Category Archives: Genetic Medicine

The coronavirus pandemic has hit older people far harder than those who are younger, but scientists are yet to fully understand why this is.

Many of the elderly people who have died have had pre-existing health conditions such as heart disease, lung disease and diabetes, all of which make fighting the virus more difficult, but many have not had any such health problems, and occasionally the virus has caused the deaths of younger, apparently healthy people.

Researchers around the world are racing to learn how the virus behaves, which health factors put people most at risk, and are trying to work out whether there may be genetic traits that could mean some people respond to the infection differently to others.

Sharing the full story, not just the headlines

There are various theories to suggest why the virus is so unusually and devastatingly selective.

Some scientists have suggested the greater the amount of virus that infects an individual known as the viral load could make a large difference to how the body is able to respond to infection.

Put simply,the larger the dose of the virus a person gets, the worse the infection is, and the least promising the outcome.

A parallel school of thought is that genetic variations between humans differences in our DNA could affect how susceptible an individual is to the virus.

And another candidate for why apparently healthy young people are dying is they may have a highly reactive immune system, which is sent into overdrive fighting off the virus. In such a scenario, a huge inflammation storm could inadvertently overwhelm vital organs such as the lungs.

None of the theories compete with one another, and aspects of all of them, as well as innumerable other factors, could be at play in an individual case.

Viral load

No hype, just the advice and analysis you need

Dr Edward Parker of the London School of Hygiene and Tropical Medicine, explained how a high viral load can impact humans. He said: After we are infected with a virus, it replicates in our bodys cells. The total amount of virus a person has inside them is referred to as their viral load. For Covid-19, early reports from China suggest the viral load is higher in patients with more severe disease, which is also the case for Sars and influenza.

The amount of virus we are exposed to at the start of an infection is referred to as the infectious dose. For influenza, we know that that initial exposure to more virus or a higher infectious dose appears to increase the chance of infection and illness. Studies in mice have also shown that repeated exposure to low doses may be just as infectious as a single high dose.

He added: So all in all, it is crucial for us to limit all possible exposures to Covid-19, whether these are to highly symptomatic individuals coughing up large quantities of virus or to asymptomatic individuals shedding small quantities. And if we are feeling unwell, we need to observe strict self-isolation measures to limit our chance of infecting others.

Professor Wendy Barclay, the head of the Department of Infectious Disease at Imperial College London, said existing knowledge of viral load means healthcare workers can be at greater risk of infection.

In general with respiratory viruses, the outcome of infection whether you get severely ill or only get a mild cold can sometimes be determined by how much virus actually got into your body and started the infection off. Its all about the size of the armies on each side of the battle, a very large virus army is difficult for our immune systems army to fight off.

So standing further away from someone when they breathe or cough out virus likely means fewer virus particles reach you and then you get infected with a lower dose and get less ill. Doctors who have to get very close to patients to take samples from them or to intubate them are at higher risk so need to wear masks.

Genetic differences between those infected

Scientists are currently preparing to scour Covid-19 patients genomes for DNA variations that might indicate why some people are more at risk than others.

The findings could then be used to identify groups most at risk of serious illness and those who might be protected, and this knowledge could then inform the hunt for effective treatments.

A huge effort to pool DNA research from patients around the world is now on, with the ultimate goal being to build a body of evidence from people with no underlying health issues, but who have reacted differently to infection by the virus.

One promising strand of research into why some people are more susceptible to the coronavirus is on the gene variation for the cell surface protein angiotensin-converting enzyme 2 (ACE2), found on the outer membranes of cells, and which the coronavirus uses to enter cells in the lungs and airways.

Variations in production of ACE2 could make it easier or more difficult for the virus to enter and infect cells.

We see huge differences in clinical outcomes and across countries. How much of that is explained by genetic susceptibility is a very open question, geneticist Andrea Ganna, of the University of Helsinkis Institute for Molecular Medicine Finland, told Science Magazine.

Another fascinating line of inquiry is whether different blood types could lead to differing levels of susceptibility to the disease.

A Chinese research team reported in a non-peer-reviewed article that people with type O blood may be protected from the virus, and those with type A blood could be at greater risk.

Were trying to figure out if those findings are robust, Stanford University human geneticist Manuel Rivas told Science Magazine.

The first results from the investigations into genetic differences and susceptibility are expected in less than two months time.

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How 'viral load' and genetics could explain why young people have died from coronavirus - The Independent

When a patient with puzzling neurological symptoms enrolled in the Undiagnosed Diseases Network, researchers led by Dr. Hugo J. Bellen were set on solving the mystery. The patient presented with an unidentified late-onset neurodegenerative disorder. The team named this new syndrome Mitchell disease in reference to the first patient to be diagnosed with this disorder and looked to identify its genetic basis.

On comparing the patients and his parents DNA, the team identified a mutation in the patient that resulted in a single amino acid substitution (N237S) in the ACOX1 protein. This change was seen only in the patient and was not present in either of his parents DNA, indicating that the patient had a de novo, or new, mutation on this gene, said Bellen, professor at Baylor College of Medicine and investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Childrens Hospital and also a Howard Hughes Medical Institute investigator. With the help of the online gene-matching tool GeneMatcher, we found two more patients who had the same new mutation in the ACOX1 gene.

All three patients, who ranged from 3 to 12 years old at the time of disease onset, had remarkably similar clinical features, including degeneration of peripheral nerves that caused a progressive loss of mobility and hearing. The three individuals had identical gene variants, a clear indication that ACOX1 dysfunction likely was the cause of the symptoms.

The finding that an ACOX1 mutation was linked to Mitchell disease initially baffled the researchers. The only known ACOX1-related disorder described in the medical literature at that time presented earlier in infancy with seizures, severe cognitive decline, neuro-inflammation and accumulation of very-long-chain-fatty acids in plasma and, more importantly, was caused by the lack of the ACOX1 protein none of which was true for these three patients.

The brain has large amounts of lipids, which are critical for the proper functioning of the nervous system. Abnormal breakdown of lipids in the brain and peripheral nervous system is associated with several neurodegenerative diseases, Bellen said.

The gene ACOX1 is involved in lipid breakdown. It produces an enzyme called Acyl-CoA oxidase 1 that initiates a series of reactions that break down very-long-chain-fatty acids in small intracellular organelles called peroxisomes.

To resolve this conundrum, the Bellen team turned to fruit flies. The first surprising discovery made by the lead author, Hyunglok Chung, was that the ACOX1 protein is abundant and critical for the maintenance of glia, cells that support neurons. This uncovered a previously unknown role of peroxisomes in glial cells and paved the way for further experiments.

To understand how ACOX1 variants affect the function of glia, they generated two mutant fly lines, the first one lacked both the copies of ACOX1 gene and the second, carried the substitution mutation (N237S) found in one of the ACOX1 genes in the Mitchell disease patients.

Flies lacking ACOX1 mimicked the symptoms of ACOX1 deficiency in humans, including elevated levels of very-long-chain-fatty acids along with dramatic loss of glia and neurons and progressively impaired neuronal function. When we reduced the synthesis of very-long-chain-fatty acids in these flies by administering the drug bezafibrate, we observed significant improvement in lifespan, vision, motor coordination and neuronal function, implicating elevated levels of these lipids and their excessive accumulation in glia as an important contributor, said Chung, postdoctoral fellow in the Bellen lab.

It is remarkable how well bezafibrate suppressed the symptoms of ACOX1 deficiency, suggesting a new therapeutic avenue for patients with this condition, Bellen said.

In contrast to the loss of ACOX1, the introduction of the single amino acid substitution (N237S) in ACOX1 gene resulted in a hyperactive ACOX1 protein. Typically, breakdown of very-long-chain-fatty acids by the enzymatic action of ACOX1 produces small amounts of highly reactive oxygen species, but glial cells quickly neutralize them. However, in Mitchells disease, hyperactive ACOX1 produces copious amounts of toxic reactive oxygen species, leading to the destruction of glia and their neighboring neurons.

The harmful effects due to hyperactive ACOX1 were potently reversed with the antioxidant N-acetyl cysteine amide (NACA). However, NACA did not suppress the lethality or toxic effects in flies that lacked ACOX1, a clear indication that the two diseases act via entirely different pathways and would need to be treated with two distinct therapeutic strategies.

This study is a prime example of how combining UDNs unique team science approach with power of fruit fly genetics is facilitating rapid and phenomenal progress in rare diseases research. We take on cases of patients with conditions never described before, uncover new diseases and find definitive molecular diagnosis for them. We make significant progress in unraveling the causes of these novel diseases and rapidly identify and test promising new treatment options, Bellen said. We have successfully identified more than 25 disease-causing genes within the past three years a task that typically takes many years.

The study appears in the journal Neuron.

Other contributors to this study include Michael F. Wangler, Paul C. Marcogliese, Juyeon Jo, Thomas A. Ravenscroft,, Zhongyuan Zuo, Lita Duraine, Sina Sadeghzadeh, David Li-Kroeger, Robert E. Schmidt, Alan Pestronk, Jill A. Rosenfeld, Lindsay Burrage, Mitchell J. Herndon, Shan Chen, Undiagnosed Diseases Network, Amelle Shillington, Marissa Vawter-Lee, Robert Hopkin, Jackeline Rodriguez-Smith Michael Henrickson, Brendan Lee, Ann B. Moser, Richard O. Jones, Paul Watkins, Taekyeong Yoo, Soe Mar, Murim Choi, Robert C. Bucelli, Shinya Yamamoto, Hyun Kyoung Lee, Carlos E. Prada, Jong-Hee Chae, and Tiphanie P. Vogel.

The authors are affiliated with one or more of the following organizations: Baylor College of Medicine, Texas Childrens Hospital, Washington University in St. Louis, Cincinnati Childrens Hospital Medical Center, Johns Hopkins School of Medicine, and Seoul National University College of Medicine.

This work is funded by NMSS via RG1508-08406, NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under Award Number(s) U01HG007709, U54NS093793 and by ORIP via R24OD022005, BCM IDDRC (supported by NICHD U54HD083092), Howard Hughes Medical Institute and Cullen Foundation.

By Ana Mara Rodrguez, Ph.D.

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Solving the puzzle of Mitchell disease - Baylor College of Medicine News

Siddhartha Mukherjee:

Well, there are several things we have learned.

First of all, we have learned that a that the virus is mainly transmitted through respiratory droplets or so-called fomites. That's the main mode of transmission.

The second thing that we have learned, or trying to learn, we're in the middle of learning, is that there are several people who are asymptomatic who may be shedding virus. That's a very, very important idea. That is to say that there may be a child or someone who doesn't have any symptoms, no fever, no diarrhea, no respiratory symptoms, but nonetheless is shedding the virus.

We need to identify those people and isolate and potentially quarantine them, so that they don't keep spreading the virus.

The third thing that we are learning, which we haven't learned for sure, is that there seems to be if you do the right kind of test, there seems to be a way to predict whether you're going to have very severe disease vs. a more mild form of the disease.

And that helps because that will help us triage patient to those who are either going to be sick and therefore require urgent attention vs. those who may become less sick and may be able to be managed more conservatively too.

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What scientists know about COVID-19 -- and what they don't - PBS NewsHour

Investigators have identified genomic alterations that appear to be associated with prognosis in men with metastatic castration-sensitive prostate cancer (mCSPC).

Astudy of 424 patients with mCSPC treated at a tertiary care center revealedthat alterations in the androgen receptor (AR), TP53, cell-cycle, MYC oncogenicsignaling pathways occur more commonly in tumors with worse overall survivaland decreased time to castration-resistant disease, whereas alterations in theSPOP and MNT pathways occur more frequently in tumors with a better prognosis,according to findings published in ClinicalCancer Research.

Thegenomics of metastatic castration-sensitive prostate cancer have not been wellcharacterized in the literature, but it is now clear that upfront treatmentintensification with taxanes or next-generation AR-directed therapies offerbenefit in the overall patient population, said the studys co-senior authorWassim Abida, MD, a medical oncologist at Memorial Sloan Kettering CancerCenter in New York. The question remains whether treatment selection ortargeted therapies can be employed based on genomic characteristics.

Theassociation between alterations in cell-cycle genes and TP53 and MYC pathwaygenes and worse outcomes may pave the way for targeted therapy in thesehigher-risk groups, Dr Abida said.

Thestudy compared genomic alterations according to clinical phenotypes: high- vslow-volume disease and de novo vsmetastatic recurrence. Of the 424 patients in the study, 213 men (50%) hadhigh-volume disease (4 or more bone metastases or visceral metastases) and 211(50%) had low-volume disease; 65% had de novometastases and 35% had metastatic recurrence. At the time of sample collection, patients had a medianage of 66 years. The investigators conducted gene sequencing from May 2015 to September2018.

High- vs low-volume disease

Inadjusted analyses, men with higher-volume disease had significant 1.8- and3.7-fold increased risks of castration-resistant disease and death,respectively, compared with men who had low-volume disease. Tumor specimensfrom men with high-volume disease had more copy number alterations.

Amongmen with high-volume disease, the highest-ranking pathways were the NOTCH,cell-cycle, and epigenetic modifiers pathways.

Althoughthe prevalence of CDK12 alterations differed between patients with de novo metastatic and those with metastaticrecurrences, the groups had similar prognoses. I was actually surprised therewere not more dramatic genomic differences between de novo and relapsed disease, said study co-senior author PhilipKantoff, MD, a medical oncologist and Chair of the Department of Medicine atMemorial Sloan Kettering Cancer Center in New York.

Afteradjusting for disease volume and other genomic pathways, the researchers foundthat the rates of castration resistance differed by 1.5-fold and up to 5-fold accordingto alterations in the AR, SPOP (inverse), TP53, cell-cycle, WNT (inverse), andMYC pathways. Overall survival (OS) rates varied from 2- to 4-fold according toalterations in the AR, SPOP (inverse), WNT (inverse), and cell-cycle pathways.PI3K pathway alterations were not associated with prognosis.

Docetaxeland next-generation AR axis-directed therapies have been shown to prolong OS, butit remains uncertain which patients benefit the most from intensifiedtherapies. We did not find any obvious genomic reason to explain thedifferences in docetaxel sensitivity between high- and low-volume disease, DrKantoff said.

Theauthors pointed out that genomic landscape studies of tumor DNA profiling inprostate cancer in general have excluded metastatic castration-sensitive tumors.Instead, most studies have focus on localized disease or metastaticcastration-resistant disease.

DrAbida and his colleagues acknowledged that their study has inherent biases becauseit was hospital based and enrolled patients at an academic referral center.

Moleculardeterminants of castration resistance or survival in patients with mHSPC have beenunclear, but the new study sheds new light on molecular alterations associatedwith poor outcomes in men with mHSPC, particularly alterations in the AR, cellcycle genes, MYC, and TP53 genes, said Joshi Alumkal, MD, the Leader of theProstate/Genitourinary Medical Oncology Section and Associate Division Chieffor Basic Research in the Hematology-Oncology Division at the University ofMichigan School of Medicine.

Severalrandomized phase 3 clinical trials now show a benefit of escalating treatmentin men with mHSPC by adding novel AR-targeting agents or chemotherapy plusmedical castration versus medical castration alone, Dr Alumkal said. Whetherthe addition of any of these specific agents to medical castration isassociated with improved outcomes in patients with poor-risk molecularalterations identified by the new study is a critical next question, he said.

Urologiconcologist James Mohler, MD, Senior Vice President for Translational Researchat Roswell Park Comprehensive Cancer Center in Buffalo, New York, said the new study found relativelysmall differences among the clinical phenotypes, but that is not surprisingbecause the temporal differences in the evolution of tumor biology occur overlong periods of time, much of which precedes clinical presentation. The hazardratios for association between mutational analysis and oncologic outcome insome cases were statistically significant, but are so small as to not beclinically significant. Part of the reason for this may be that prostatecancer, once metastatic, is so complex that no single mutation or single genepathway is driving growth and hence targetable at a high rate beyond the long provenbenefit from androgen deprivation therapy, Dr Mohler said.

Theresults reported by these authors may be disappointing to many clinicians, butare important because they represent a comprehensive analysis of mCSPC. Theauthors appropriately acknowledge that better tumor sampling and morecomprehensive genetic analysis and larger numbers of patients may be requiredto find any benefit to genomic or somatic sequencing, Dr Mohler said. I amafraid that these limitations are not just of their work but a biologicallimitation of aggressive prostate cancer, which makes improving treatment ofadvanced prostate cancer in an individual patient extremely challenging.

Reference

Stopsack KH, Nandakumar S, Wibmer AG, et al. Oncogenic genomic alterations, clinical phenotypes, and outcomes in metastatic castration-sensitive prostate cancer [published online March 27, 2020]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-20-0168

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Genomic Alterations Linked to Outcomes in mCSPC - Renal and Urology News

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The repertoire of therapeutic options has improved drasticallyover the past few decades. Some of these options are remarkable, innovative, andat the frontiers of science, such as chimeric antigen receptor (CAR) T-cells forblood cancer.

But despite vast efforts to develop new therapeutics, some diseases remain, at least for now, undruggable. This mainly applies to rare diseases such as genetic disorders, but also to those that are more common and complex, including neurological disorders like Alzheimers as well as solid tumors. Another major issue for cancer is the resistance to targeted therapies and relapses, demanding the urgent development of new drugs.

In these contexts where there is a lack of therapeuticoptions, a new class of therapeutics has emerged: antisense oligonucleotides (ASOs).

ASOs are short sequences of chemically modified oligonucleotides that have the capacity to enter the cellular compartment and bind specifically to RNA transcripts. Sequence complementarity with their target RNA warrants high specificity. The versatility of ASO functioning according to their modality of interaction with their target RNA constitute promising strategies for numerous pathologies.

In a recent article published in WIREs RNA, researchers show the span of possibilities offered by ASOs as a potential solution to this therapeutic dead-end. Virtually, ASOs bind specifically to their cognate RNA target and act as an eraser to correct a disorder.

To improve the ASO therapeutic index, key chemical modifications of the ASO backbone/structure have already been made to increase ASO stability, bioavailability, and tissue specificity, and to reduce toxicity. But further optimizations are still needed to raise the therapeutic index even more.

The working principle of ASOs is based on the mechanisms of RNA interference discovered a few years ago. The idea was to recapitulate miRNA-induced mRNA decay. ASOs can be designed to target any mRNA in order to reduce its quantity in this way, they mimic endogenous miRNA. By using different chemical modifications, it is possible to extend their mode of action to non-degradation activity.

ASOs can thus act as stearic blockers to correct or force splicing, obstruct mRNA degradation by miRNA, or release sequestered protein. The versatility of their mode of action makes ASO a very promising option for many diseases. Numerous molecules are already FDA- and/or EMA-approved and many more are currently being tested in clinical trials.

ASOs are not only a so-called targeted therapy, acting only in cells expressing the target RNA. They may constitute one of the most advanced strategies in personalized medicine. The flexibility of their design offers the possibility to target any alteration in a given cell of a single patient.

This flexibility has been demonstrated recently. Milasen, an FDA-approved molecule, was designed for a single young girl with a rare neurological disorder caused by a never-before-seen genetic mutation. This case was a real revolution for drug development and orphan diseases.

ASOs open a new avenue of personalized medicine and could potentially revolutionize practice medicine. The time has come for researchers, clinicians, and companies to use the blackboard approach to design ASOs by hand to cure their favorite disorders.

Article written byAnas M. Quemener and Marie-Dominique Galibert

Reference: A.M. Quemener et al. The powerful world of antisense oligonucleotides: From bench to bedside. WIREs RNA (2020). DOI: 10.1002/wrna.1594

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Targeting the untargetable and treating the untreatable - Advanced Science News

Newswise Researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) have uncovered a genetic variant in a gene called MET that is responsible for more aggressive growth of head and neck, and lung cancers. A further probe into the finding revealed therapeutic strategies that could potentially target this genetic alteration, thereby paving the way for clinicians to develop better and more effective treatments for cancer patients of such profile.

The study, published in prestigious scientific journal Nature Communications on 25 March 2020, was conducted in close collaboration with clinicians from the National University Cancer Institute, as well as researchers from the National Cancer Centre Singapore and the Bioinformatics Institute at the Agency for Science, Technology and Research, Singapore.

The MET gene encodes for a cancer promoting protein that relays growth, survival and transmission of signals in cancer cells. In the study led by Professor Goh Boon Cher and Dr Kong Li Ren from CSI Singapore, the team of researchers identified a form of MET protein, which showed ethnic preference with higher incidence among Asians, and is associated with poorer prognosis in patients diagnosed with head and neck squamous cell carcinoma or lung squamous cell carcinoma. Even though the MET variant does not seem to predispose an individual to cancer, it leads to more aggressive growth of cancers that have already developed.

Unlike other MET mutants, this genetic variant also does not appear to be inhibited by existing MET-blocking drugs that have been developed and approved in the clinical setting, prompting the researchers to conduct further investigation on the mechanism behind the genetic alteration.

Leveraging the research teams multi-disciplinary expertise and state-of-the-art molecular modelling, the team found that the single amino-acid change in the MET receptor from the genetic alternation leads to preferential strong binding to another cancer promoting protein, HER2. Both proteins then work cooperatively to drive cancer aggression and enable cancer cells to survive therapies involving MET-blocking drugs.

The mechanism of this MET variant is novel and unreported. This finding contributes to the growing evidence of the role of genetic variants in affecting clinical outcome, and underscores the importance of diving deep into our genetic inheritance in cancer research, said Dr Kong, Research Fellow at CSI Singapore who initiated the study.

Knowledge of this unique mechanism also facilitated the team in identifying several HER2 inhibitors capable of blocking cancer progression caused by this genetic alteration using laboratory models.

Prof Goh, Deputy Director and Senior Principal Investigator at CSI Singapore, said, Our study represents a conceptual advancement to cancer research, as we have shown that it is possible to block the activity of a cancer-driving gene by administrating a targeted therapy directed not against the mutant protein in question, but rather, a corresponding protein with which it binds to. The remarkable anti-tumour responses observed in our experimental models, coupled with the availability of FDA-approved HER2 inhibitors also presents a huge opportunity for clinicians to improve disease outcome of this genetic alteration via precision medicine.

The research team is now translating the findings to a clinical trial where patients tested positive for this MET variant gene are treated with suitable medications that have shown effectiveness in the laboratory.

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NUS researchers uncover hereditary mutation that drives aggressive head and neck, and lung cancers in Asian population - Newswise