematic work combining the identification from a genome-wide association study of high dimensional brain-imaging data and experimental validation so perfectly in Alzheimers disease, Zhu said.

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Gene and Associated Protein May be Key to Slow Alzheimer's Progression - Clinical OMICs News

Chemical nerve agents are some of the most horrifying tools of war today. The compounds kill by paralyzing the nervous system and have been used in devastating attacks on civilians or soldiers in war zones. And they can appear, albeit in smaller doses, in pesticides used in developing countries, endangering farm workers after prolonged exposure.

For years, researchers have been searching for antidotes or treatments that could save those afflicted by these deadly chemicals. In a paper out today in Science Translational Medicine, a team from the U.S. Army Medical Research Institute of Chemical Defense has announced a potential solution: a gene therapy that grants immunity to the effects of nerve agents like sarin.

Nerve agents are compounds that interfere with a persons nervous system. As the chemicals pass through a body after exposure to skin or through inhalation, they disable an enzyme called acetylcholinesterase thats needed for communication between neurons. The results are devastating: An affected person will involuntarily discharge tears, saliva, urine and feces, experience seizures and paralysis, and rapidly die from asphyxiation.

Scientists have found that that certain enzymes in the body called bioscavengers find and break down the toxic nerve agent molecules in the body, disabling them and preventing harm. In earlier work, the Maryland-based team found that a certain variation of a enzyme made in the liver called PON1 was particularly effective. When injected into a mouse, it granted immunity to nerve agents effects temporarily. But now the team has used a gene therapy to coax the body to make the enzyme, continually, on its own.

In the new study, the team focused on a gene that carries the instructions for the most potent version of the PON1 enzyme, called PON1-IF11. By putting the gene into a virus a common technique used to deliver a gene to a host they were able to successfully introduce PON1-IF11 into mice. After injecting the rodents, just once, with the viral vector containing the gene, the mice became immune to the common nerve agents tabun, sarin, cyclosarin and soman.

The results were encouraging. "[I felt] great satisfaction and excitement," said Venkaiah Betapudi, a molecular cell biologist and first author of the paper, in an email. "[I'm] anxious to take this work to next level and make this modern medicine available to our soldiers."

The immunity lasted for the full 5 months of the study, but in theory, it should last for the lifetime of the animal.

As long as the animal lives, the enzyme is there," says Nageswararao Chilukuri, who leads the research group. "We stopped [the study] at five months after the injection, but if we had measured 6 months, 7 months, 8 months I think it will be there. We just dont have the data to show it.

But Chilukuri emphasizes that were a long way from seeing anything close to a nerve agent vaccine for humans that uses the new technique.

Gene therapy products are only for diseases right now, he explains. We are trying to use this for healthy people. We dont know the long-term safety profile of the viral vectors. We have to be absolutely sure that when we inject a virus, that 50 years from now it will not be toxic or cause any complications.

But when it does come of age, it could have broad applications. "This modern medicine can protect sniffing dogs in the battlefield and TSA and border security operations," says Betapudi.

Luckily, many researchers studying gene therapy more broadly are asking these questions too, so answers may soon emerge regarding the safety of this type of gene therapy.

[Editor's note: This post has been updated to include comments from Venkaiah Betapudi, and to clarify the respective contributions of Nageswararao Chilukuri and Betapudi.]

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New Gene Therapy In Mice Could Offer Lasting Protection Against Nerve Agents - Discover Magazine

Jan. 24, 2020 06:00 UTC

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the Phase III IMvigor010 study evaluating Tecentriq (atezolizumab) as an adjuvant (after surgery) monotherapy treatment did not meet its primary endpoint of disease-free survival (DFS) compared to observation in people with muscle-invasive urothelial cancer (MIUC). Safety for Tecentriq appeared consistent with the known safety profile of the medicine, and no new safety signals were identified.

Reducing the risk that muscle-invasive urothelial cancer will recur after surgery is very difficult, and we are disappointed that we were not able to significantly prolong disease-free survival, said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. We remain committed to exploring the potential benefits of immunotherapy for more people with early cancers.

The goal in treating MIUC early is to reduce the risk of the disease recurring or spreading to other parts of the body. More treatment options following surgery are needed as approximately half of people with MIUC will develop a recurrence of their disease within two years of surgery.

In addition to ongoing Phase III studies in early and advanced bladder cancer, Genentech has an extensive development program for Tecentriq, including multiple ongoing and planned Phase III studies across genitourinary, skin, breast, gastrointestinal, gynecological and head and neck cancers. This includes studies evaluating Tecentriq both alone and in combination with other medicines.

About the IMvigor010 study

IMvigor010 is a global Phase III, open-label, randomized, controlled study designed to evaluate the efficacy and safety of adjuvant treatment with Tecentriq compared with observation in 809 people with MIUC, who are at high risk for recurrence following resection. The primary endpoint is DFS as assessed by investigator, which is defined as the time from randomization to invasive urothelial cancer recurrence or death.

About bladder cancer

According to the American Cancer Society (ACS), it is estimated that more than 81,000 Americans will be diagnosed with bladder cancer in 2020. Urothelial cancer is the most common type of bladder cancer, accounting for about 90-95% of all cases. MIUC is a type of urothelial cancer that has spread into the muscle wall of the bladder, ureter, or renal pelvis. Approximately 25% of people newly diagnosed with bladder cancer are diagnosed with muscle-invasive disease, which is associated with a poorer prognosis than non-MIUC.

About Tecentriq (atezolizumab)

Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1. Tecentriq is designed to bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq may enable the re-activation of T cells. Tecentriq may also affect normal cells.

Tecentriq U.S. Bladder Indications

Tecentriq is a prescription medicine used to treat adults with:

A type of bladder and urinary tract cancer called urothelial carcinoma. Tecentriq may be used when your bladder cancer:

The approval of Tecentriq in these patients is based on a study that measured response rate and duration of response. Continued approval for this use may depend on the results of an ongoing study to confirm benefit.

It is not known if Tecentriq is safe and effective in children.

Important Safety Information What is the most important information about Tecentriq? Tecentriq can cause the immune system to attack normal organs and tissues and can affect the way they work. These problems can sometimes become serious or life threatening and can lead to death.

Patients should call or see their healthcare provider right away if they get any symptoms of the following problems or these symptoms get worse.

Tecentriq can cause serious side effects, including:

Getting medical treatment right away may help keep these problems from becoming more serious. A healthcare provider may treat patients with corticosteroid or hormone replacement medicines. A healthcare provider may delay or completely stop treatment with Tecentriq if patients have severe side effects.

Before receiving Tecentriq, patients should tell their healthcare provider about all of their medical conditions, including if they:

Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

The most common side effects of Tecentriq when used alone include:

Tecentriq may cause fertility problems in females, which may affect the ability to have children. Patients should talk to their healthcare provider if they have concerns about fertility.

These are not all the possible side effects of Tecentriq. Patients should ask their healthcare provider or pharmacist for more information about the benefits and side effects of Tecentriq.

Report side effects to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.Report side effects to Genentech at 1-888-835-2555.

Please visit http://www.Tecentriq.com for the Tecentriq full Prescribing Information for additional Important Safety Information.

About Genentech in personalized cancer immunotherapy

For more than 30 years, Genentech has been developing medicines with the goal to redefine treatment in oncology. Today, were investing more than ever to bring personalized cancer immunotherapy (PCI) to people with cancer. The goal of PCI is to provide each person with a treatment tailored to harness his or her own immune system to fight cancer. Genentech is studying more than 10 cancer immunotherapy medicines across 70 clinical trials alone or in combination with other medicines. In every study we are evaluating biomarkers to identify which people may be appropriate candidates for our medicines. For more information visit http://www.gene.com/cancer-immunotherapy.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200123005903/en/

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Genentech Provides an Update on Phase III Study of Tecentriq in People With Muscle-invasive Urothelial Cancer - BioSpace

Danlei Yang, 1 Ying Yan, 2 Fen Hu, 1 Tao Wang 1

1Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Peoples Republic of China; 2Department of Respiratory and Critical Care Medicine, Ningxia Peoples Hospital, Yinchuan 750002, Peoples Republic of China

Correspondence: Tao WangDepartment of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Peoples Republic of ChinaTel +86-13971477320Email Tomwang_1095@163.com

Purpose: Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by poor airflow. The purpose of this study was to explore the mechanisms involved in the development of COPD.Patients and Methods: The mRNA expression profile GSE100281, consisting of 79 COPD and 16 healthy samples, was acquired from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) between COPD samples and healthy samples were analyzed using the limma package. Functional enrichment analysis for the DEGs was carried out using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) tool. Furthermore, DEG-compound pairs were predicted using the Comparative Toxicogenomics Database. The KEGG metabolite IDs corresponding to the compounds were also obtained through the MetaboAnalyst pipeline. Based on the diffusion algorithm, the metabolite network was constructed. Finally, the expression levels of key genes were determined using quantitative PCR (qPCR).Results: There were 594 DEGs identified between the COPD and healthy samples, including 242 upregulated and 352 downregulated genes. A total of 696 DEG-compound pairs, such as BCL2-C00469 (ethanol) and BCL2-C00389 (quercetin) pairs, were predicted. CYP1B1, VEGFA, BCL2, and CDKN1A were included in the top 10 DEG-compound pairs. Additionally, 57 metabolites were obtained. In particular, hsa04750 (inflammatory mediator regulation of TRP channels)-C00469 (ethanol) and hsa04152 (AMPK signaling pathway)-C00389 (quercetin) pairs were found in the metabolite network. The results of qPCR showed that the expression of CYP1B1, VEGFA, BCL2, and CDKN1A was consistent with that predicted using bioinformatic analysis.Conclusion: CYP1B1, VEGFA, BCL2, and CDKN1A may play important functions in the development and progression of COPD.

Keywords: chronic obstructive pulmonary disease, differentially expressed genes, enrichment analysis, disease metabolites, metabolite network

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CYP1B1, VEGFA, BCL2, and CDKN1A Affect the Development of Chronic Obst | COPD - Dove Medical Press