Category Archives: Gene Medicine

Research, published today in the journal Neurology, describes how mutations in a specific gene that codes for a neural growth factor appear to predict how quickly memory loss will progress in people with Alzheimer's disease.

Alzheimer's disease is the most common form of dementia in older adults. It is a degenerative condition, characterized by a steady loss of memory and a reduced ability to carry out daily activities.

Today, an estimated 5 million people in the United States are living with the disease.

The hallmark of Alzheimer's disease is a buildup of two types of protein: beta-amyloid plaques outside of nerve cells, and tau tangles within neurons.

Although these proteins appear to be involved in the pathology of Alzheimer's, little is known about why the condition begins and how it progresses. Early detection is still difficult, and treatment options are poor.

Because of the aging population in Western societies, the number of people with Alzheimer's is steadily rising. As a result of this, and together with the lack of successful pharmacological interventions, research focused on understanding the condition is vital.

Researchers from University of Wisconsin School of Medicine in Madison recently set out to investigate whether they could identify an early marker for Alzheimer's disease. They focused on brain-derived neurotrophic factor (BDNF), a protein coded by a gene of the same name.

BDNF is known to support nerve cells, helping them to grow, specialize, and survive. This makes it a good target for Alzheimer's research. Earlier research has not always found solid links between levels of BDNF and Alzheimer's, so this time, the team looked specifically at a gene mutation called the BDNF Val66Met allele, or simply Met allele.

In total, 1,023 participants - aged 55 on average - were included, and all were healthy but at risk of developing Alzheimer's. They were followed for a maximum of 13 years. At the start of the study, blood samples were taken to test for the Met allele mutation, and it was found to be present in 32 percent of the individuals.

All participants carried out cognitive and memory tests at the beginning of the trial and up to five more times throughout the study's duration. Also, 140 of them underwent neuroimaging to look for beta-amyloid plaques.

The data showed that those with the Met allele mutation lost cognitive and memory skills "more rapidly" when compared with those who did not have the mutation. Furthermore, individuals who carried both the mutation and plaques experienced an even quicker decline.

In verbal learning and memory tests, individuals without the gene mutation improved by 0.002 units per year, whereas those with the mutation worsened by 0.021 units each year.

"When there is no mutation, it is possible the BDNF gene, and the protein it produces are better able to be protective, thereby preserving memory and thinking skills. This is especially interesting because previous studies have shown that exercise can increase levels of BDNF.

It is critical for future studies to further investigate the role that the BDNF gene and protein have in beta-amyloid accumulation in the brain."

Study author Ozioma Okonkwo, Ph.D.

Because current treatment is most successful if given earlier in the disease's progression, this could be a vital part of the jigsaw. As Okonkwo says, "Because this gene can be detected before the symptoms of Alzheimer's start, and because this presymptomatic phase is thought to be a critical period for treatments that could delay or prevent the disease, it could be a great target for early treatments."

There are some shortfalls in the research. These include the fact that all participants were white, whereas various ethnicities are affected differently by the disease. For instance, African Americans appear to be more susceptible. Another shortfall of the study is that the beta-amyloid data were limited.

However, the study carries some weight because it involved a large number of participants, and the findings are sure to spark more research.

Learn about the link between Alzheimer's and vascular disease.

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Alzheimer's disease progression predicted by gene mutation ... - Medical News Today

Worldwide, tens of millions of people are living with HIV. While scientists and medical professionals do not yet have a permanent cure for the virus, researchers have just made a breakthrough: they managed to eliminate the HIV-1 infection in mice.

According to the Centers for Disease Control and Prevention (CDC), more than 36 million people across the world are HIV positive, and approximately 1.2 million people in the United States live with the virus.

While there is currently no cure for the infection, scientists have just moved closer to finding one. Using a gene editing technology called "CRISPR/Cas9," the researchers successfully excised the HIV-1 provirus in three animal models.

A provirus is an inactive form of virus. It occurs when the virus has integrated into the genes of a cell. In the case of HIV, these host cells are the so-called CD4 cells - once the virus has been incorporated into the DNA of the CD4 cells, it replicates itself with each generation of CD4 cells.

The three mouse models used in the current research included a "humanized" model, in which the mice were genetically modified to have human immune cells, which were then infected with HIV-1.

The team was co-led by Dr. Wenhui Hu, Ph.D., associate professor in the Center for Metabolic Disease Research and the Department of Pathology at the Lewis Katz School of Medicine (LKSOM) at Temple University in Philadelphia, together with Kamel Khalili, Ph.D., Laura H. Carnell Professor and chair of the Department of Neuroscience at LKSOM, and Won-Bin Young, Ph.D, who just recently joined LKSOM.

The new study - published in the journal Molecular Therapy - builds on previous research by the same team, during which they used genetically modified rodents to demonstrate that their gene editing technology could eliminate the HIV-1-infected segments of DNA.

"Our new study is more comprehensive," Dr. Hu explains. "We confirmed the data from our previous work and have improved the efficiency of our gene editing strategy. We also show that the strategy is effective in two additional mouse models, one representing acute infection in mouse cells and the other representing chronic, or latent, infection in human cells."

Dr. Hu and team inactivated HIV-1, significantly reducing the RNA expression of viral genes in the organs and tissues of genetically modified mice.

Specifically, the RNA expression was reduced by approximately 60 to 95 percent.

The researchers then tested their findings by acutely infecting mice with EcoHIV - the equivalent of the HIV-1 in humans. Dr. Khalili explains the procedure:

"During acute infection, HIV actively replicates. With EcoHIV mice, we were able to investigate the ability of the CRISPR/Cas9 strategy to block viral replication and potentially prevent systemic infection."

The CRISPR/Cas9 method was up to 96 percent efficacious in eradicating EcoHIV in mice.

Finally, in the third model, mice received a transplant of human immune cells, including T cells, which were then infected with HIV-1.

One of the main reasons that a cure for HIV has yet to be discovered is the virus's ability to "hide" in the genomes of T cells, where it lives latently. This is why researchers applied the CRISPR/Cas9 technology to these mice with infected T cells.

After a single round of gene editing, the viral segments were excised from the human cells that had been integrated into the mouse tissues and organs. They removed the provirus from the mice's spleen, lungs, heart, colon, and brain after only one therapy injection.

The injection was with "quadruplex sgRNAs/saCas9 AAV-DJ/8" - an improved adeno-associated viral (AAV) vector.

AAV vectors are commonly used in gene therapy, but "the AAV-DJ/8 subtype combines multiple serotypes, giving us a broader range of cell targets for the delivery of our CRISPR/Cas9 system," Dr. Hu explains.

To assess the success of the genetic interventions, the team measured HIV-1 RNA levels using live bioluminescence imaging.

This is the first time that a team of researchers has managed to halt the replication of the HIV-1 virus and eliminate it completely from the infected cells in animals.

The team also provided the first evidence that HIV-1 can be successfully eradicated and full infection with the virus can be prevented using the CRISPR/Cas9 gene editing strategy.

The study was deemed "a significant step towards human clinical trials" by the authors, and the findings represent a breakthrough in the search for an HIV cure.

"The next stage would be to repeat the study in primates, a more suitable animal model where HIV infection induces disease, in order to further demonstrate elimination of HIV-1 DNA in latently infected T cells and other sanctuary sites for HIV-1, including brain cells. Our eventual goal is a clinical trial in human patients."

Kamel Khalili, Ph.D.

Learn how an HIV 'fingerprint' tool could greatly assist vaccine development.

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HIV breakthrough: Scientists remove virus in animals using gene editing - Medical News Today

May 3, 2017 Diagram of the brain of a person with Alzheimer's Disease. Credit: Wikipedia/public domain.

A gene mutation may accelerate the loss of memory and thinking skills in people who are at risk for Alzheimer's disease, according to a study published in the May 3, 2017, online issue of Neurology, the medical journal of the American Academy of Neurology. The gene mutation is called the BDNF Val66Met allele, or just the Met allele.

Brain derived neurotrophic factor (BDNF) is a protein produced by the gene of the same name. It is one of a group of proteins called neurotrophins that help nerve cells grow, specialize and survive. Alleles are parts of genes that work in pairs on the chromosomes to determine a person's traits.

"We found that people with Alzheimer's risk who have this BDNF gene mutation called the Met allele may have a more rapid decline of memory and thinking skills," said study author Ozioma Okonkwo, PhD, of the University of Wisconsin School of Medicine in Madison, Wisc. "Because this gene can be detected before the symptoms of Alzheimer's start, and because this presymptomatic phase is thought to be a critical period for treatments that could delay or prevent the disease, it could be a great target for early treatments."

For the study, researchers followed 1,023 people with an average age of 55 for up to 13 years who were at risk for Alzheimer's disease but at the start were still healthy. Participants gave blood samples which were tested for the Met allele gene mutation. Their memory and thinking skills were evaluated at the start of the study and at each study visit, up to five visits. Of that group, 140 were also tested with neuroimaging for beta-amyloid, a sticky protein that can build up into plaques found in the brains of people with Alzheimer's disease.

A total of 32 percent of the participants had the Met allele. Researchers found that when compared to people without the gene mutation, those with the mutation lost memory and thinking skills more rapidly. On tests of verbal learning and memory, those with no gene mutation improved by 0.002 units per year, while the scores of people with the mutation declined by 0.021 units per year.

The researchers also found that people with the gene mutation who also had more beta-amyloid had an even steeper rate of decline.

"When there is no mutation, it is possible the BDNF gene and the protein it produces are better able to be protective, thereby preserving memory and thinking skills," Okonkwo said. "This is especially interesting because previous studies have shown that exercise can increase levels of BDNF. It is critical for future studies to further investigate the role that the BDNF gene and protein have in beta-amyloid accumulation in the brain."

A major strength of the study is that it was one of the largest studies investigating this mutation. A limitation is that the study participants were predominantly white. Also, the number of people with beta-amyloid data was limited.

Explore further: Growth factor in brain tied to slower mental decline

Older people with higher amounts of a key protein in their brains also had slower decline in their memory and thinking abilities than people with lower amounts of protein from the gene called brain-derived neurotrophic factor, ...

A new study shows that having a high amount of beta amyloid or "plaques" in the brain associated with Alzheimer's disease may cause steeper memory decline in mentally healthy older people than does having the APOE 4 allele, ...

A gene that protects the brain from the harmful build-up of amyloid-beta, one of the causative proteins implicated in Alzheimer's disease, has been identified as a new target for therapy by NeuRA researchers.

A University of Adelaide analysis of genetic mutations which cause early-onset Alzheimer's disease suggests a new focus for research into the causes of the disease.

Researchers at the University of California, San Diego School of Medicine have identified a gene variant that may be used to predict people most likely to respond to an investigational therapy under development for Alzheimer's ...

A single variation in the gene for brain-derived neurotropic factor (BDNF) may influence obesity in children and adults, according to a new study funded by the National Institutes of Health. The study suggests that a less ...

A gene mutation may accelerate the loss of memory and thinking skills in people who are at risk for Alzheimer's disease, according to a study published in the May 3, 2017, online issue of Neurology, the medical journal of ...

Positive social support from adult children is associated with reduced risk of developing dementia, according to a new research published today.

Working with human brain tissue samples and genetically engineered mice, Johns Hopkins Medicine researchers together with colleagues at the National Institutes of Health, the University of California San Diego Shiley-Marcos ...

Scientists from the Gladstone Institutes identified that mutations in a protein commonly linked to frontotemporal dementia (FTD) result in obsessive-like behaviors. They linked these behaviors to immune pathways, implicating ...

Damaging tangles of the protein tau dot the brains of people with Alzheimer's and many other neurodegenerative diseases, including chronic traumatic encephalopathy, which plagues professional boxers and football players. ...

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Gene mutation may speed up memory loss in Alzheimer's disease - Medical Xpress

In recent years was proved that the best technique in the investigation of malignant lymphocytes is the. Fluorescence in situ hybridization (FISH). In the literature it was registered, in previous years, on an international study, conducted on 109 cases of CLL, 79 cases (72.5%) who had more genetic abnormalities: the remaining 30 cases (27.5%) had normal results, using FISH. The presence of del(11q), del(17p), mutated TP53, and unmutated IGHV typically predict for poor survival. Genetic Events in Chronic Lymphocytic Leukemia

In the normal cells, suppressor P-53 gene, coding proteins that bind to DNA and regulate the expression of genes, prevents the genome mutations. A mutation of the gene P-53 will inevitably lead to a process of carcinogenesis in which the cell divides endlessly. In recent years was proved that the best technique in the investigation of malignant lymphocytes, in the processes of deletions and rearrangements of chromosome genes, is the Florescence in situ Hybridization, (FISH) technique and this method is used as an alternative to chromosomal banding, a conventional application in molecular medicine, (Nelson BP et al, 2007).

In the literature of field in molecular medicine, it was registered, in previous years, on an international study, conducted on 109 cases of CLL, 79 cases (72.5%) who had more genetic abnormalities of p53 gene; the remaining 30 cases (27.5%) had normal results, using the same technique, FISH. The majority of patients, 67% (53.79) had a single anomaly and the remaining 33% had two or three genetic abnormalities. The chromosomes 14q32-17p translocation in LLC genome, which appeared similar to some common, had demonstrated abnormalities involving IGH gene, located on chromosome14q32, (Zerdoumi A et al, 2015).

Identification of P53 gene mutations in regions of 17 chromosome of hematological neoplasm is important because these mutations have an impact on the clinical course of patients and requires an attitude adjustment therapeutic adequate. Restoring function to p53 can induce lymphoma, apoptosis. Recent, endogenous somatic gene therapy research is a basic of trial clinical and therapeutic trial.

The DNA, (either integrated into the genome or episome external plasmid) is used to treat a disease arising as a result of mutations in chromosomal regions. In the past few years, this method has been included in the treatment of CLL, acute lymphocytic leukemia, [ALL], or multiple myeloma [MM], (Jump up^ "Gene Therapy". ama-assn.org. 4 April 2014. Retrieved22 March 2015).

The frequencies of P53 gene mutations in CLL can be categorized as individual biomarkers in proteomic and genomic profile for this type of leukemia that can be implemented in targeted patient treatment, within personalized medicine. Keywords: Gene P53, Chronic Lymphocytic Leukemia, Apoptosis, Fluorescence in situ Hybridization, Cancer. Conference: International Symposium on Clinical Neuroscience: Clinical Neuroscience for Optimization of Human Function, Orlando, USA, 7 Oct - 9 Oct, 2016. Presentation Type: Poster Presentation Topic: Abstracts ISCN 2016 Citation: UDRISTIOIU A (2016). Role of P53 gene in oncogenenesis of Chronic Lymphocytic Leukemia. Front. Neurol. Conference Abstract: International Symposium on Clinical Neuroscience: Clinical Neuroscience for Optimization of Human Function. doi: 10.3389/conf.fneur.2016.59.00101 Received: 01 May 2016; Published Online: 07 Sep 2016. * Correspondence: AURELIAN UDRISTIOIU, Emergency County Hospital Targu Jiu, Clinical Laboratory, Targu Jiu, Romania, aurelianu2007@yahoo.com

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Genetic Events in Chronic Lymphocytic Leukemia - Cordis News

Sangamo's fourth lead clinical program, SB-318 in vivo genome editing treatment for MPS I, has already received Orphan Drug and RPD designations. FDA has cleared an IND for this program, and a Phase 1/2 clinical trial evaluating SB-318 in adults with MPS I is open and screening subjects for enrollment.

Sangamo's In Vivo Genome Editing Approach Sangamo's ZFN-mediated in vivo genome editing approach makes use of the endogenous albumin gene locus, a highly expressing and liver-specific site that can be edited with ZFNs to accept and express therapeutic genes. The approach is designed to enable the patient's liver to permanently produce circulating therapeutic levels of a corrective protein. The ability to permanently integrate the therapeutic gene in a highly specific, targeted fashion significantly differentiates Sangamo's in vivo genome editing approach from conventional AAV cDNA gene therapy. Ultimately, the target population for these programs will include pediatric patients, and it will be important in this population to be able to produce stable levels of therapeutic protein for the lifetime of the patient.

About Sangamo Therapeutics Sangamo Therapeutics, Inc. is focused on translating ground-breaking science into genomic therapies that transform patients' lives using the company's industry leading platform technologies in genome editing, gene therapy, gene regulation and cell therapy. The Company is advancing Phase 1/2 clinical programs in hemophilia A and hemophilia B, and lysosomal storage disorders MPS I and MPS II. Sangamo has a strategic collaboration with Bioverativ Inc. for hemoglobinopathies, including beta thalassemia and sickle cell disease, and with Shire International GmbH to develop therapeutics for Huntington's disease. In addition, it has established strategic partnerships with companies in non-therapeutic applications of its technology, including Sigma-Aldrich Corporation and Dow AgroSciences. For more information about Sangamo, visit the Company's website at http://www.sangamo.com.

Forward Looking Statements This press release may contain forward-looking statements based on Sangamo's current expectations. These forward-looking statements include, without limitation, references relating to research and development of therapeutic applications of Sangamo's gene therapy and ZFP technology platforms, the potential of Sangamo's technology to treat hemophilia and lysosomal storage disorders, the expected timing of these clinical trials and the release of data from these trials, the impact of Sangamo's clinical trials on the field of genetic medicine and the benefit of orphan drug status, rare pediatric disease status and fast track status. Actual results may differ materially from these forward-looking statements due to a number of factors, including uncertainties relating to substantial dependence on the clinical success of lead therapeutic programs, the initiation and completion of stages of our clinical trials, whether the clinical trials will validate and support the tolerability and efficacy of ZFNs, technological challenges, Sangamo's ability to develop commercially viable products and technological developments by our competitors. For a more detailed discussion of these and other risks, please see Sangamo's SEC filings, including the risk factors described in its Annual Report on Form 10-K and its most recent Quarterly Report on Form 10-Q. Sangamo Therapeutics, Inc. assumes no obligation to update the forward-looking information contained in this press release.

To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/sangamo-therapeutics-announces-special-regulatory-designations-from-the-fda-for-three-clinical-programs-300451381.html

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Sangamo Therapeutics Announces Special Regulatory ... - PR Newswire (press release)

WEST HAVEN >> Our genes define our individuality, including what diseases to which we may be susceptible.

In just a few days, gene-sequencing machines can map all of a persons genes, revealing the cause of a genetic illness and even suggesting the best possible treatment.

On Monday, the Yale School of Medicine, partnering with Yale New Haven Hospital, took the next step toward personalized medicine, cutting the ribbon on its Center for Genome Analysis on Yales West Campus.

Dr. Murat Gunel, professor of genetics and neuroscience in the medical school, gave a vivid example of how gene sequencing can save lives:

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About three months ago a baby was born in New Haven with a really, really significant skin disease that we had to transfer him to the intensive care unit. And he was dying, and we didnt know what was wrong with him, Gunel said. In six days we were able to sequence his genome, understand his disease and he is at home playing with his mother now.

The baby suffered from dystrophic epidermolysis bullosa, which makes the skin extremely fragile, and its caused by a mutation in just one gene: COL7A1. Gunel said Dr. Keith Choate first saw the baby on a Saturday and by Friday had the diagnosis. This is a daily occurrence, Gunel said.

Choate said the genetic analysis showed the infant had a mild case of the disease, which was limited to the hands and feet. He is receiving advanced wound care, Choate said.

The pair of NovaSeq 6000 gene-sequencing machines that are churning out this information with three more on the way will help researchers find treatments and cures for cancers, prenatal diseases and others at a faster and faster pace.

Of 20,000 genes in the human genome, 57 have been identified for which preventive measures can be taken or treatment can be prescribed if an abnormality or mutation is found. For example, mutations in the BRCA1 or BRCA2 genes increase a womans risk of developing breast or uterine cancer.

We are sequencing every cancer at Smilow now, understanding what is specific for that cancer and giving treatment specific to that individual, Gunel said. We want to take from these specific diseases not only for prenatal, not only for newborn, not only for cancer, but [to] understand the health of an individual. We want to make Connecticut the healthiest state in the nation by sequencing and understanding the differences between all of us.

Dr. Robert Alpern, dean of the Yale School of Medicine, said, The idea is that you can know the total sequence of a patient and then follow their history, their health, what happens to them and then correlate them together so that someday we will be able to predict everything about ones health just from their DNA sequence.

Yale has done so much for New Haven, so much for New Haven County and now so much for this country, said Senate Republican President Pro Tem Len Fasano of North Haven.

Referring to the ability to map a persons genome within days, Fasano said, You can take that and figure out how the environment affects different lives by looking at different gene structure, comparing to different parts of the country or whether its an urban area versus a suburban area. The research that can stem from this is pretty amazing when you think of it.

The growing field also is a boon to the states economy. Senate Democratic President Pro Tem Martin Looney of New Haven said, This commitment to the advancement of health and medicine will have far-reaching and positive impacts on our economy and overall well-being for years to come. We know were going to need data scientists, health information specialists, clinical analysts, genomic counselors, to name just a few of the specialties that are going to create huge opportunities for new employment in our state.

Marna Borgstrom, CEO of Yale New Haven Health, which includes the hospital, said, Theres great work being done here and our interest has been, who does this apply to and how can we make this available to patients? And with our partners at the medical school were committed to providing unparalleled value to people we serve, and part of value is giving people outcomes that are meaningful to them.

And so you start to think about areas like prenatal diagnoses, like certain newborn diseases, difficult cancers and the ability to take all of the drugs and the treatments and the information thats out there but actually create a specialized plan for each patient as each patients going to respond differently, she said.

Call Ed Stannard at 203-680-9382.

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Gene sequencing at Yale finding personalized root of disease; new center opens in West Haven - New Haven Register

Oxford Genetics founder and CEO Ryan Cawood told me about his companys improvements to DNA design for better biologicals.

Last month at Synbiobeta, I caught up with Ryan Cawood, who created one of the most successful synthetic biology companies around, Oxford Genetics. Our direction actually took off from this conference, he told me. We saw that the cost of DNA synthesis is going to be driven down, so this was not a market for us to compete in.

Instead of focusing on making DNA engineering cheaper, Cawood decided to explore how to improve the quality of its products. Specific inspiration came in the form of frustration as he was trying to finish his PhD in genetics at Oxford University

I was making gene therapy plasmids, and they were increasingly hard to test because we just couldnt make them. They were 50 to 100 kilobases for different viruses with no standardization one section camefrom Spain, one section from the US, and one from the back of the freezerit was a sort of genetic car crash, as my PI, Len Seymour, called it.

As a company, we set out to improve this by focusing on DNA design we now help other companies working on therapeutics develop them better with SnapFast, a lego-like core DNA system.

In 2011, I formed the company by taking out bank loan. Then I negotiated a lab bench from local company in return for gene engineering for them. Finally, I built a website. Ive since obtained seven grants and connected with solid investors. Mercia Technologies has invested three times now the first time was in 2013 and on this next round, someone else will probably come in as well.

Len, my former lab PI, is still on the board as one of the cofounders. He was actually involved in founding two biotech companies before hand, one for oncolytic viruses (PsiOxus Therapeutics) and one for protein expression (The Native Antigen Company).

Cawoods lightning talk at Synbiobeta: fromsynthetic biology, Oxford Genetics is building up to improve biological drugsto reachpersonalised versions.

Well, our trajectory and plan was to build better DNA tech for the design and synthesis to discover and manufacture biologicals better. Fundamentally, youre always trying to build a tool to develop these better.

What Id like to see from the field is a major advancement of human therapeutics. There are four major challenges in biological development that were working to address: discovery, design, production and delivery basically every step.

We think Snapfast DNA will improve all of them because DNA is an integral part of each. So, we can absolutely use synbio to improve cell and gene therapies and biologics.

People who work in the area think of synbio as making things in algae, or making new genetic circuits etc, but dont necessarily see consequences for human health. The field has a huge role to play in tying the genetics of an individual human to a therapeutic treatment based on DNA. At the moment, there is no such pairing were a long way from that, but with synbio well get there.

We take a sort of blunt hammer approach now: its very inefficient therapeutically, and its a very inefficient use of government funds. By funding a better understanding of people, youll see significant gains intreatmentefficiencies.

The current approach is far too retrospective at the moment: we give a drug and then try to figure out why it worked in some people afterwards, or we just carry on giving it everyone knowing only a few people will benefit, in the future I hope we can predict efficacy and act upon that calculation.

Im still very much motivated by the therapeutic side of synthetic biology. Not everyone working at the company has a background in human genetics some come from working on archaea, but they all are oriented towards working towards therapeutics. Even my PA has first class degree in genetics.

DNA foundries are all the rage in synbio now, but we were much more interested in biology than physical manufacture that is, were much more focused on end goal versus how you get there. This thinking has changed the company a lot: instead of just making things, were designing things.

Images from Oxford Genetics,author at Synbiobeta, 04 April 2017, Mercia, & Sergei Drozd, Saibarakova Ilona /shutterstock.com

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This Founder is using Synbio to Revolutionize Genetic Medicine - Labiotech.eu (blog)

May 1, 2017 Credit: Vera Kratochvil/public domain

Researchers have found a genetic explanation for how smoking can lead to coronary heart disease (CHD). Many people have a protective gene type that reduces levels of an enzyme connected to artery-clogging fatty plaques and CHD. However, in people carrying this gene, smoking counteracts the protective effect.

"Our finding suggest that interventions to inhibit this enzyme would be particularly beneficial for smokers, and they may also prove useful for anyone at heightened risk of coronary heart disease," said study leader Muredach P. Reilly, MBBCH, MSCE, the Herbert and Florence Irving Professor of Medicine (in Cardiology) and director of the Irving Institute for Clinical and Translational Research at Columbia University Medical Center (CUMC).

The study, the largest of its kind, was published online today in the journal Circulation.

Cigarette smoking is known to cause about one in five cases of CHD, and is linked to approximately 1.6 million deaths worldwide each year. But the precise mechanisms by which smoking leads to CHD has not been clear. To learn more about how genetics affect the interplay between smoking and heart disease, the researchers pooled genetic data on more than 140,000 people from 29 previous studies. They analyzed 45 small regions of the genome that have been previously associated with a heightened risk of CHD. They hypothesized that for some of these regions, the associated heart risk would be different in smokers than in non-smokers.

The analysis showed that a change in a single DNA "letter" on chromosome 15, near the gene that expresses an enzyme (ADAMTS7) produced in blood vessels, was associated with a 12 percent reduction in heart risk in non-smokers. However, smokers with this same variation had only a 5 percent lower risk of CHDreducing by over half the protective effect of this genetic variation.

DNA variations located near a gene sometimes inhibit the gene's activity, causing below-normal levels of the protein it produces. In this case, the researchers discovered that the single-letter DNA variation that protected patients from CHD resulted in a significant decline in the production of ADAMTS7.

In a separate recent mouse study, Dr. Reilly's lab demonstrated that genetic deletion of ADAMTS7 reduced the buildup of fatty plaques in arteries, suggesting that blocking the production or function of this enzyme might be a way to lower the risk of CHD.

In the current study, when the researchers applied a liquid extract of cigarette smoke to coronary artery cells, the cells' production of ADAMTS7 more than doubled, supporting the conclusion that smoking may counteract the genetic protection from CHD by increasing the level of ADAMTS7 in the artery wall.

"This has been one of the first big steps towards solving the complex puzzle of gene-environment interactions that lead to CHD," said lead author Danish Saleheen, PhD, assistant professor of biostatistics and epidemiology at the Perelman School of Medicine at the University of Pennsylvania.

In future studies, the researchers hope to establish exactly how the ADAMTS7 variants protect against CHD, how cigarette smoking affects the activity of the gene that produces the enzyme, and whether reducing or inhibiting ADAMTS7 can slow the progression of atherosclerosis due to cigarette smoking.

"This study is an important example of the emerging field of precision medicine and precision public health," said Dr. Reilly. "Through these large-scale genetic studies, we're beginning to understand the genetic variations that drive risk in response to certain environmental exposures or lifestyle behaviors. Not everyone reacts the same to the same exposures or behaviors. For example, some people who don't exercise develop diabetes while others do not. So, instead of saying there are rules for everybody, we can specify which interventions will be especially beneficial for specific populations or individuals and focus our health resources more efficiently."

The study is titled, "Loss of Cardio-Protective Effects at the ADAMTS7 Locus Due to Gene-Smoking Interactions."

Explore further: Scientists identify new therapeutic target for coronary heart disease

More information: Danish Saleheen et al. Loss of Cardio-Protective Effects at theLocus Due to Gene-Smoking Interactions, Circulation (2017). DOI: 10.1161/CIRCULATIONAHA.116.022069 , circ.ahajournals.org/content/early/2017/04/20/CIRCULATIONAHA.116.022069

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Smoking-related heart disease tied to effects of a single gene - Medical Xpress

The recent FDA approval of 23andMes direct-to-consumer genetic testing is an interesting and inevitable milestone in the dissemination of medical knowledge to the public. However, we must proceed with caution to ensure that this information is understandable and not anxiety provoking.

Over the past two decades, we have seen a dramatic increase in our knowledge about the genetic basis of many diseases. Most of the clinical use of this genetic information has been to counsel selected populations that were deemed high risk based on family history or other features. The information was conveyed to patients under the guidance of medical professionals who are skilled at interpreting the prognostic implications of the test results and who can advise patients about treatment options.

Recent advances in technology permit the whole genome to be screened for serious diseases at reasonable costs. Given the thirst by consumers for access to health information, direct-to-consumer testing was bound to happen.

Overall, I believe that readily accessible genetic information has the potential to improve public health if also accompanied by access to medical interpretation and counseling regarding test results.

For many, the implications of genetic mutations are quite complex, as they may only indicate increased risks of disease, not the inevitability of disease occurrence. Additionally, implications for social and family consequences of test results must be addressed. It is interesting that the first set of diseases chosen by 23andMe are diseases with public fear factors such as Alzheimers and Parkinsons rather than the more lethal conditions that can be identified by genetic testing. For example, the American College of Medical Genetics (ACMG) has published a list of 56 serious diseases that may be incidentally found during genetic screening (during research studies or exams for other conditions). These include genetic predispositions to cancer, heart disease, and neuromuscular diseases. Careful medical counseling is required when these genetic alterations are identified.

It is not a question of if but rather when the public will demand over-the-counter access to screening for more serious diseases, including the BRCA breast cancer genes or hereditary colon cancer genes.How the public will handle this information is unclear, but most studies on medically supervised genetic testing have been favorable. And based on the feedback I hear from patients and their families in my oncology practice, they would all encourage greater public awareness and testing for these conditions.

But even before we reach that stage, the current lack of required professional counseling regarding the interpretation of test results is troubling. The cautionary concerns that have bubbled up in recent years around Dr. Google and the surge in self-diagnosis from sites such as WebMD will need to extend to genetic testing. For example, some individuals may welcome the reassurance that they do not carry high-risk genes. But a positive test result could be met with great angst without understanding that for some mutations the risk of disease can be high, but for other genes the risk can be low. This is where counseling is critical.It will be incumbent on test manufacturers to provide access to genetic counselors so the results can be placed into proper context.The public must be properly informed that merely carrying a certain gene does not doom an individual to developing a disease, but similarly must be counseled when medical actions are appropriate.

Although direct-to-consumer advancement and FDA approval should be celebrated, it is by no means an endorsement to open a floodgate of genetic testing. When we consider the growing consumerization of medicine and the reduction in genetic testing costs, this was a logical progression. I hope that we will see more in terms of increasing access to medical advances and that more private enterprises will step up to satisfy the publics thirst for credible medical information. Other advances in technology including healthcare monitors and wearables, home diabetes monitoring and medication reminders will place consumers in more control of their own health. Changes in data exchange, including greater access to electronic medical records and direct transfer of laboratory results, will also help patients stay aware of their diseases.

The increased benchmarking of doctors and hospital systems will also help consumers make more informed choices about where to receive healthcare. What the medical community learns from these advancements and how consumers respond will we all be willing to give more for science or vice versa? could easily accelerate our path to moonshot. Or perhaps we will see a recoil and consider this a time of oversharing of too much information. Time will tell. But in the meantime, I look forward to the next logical step: More channels and greater access to counseling so patients are not interpreting these results in a vacuum.

Photo: DrAfter123, Getty Images

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This is the direction direct-to-consumer genetic testing needs to take - MedCity News

People who smoke cigarettes may boost their risk of clogged heart arteries by weakening a gene that is otherwise protective of these important blood vessels, US researchers said Monday.

The findings point to a genetic explanation for how smoking can lead to the plaque buildup that stiffens arteries and causes heart disease, said the report in the journal Circulation.

"This has been one of the first big steps towards solving the complex puzzle of gene-environment interactions that lead to coronary heart disease," said co-author Danish Saleheen, assistant professor of biostatistics and epidemiology at the Perelman School of Medicine at the University of Pennsylvania.

Researchers pooled genetic data on more than 140,000 people from more than two dozen earlier studies, with a particular focus on regions of the genome that have been previously associated with a higher risk of plaque buildup in the heart's arteries.

"A change in a single DNA 'letter' on chromosome 15, near the gene that expresses an enzyme (ADAMTS7) produced in blood vessels, was associated with a 12 percent reduction in heart risk in nonsmokers," said the report.

"However, smokers with this same variation had only a five percent lower risk of coronary heart disease -- reducing by over half the protective effect of this genetic variation."

Follow-up lab studies showed that in cells that line arteries of the human heart, the production of the enzyme ADAMTS7 dropped significantly when the cells contained this single-letter DNA variant.

Another experiment showed when coronary artery-lining cells were exposed to the liquid extract of cigarette smoke, the cells' production of ADAMTS7 more than doubled.

If researchers can find other ways to inhibit this enzyme, they might be able to help smokers and others at heightened risk of coronary heart disease, said co-author Muredach Reilly, director of the Irving Institute for Clinical and Translational Research at Columbia University Medical Center.

Cigarette smoking is known to cause about one in five cases of coronary heart disease, and is linked to approximately 1.6 million deaths worldwide each year.

"Through these large-scale genetic studies, we're beginning to understand the genetic variations that drive risk in response to certain environmental exposures or lifestyle behaviors," said Reilly.

"Not everyone reacts the same to the same exposures or behaviors. For example, some people who don't exercise develop diabetes while others do not," he added.

"So, instead of saying there are rules for everybody, we can specify which interventions will be especially beneficial for specific populations or individuals and focus our health resources more efficiently."

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Smoking Weakens a Gene That Protects Arteries - Newsmax