Category Archives: Gene Medicine

A team at the Case Western Reserve University has been awarded up to $3.7 million from the National Heart, Lung, and Blood Institute (NHLBI) to conduct early studies of emerging gene therapies for sickle cell disease (SCD).

Led by Umut Gurkan,PhD, the team will examine blood samples collected from SCD patients before and after they receive gene therapies, and test them for improvements in red blood cells.

These potential gene therapies work by modifying a patients own hematopoietic stem cells, which generate red and other blood cells. Then, the modified stem cells are given back to the patient via a bone marrow transplant, which overcomes the difficulty in finding matched donors in those with SCD.

Patients will receive the therapies over the next two years as part of clinical trials conducted at leading U.S research universities and hospitals, includingStanford University, the University of California San Francisco, Emory University, the University of North Carolina, and Albert Einstein College of Medicine.

The overall goal is to make genetic therapies for SCD available within five to 10 years.

The big-picture potential here is to test whether this is dream or reality when it comes to gene therapy curing sickle cell, Gurkan said in a press release. We dont know the answers yet, but we have to ask whether these gene therapies are safe and effective in alleviating the symptoms and curing the disease and if we have the right tools.

Due to a mutation in the HBBgene, red blood cells of SCD patients acquire an abnormal and more rigid shape, while also becoming stickier than normal. This contributes to the formation of clogs that prevent or slow blood flow in small vessels, depriving tissues of oxygen.

Using a kind of lab-on-a-chip approach, researchers essentially mirror the tiny capillaries of the human body, which allows them to investigate how red blood cells move in these engineered capillaries.

The Case team will investigate if the gene therapies improve blood flow and test for improvements in red blood cell stickiness, as well as density, and shape.

If a curative therapy is successful and effective, we should see a significant improvement in these vital properties of blood, Gurkan said. Essentially we would like to objectively and quantitatively assess how well the blood cells flow in tiny capillaries after a gene-based therapy.

According to Gurkan, Case University has been playing an important role in the development of these new blood tests, which could help identify patients who respond to a given therapy early on.

As the genetic cure for sickle cell becomes a clinical reality, longitudinal, simple and accurate assessment and control through the tests that Dr. Gurkan has developed becomes ideal and opens up this new treatment to patients across the world, said Stanton Gerson, MD, director of the Case Comprehensive Cancer Center.

Our team is committed to making these new blood tests available for translation on global scale in both high- and low-resource settings, Gurkan said.

The work at Case will be conducted in collaboration with researchers at multiple other institutions, which, in addition to the centers conducting the clinical studies, include University Hospitals Rainbow Babies and Childrens Hospital, Childrens Healthcare of Atlanta, and Childrens Hospital of Montefiore.

Success in SCD could pave the way for similar benefits in other genetic diseases, which is the goal of the National Institutes of Health (NIH).

The reason the NIH is so focused on curing SCD is that it is the poster child for gene-editing efforts, said Gurkan. If we can prove that we can cure an inherited mutation like SCD effectively and safely, then you convince the funders and the public that it is worth the expense and the effort to go after more complex inherited diseases which are less understood.

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Case Researchers Awarded $3.7 Million to Test Emerging SCD Gene... - Sickle Cell Anemia News

Induced pluripotent stem cells made to produce insulin and CRISPR, used to correct a genetic defect, cured Wolfram syndrome in mice.

Using induced pluripotent stem cells (iPSCs) produced from the skin of a patient with a rare, genetic form of insulin-dependent diabetes called Wolfram syndrome, researchers transformed the human stem cells into insulin-producing cells and used CRISPR-Cas9 to correct a genetic defect that had caused the syndrome. They then implanted the cells into lab mice and cured the unrelenting diabetes in those models.

The findings, from researchers at Washington University School of Medicine in St. Louis, US, suggest this CRISPR-Cas9 technique may hold promise as a treatment for diabetes, particularly the forms caused by a single gene mutation and it also may be useful one day in some patients with the more common forms of diabetes, such as type 1 and type 2.

This is the first time CRISPR has been used to fix a patients diabetes-causing genetic defect and successfully reverse diabetes, said co-senior investigator Dr Jeffrey Millman, an assistant professor of medicine and of biomedical engineering at Washington University. For this study, we used cells from a patient with Wolfram syndrome because, conceptually, we knew it would be easier to correct a defect caused by a single gene. But we see this as a stepping stone toward applying gene therapy to a broader population of patients with diabetes.

Wolfram syndrome is caused by mutations to a single gene, providing the researchers an opportunity to determine whether combining stem cell technology with CRISPR to correct the genetic error also might correct the diabetes caused by the mutation.

Researchers at Washington University School of Medicine in St. Louis have transformed stem cells into insulin-producing cells. They used the CRISPR gene-editing tool to correct a defect that caused a form of diabetes, and implanted the cells into mice to reverse diabetes in the animals. Shown is a microscopic image of insulin-secreting beta cells (insulin is green) that were made from stem cells produced from the skin of a patient with Wolfram syndrome [credit: Millman lab Washington University].

Millman and his colleagues had previously discovered how to convert human stem cells into pancreatic beta cells. When such cells encounter blood sugar, they secrete insulin. Recently, these researchers developed a new technique to more efficiently convert human stem cells into beta cells that are considerably better at controlling blood sugar.

In this study, they took the additional steps of deriving these cells from patients and using the CRISPR-Cas9 gene-editing tool on those cells to correct a mutation to the gene that causes Wolfram syndrome (WFS1). Then, the researchers compared the gene-edited cells to insulin-secreting beta cells from the same batch of stem cells that had not undergone editing with CRISPR.

In the test tube and in mice with a severe form of diabetes, the newly grown beta cells that were edited with CRISPR more efficiently secreted insulin in response to glucose. Diabetes disappeared in mice with the CRISPR-edited cells implanted beneath the skin and the animals blood sugar levels remained in normal range for the entire six months they were monitored. Animals receiving unedited beta cells remained diabetic. Although their newly implanted beta cells could produce insulin, it was not enough to reverse their diabetes.

We basically were able to use these cells to cure the problem, making normal beta cells by correcting this mutation, said co-senior investigator Dr Fumihiko Urano, the Samuel E. Schechter Professor of Medicine and a professor of pathology and immunology. Its a proof of concept demonstrating that correcting gene defects that cause or contribute to diabetes in this case, in the Wolfram syndrome gene we can make beta cells that more effectively control blood sugar. Its also possible that by correcting the genetic defects in these cells, we may correct other problems Wolfram syndrome patients experience, such as visual impairment and neurodegeneration.

Were excited about the fact that we were able to combine these two technologies growing beta cells from induced pluripotent stem cells and using CRISPR to correct genetic defects, Millman said. In fact, we found that corrected beta cells were indistinguishable from beta cells made from the stem cells of healthy people without diabetes.

Moving forward, the process of making beta cells from stem cells should get easier, the researchers said. For example, the scientists have developed less intrusive methods, making iPSCs from blood and they are working on developing stem cells from urine samples.

The study is published in Science Translational Medicine.

Read this article:
Induced pluripotent stem cells and CRISPR reversed diabetes in mice - Drug Target Review

Global Gene Therapy for Inherited Genetic Disorders Market: Overview

Rapid advances in mammalian DNA sequencing technologies over the past several years have enabled the identification of the aberrant genes responsible for a vast spectrum of genetic disorders. Gene therapy as a novel approach inarguably holds profound potential in finding universal therapeutic alternatives to treating inherited genetic disorders. Gene therapy for inherited genetic disorders entails introducing a functional copy of the defective gene to make up for the missing function, and can be accomplished using in vivo or ex vivo gene transfer.

Gene therapy for inherited genetic disorders has generated groundswell of interest in the research fraternity in finding cure for or in treatment of Mendelian genetic error causing rare diseases. Particularly, gene therapy in recent years has held promising potential in the treatment of a range of recessive gene disorders most notably sickle cell anemia, hemophilia, muscular dystrophy, cystic fibrosis, and other monogenic disorders. The axes of developments in the gene therapy for inherited genetic disorders market have been in the U.S., Europe, China, and Australia.

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Global Gene Therapy for Inherited Genetic Disorders Market: Notable Developments

Growing body of clinical studies done on mice models have unrivalled troves of preclinical data, which bodes well for the effectiveness of gene therapy for inherited genetic disorders. New approaches in the gene therapy for inherited genetic disorders market are being adopted to bring progress in this direction. In this regard, Salmeterol, a medicine approved for asthma, has shone a new light. The vasodilator to be used along with gene therapy has shown potential in increasing the effectiveness of the therapy for Glycogen storage disease type II (Pompe disease).

A team of investigator led by the researcher at Duke University Medical School discussed the preclinical data recently at 2019 annual meeting of the American Society of Gene & Cell Therapy. The preclinical data showed that the Asthma medicine reduces the accumulation of toxic glycogen accumulated in lysosome. The researchers concluded that it holds potential as an adjunctive therapy, and building on that may pave way for novel approaches on gene therapy for inherited genetic disorders.

Efforts to translate the findings of clinical research on gene therapy for inherited disorders to make the therapy a part of standard treatment has caught momentum in recent times. In this regard, vectors containing non-viral vectors have attracted the attention of scientists. A team of researchers at Fred Hutchinson Cancer Research Center in 2019 found that gold nanoparticles enable them to deliver gene-editing tools to blood stem cells in lab models. This might, they opined, pave way for more practicaland accessiblegene therapies for inherited disorders, notably for treating life-threatening blood disorders. Gene therapies were mediated by CRISPR. In the coming years they hope to collaborate with companies with commercial interest to develop the therapy for patient populations.

Some of the bigplayerseyeing promising stakes in the gene therapy for inherited genetic disorders market areSpark Therapeutics Inc., Orchard Therapeutics, Novartis AG, bluebird bio Inc., and BioMarin Pharmaceutical.

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Global Gene Therapy for Inherited Genetic Disorders Market: Key Drivers

Since 2000, scores of clinical trials involving patients with inherited genetic disorders have raised hopes of the medical fraternity of the potential of gene therapies. Thus far, more than 5000 clinical trials on gene therapy have been conducted, especially for hard-to-treat diseases. Diseases such as inherited blindness and leukemia have seen the efficacy and safety of gene therapies. Advances in bioengineering are expected to invigorate pre-clinical pipelines. In the not-so-distant future, success of more protocols will catalyze the prospects of the gene therapy for inherited genetic disorders market.

Further, advances have been made in viral and non-viral vectors with the purpose of making gene transfer more efficient, thereby boosting the gene therapy for inherited genetic disorders market. Particularly, new approaches emerged with the aim of making vectors more powerful.

Global Gene Therapy for Inherited Genetic Disorders Market: Regional Assessment

On the regional front, Asia Pacific bears considerable potential in the gene therapy for inherited disorders market. Of note, numerous strategic alliances have shifted their focus on the region, particularly China. The North America market has also been rising at a promising pace, driven by several gene-therapy tools and related drugs in the final stages of clinical trials. Favorable reimbursement models has also encouraged research into the gene therapy for inherited disorders.

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Gene Therapy for Inherited Genetic Disorders Market Key Companies and Analysis Top Trends by 2028 Cole Reports - Cole of Duty

Genetic variants that are unrelated to the IOP are associated with a family history of glaucoma and play a role in the onset of primary open-angle glaucoma (POAG). Genetic variants that are related to the IOP are associated with the age at which glaucoma is diagnosed and are associated with disease progression.

What is known about POAG, the most prevalent form of glaucoma, is that increased IOP and myopia are risk factors for damage to the optic nerve in POAG.

Related: Stent offers IOP stability more than three years after surgery

A family history of glaucoma is a major risk factor for development of POAG, in light of which, therefore, genetic factors are thought to be important in the disease pathogenesis and a few genes mutations have been identified as causing POAG, according to Fumihiko Mabuchi, MD, PhD, professor, Department of Ophthalmology, Faculty of Medicine, University of Yamanashi, Kofu, Japan.

Myopia has been shown to be a risk factor for POAG in several studies. However, it can be difficult to diagnose true POAG in myopic patients and controversy exists over whether it is real risk factor.

Myopic optic discs are notoriously difficult to assess, and myopic patients may have visual field defects unrelated to any glaucomatous process.

The prevalence of POAG increases with age, even after compensating for the association between age and IOP.

Related: Preservative-free tafluprost/timolol lowers IOP well, glaucoma study shows

Part of the storyDr. Mabuchi and his and colleagues, recounted that these factors are only part of the story.

According to Dr. Mabuchi and his colleagues, cases of POAG caused by these gene mutations account for several percent of all POAG cases, and most POAG is presumed to be a polygenic disease.

Recent genetic analyses, the investigators explained, have reported genetic variants that predispose patients to development of POAG and the additive effect of these variants on POAG, which are classified as two types.

The first genetics variants are associated with IOP elevation.

Related: Sustained-release implant offers long-term IOP control, preserved visual function

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Genetic variants linked with onset, progression of POAG - Ophthalmology Times

CLAIM

"this coronavirus genome contained sequences of another virus [] the HIV virus (AIDS virus)"

DETAILS

Inaccurate: Genomic analyses indicate that the virus has a natural origin, and was not engineered. The so-called unique protein sequence insertions found in the 2019 novel coronavirus can be found in many other organisms, not just HIV.

KEY TAKE AWAY

Genomic analyses of the novel coronavirus show that it was not engineered. In addition, the claim that its genome contains inserted HIV sequences is based on a now-withdrawn preprint of a study that contained significant flaws in design and execution. The so-called HIV insertions identified by the authors are in fact gene sequences that can also be found in many other organisms besides HIV.

REVIEW Numerous articles published in April 2020 report that Nobel laureate Luc Montagnier claimed that SARS-CoV-2 is a manipulated virus that was accidentally released from a laboratory in Wuhan, China and that Indian researchers have already tried to publish the results of the analyses that showed that this coronavirus genome contained sequences of another virus [] the HIV virus (AIDS virus). The claim that SARS-CoV-2 contains HIV insertions began circulating in January 2020, and was propagated by outlets such as Zero Hedge and Infowars. Health Feedback covered this claim in early February 2020, and found it to be inaccurate.

Firstly, genomic analysis of the novel coronavirus, published in Nature Medicine, has demonstrated that the virus is not the product of bioengineering, but is rather of natural origin[1]. The current most likely theory, based on what scientists know about viral evolution, is that the virus first emerged in pangolins or bats (or both) and later developed the ability to infect humans. This ability to infect human cells is conferred by the so-called spike (S) protein, which is located on the surface of the enveloping membrane of SARS-CoV-2.

After the 2003-2005 SARS outbreak, researchers identified a set of key amino acids within the S protein which give SARS-CoV-1 a super-affinity for the ACE2 target receptor located on the surface of human cells[2,3]. Surprisingly, the S protein of the current SARS-CoV-2 does not contain this optimal set of amino acids[1], yet is nonetheless able to bind ACE2 with a greater affinity than SARS-CoV-1[4]. This finding suggests that SARS-CoV-2 evolved independently and undermines the claim that it was manmade[1]. Indeed, the best engineering strategy would have been to harness the known and efficient amino acid sequences already described in SARS-CoV-1 order to produce a more optimal molecular design for SARS-CoV-2. The authors of the Nature Medicine study[1] concluded that Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus.

Secondly, the claim that SARS-CoV-2 contains HIV insertions is based on a preprint of a research study uploaded to bioRxiv on 2 February 2020. A preprint is a study in progress that has not been peer-reviewed by other scientists. The authors of the preprint, titled Uncanny similarity of unique inserts in the 2019-nCoV spike protein to HIV-1 gp120 and Gag, claimed to have found 4 insertions in the spike glycoprotein (S) which are unique to 2019-nCoV and are not present in other coronaviruses. The authors further asserted that all of [these inserts] have identity/similarity to amino acids residues in key structural proteins of HIV-1 [which] is unlikely to be fortuitous in nature.

The work was swiftly criticized by experts. In this Forbes article, Arinjay Banerjee, a postdoctoral fellow at McMaster University who has studied coronaviruses, said that:

The authors compared very short regions of proteins in the novel coronavirus and concluded that the small segments of proteins were similar to segments in HIV proteins. Comparing very short segments can often generate false positives and it is difficult to make these conclusions using small protein segments.

Researchers also took to Twitter to demonstrate this problem first-hand. Trevor Bedford, a faculty member at the Fred Hutchinson Cancer Research Center who studies viral evolution, re-analyzed the gene and protein sequences used by the authors and found that the so-called unique inserts appeared in many other organisms, including Cryptosporidium and Plasmodium malariae, which cause cryptosporidiosis and malaria, respectively.

Assistant professor at Stanford University Silvana Konermann also checked the authors findings and came to the same conclusion, calling the similarity spurious.

This has also been independently confirmed in another published analysis[5]. In other words, these sequences are not insertions, but are rather common sequences found in numerous other organisms such as bacteria and parasites. Therefore, the existence of these sequences in SARS-CoV-2 does not provide evidence of a link to HIV, nor that scientists purposely inserted HIV sequences into the SARS-CoV-2 genome.

In summary, genomic analysis of the virus indicates that it does not contain so-called HIV insertions and that it was not engineered in a lab. Evidence points to the virus having a natural origin.

The only thing accurate about these articles is that Nobel Prize winner and virologist Luc Montagnier did in fact make these claims. Although he holds impressive scientific credentials, his claims run contrary to credible scientific evidence. And despite having won the Nobel Prize in Physiology or Medicine in 2008 for his co-discovery of the link between HIV and AIDS, Montagnier now promotes widely discredited theories such as the pseudoscience of homeopathy and that autism is caused by bacteria that emit electromagnetic waves. Articles which repeat Montagniers claims without critically evaluating their veracity exhibit the common appeal to authority fallacy, in which something is assumed to be true simply because the person saying it is considered to be an expert, thereby misleading readers into believing that this theory is scientifically credible. This demonstrates the importance of verifying scientific claims with other experts in the same field, rather than simply taking such claims from a single expert at face value.

SCIENTISTS FEEDBACK [These comments come from an evaluation of a related claim.] Aaron T. Irving, Senior Research Fellow, Duke-NUS Medical School:Its easier to believe misinformation when it is mixed with truth. The region highlighted in the pre-print is indeed an insertion in nCoV-2019 relative to its bat ancestors and indeed it has high identity to the HIV gp120/gag. However, the authors chose to align only this small region and not do a basic check on whether there were other sequences which were also homologous (showing high degree of similarity/identity). As it turned out, the region is also homologous to many unrelated sequences. As such, the conclusions drawn from the data are no longer valid and there are many open-ended questions regarding this region highlighted. I see the authors themselves agree with this criticism by other scientists and have voluntarily withdrawn their preprint pending a much deeper investigation.

The author of this article by European Scientist also compared the genome sequences of SARS-CoV-2 and HIV using the Basic Local Alignment Search Tool (BLAST), developed by the U.S. National Institutes of Health, and found no significant similarity, explaining that In plain English, SARS-CoV-2 is not made of the bat coronavirus and small bits of the HIV virus. Readers who wish to verify the level of sequence identity between the two viruses for themselves are welcome to follow the steps listed in the article.

Read more:
Nobel laureate Luc Montagnier inaccurately claims that the novel coronavirus is man-made and contains genetic material from HIV - Health Feedback

Today, a new personalized cancer treatment was approved for NHS use in England.

But this was no ordinary drug approval. Larotrectinib (Vitrakvi) is a highly innovative new treatment that, unlike most cancer drugs, is designed to target specific changes in cancer cells DNA rather than where the cancer is growing in the body.

This means patients with various types of cancer may be able to benefit.

Its the first drug licensed in Europe that works in this way. And its been called revolutionary by the head of NHS England, Simon Stevens.

But drugs like larotrectinib also pose unique and complex challenges for the NHS, which have been exacerbated by the COVID-19 pandemic.

The latest decision

Larotrectinib was originally rejected for funding on the NHS in England back in January. Since then, the manufacturer and NHS England have negotiated a new price for the drug, which has made it possible for it to go into the Cancer Drugs Fund (CDF).

Because the drug is so innovative, its been more challenging than usual for NICE (the body that recommends whether the NHS should pay for new medicines in England) to answer key questions about how the treatment should be used and how effective it is.

This uncertainty is why the drug was initially rejected. Its taken a lot of work from all sidesthe NHS, NICE and the drugs manufacturerto overcome these challenges.

But now the drugs been approved for the Cancer Drugs Fund, the NHS will pay for it for a time-limited period, while more data is collectedincluding from NHS patientsto help resolve these questions. And if this data shows the drug is cost effective for the NHS, it will become available on a permanent basis.

Meindert Boysen, deputy chief executive and director of the Centre for Health Technology Evaluation at NICE, said: These cutting-edge therapies can be used to treat tumors with often rare genetic mutations regardless of where in the body the tumor originated.

The clinical evidence is usually based on extremely small sample sizes, requiring novel approaches to testing them in clinical trials and translation into models of assessment for potential value in NHS practice.

Drugs in the CDF are also usually made available to patients in Wales and Northern Ireland, through bespoke funding routes in those nations. Scotland has a separate system for appraising new drugs and larotrectinib hasnt been considered there yet.

Why it matters

Larotrectinib will be used to treat people whose tumors test positive for a particular genetic change, called an NTRK fusion, and who have run out of other treatment options.

This is hugely significant for these patients, but according to Professor Peter Johnson, national clinical director for cancer at NHS England, its also a great example of how the NHS can bring to bear its recent investment in genomic (genetic) testing in England to improve cancer treatment.

Johnson says work in this area has been building at a national level, ever since Cancer Research UK started our Stratified Medicine programme in 2010.

And while the NHS has offered genomic tests to help guide decisions on patients treatment for many years, NHS England has been working to coordinate and expand genomic testing services in seven hubs in England. This aims to make access to these tests more consistent across the country and help to speed up the introduction of new targeted drugs like larotrectinib in the future.

According to Johnson, whats come together are the development of the genomic laboratory hubs across England, and the first targeted drugs coming through from research that are effective across multiple tumor types. This is an exciting convergence of these two strands of work.

Testing challenges in rollout

But despite this convergence, there are still challenges to overcome before larotrectinib will be available to patients. And as weve previously explained, chief among these is making sure the NHS can test patients appropriately to see who might benefit from the drug.

The NHS intends to test up to 100,000 patients a year for this genetic change eventually. But its not in a position to make the test that widely available yet.

To balance this, its going to stagger the roll out of larotrectinib, beginning with people with rare cancers where the genetic change is most common, and children and young people.

According to NICE, between 600700 people in England have solid tumors with NTRK gene fusions. And a proportion of these people with no satisfactory treatment options will be eligible for treatment within the first year that its available on the CDF.

The impact of coronavirus

Rolling out a treatment like larotrectinib would be challenging at the best of times, but the COVID-19 pandemic makes things even more complicated and means it will take longer to scale up testing to the wider population.

Because of the crisis equipment and people have been diverted from Genomic Laboratory Hubs to support testing for coronavirus, says Johnson.

As soon as we can, we will introduce the capacity to continue rolling this out in a phased way to a much wider population of people for whom conventional treatment has not been successful.

And while the NHS is under a huge amount of strain with COVID-19, Johnson believes its vital that the NHS continues to assess and introduce new treatments.

We will get through the coronavirus crisis and are planning to put cancer services back on a firm footing in the future. Having new therapies coming through and the diagnostics to find out who could benefit is as important as it has ever been.

Provided byCancer Research UK

More:
What does the new personalized cancer medicine approved in England mean for patients?. - Brinkwire