Category Archives: Genetic Therapy

Double dose: Mice with mutations in both copies of SHANK3 have more behavioral differences than animals with mutations in one copy of the gene.

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Correcting a mutation in the autism gene SHANK3 in fetal mice lessens some autism-like behaviors after birth, according to a new study1. The work adds to evidence that gene therapy may help some people with SHANK3 mutations.

In people, mutations in SHANK3 can lead to Phelan-McDermid syndrome, a condition that causes developmental delays and often autism. Up to 2 percent of people with autism have a mutation in SHANK32.

Our findings imply that early genetic correction of SHANK3 has the potential to provide therapeutic benefit for patients, lead investigator Craig Powell, professor of neurobiology at the University of Alabama at Birmingham, wrote in an email.

A 2016 study showed that correcting mutations in SHANK3 in both young and adult mice can decrease excessive grooming, which is thought to correspond to repetitive behaviors in people with autism.

Last year, Powell and his team also showed that correcting SHANK3 mutations in adult mice eliminates some autism-like behaviors3. But the results were difficult to interpret. The team reversed the mutation using an enzyme called Cre-recombinase that could edit SHANK3 if the animals were given a drug called tamoxifen. Control mice in that study that did not receive tamoxifen but had the gene for Cre still showed behavior changes, raising the possibility that the enzyme affected their brains.

In the new work, Powells team used a different approach. They engineered mice with a mutation in both or only one copy of SHANK3 the latter more closely mirrors what happens in people. Some animals had the Cre gene, but some also had another gene for a Cre-activating protein that is naturally expressed when the animals are in utero. By using this protein, the researchers could avoid using tamoxifen, which some studies have shown may also cause behavioral changes in mice4.

The control mice had either the gene for Cre-recombinase or fortheCre-activating protein, but not both, allowing the researchers to isolate any effects from the method itself.

They found that correcting the mutation lowers some but not all of the animals autism-like behaviors, a finding Powell says is surprising. The mice groom less and are more social by some measures, but they still prefer interacting with an object than with another mouse.

We dont really know why some behaviors are affected and not others, Powell says.

Mice with one mutated copy of SHANK3 have fewer behavioral differences than mice with two, they also found, which indicates the value of using both kinds of animals in gene-reversal studies, experts say.

The fact that they did analyze both side by side, and they did see some differences, I find quite intriguing, says Gaia Novarino, professor of neuroscience at the Institute of Science and Technology in Klosterneuburg, Austria.

The team originally planned to consider when and where in the brain SHANK3 was corrected. But the Cre-activating protein involved in the study was expressed throughout the brain, preventing region-specific findings.

The team gave some mice the antibiotic doxycycline to suppress Cre expression, in hopes of also testing the effects of correcting SHANK3 in adulthood. But the method failed, for unknown reasons.

It is also important to publish experiments that do not work out exactly as planned, Powell says.

The teams openness about the studys shortcomings could help others design their own studies or re-evaluate previous work, says Yong-Hui Jiang, chief of medical genetics at Yale University.

People will learn from the difficulties and the experience, Jiang says.

It would still be helpful to test whether correcting SHANK3 mutations can reverse autism-like behaviors in adult mice without using tamoxifen, other researchers say.

Its beneficial to do experiments in such a way where you leave very little room for alternative interpretations, says Gavin Rumbaugh, professor of neuroscience at the Scripps Research Institute in Jupiter, Florida. He suggests using a mouse that does not express Cre until the animal is administered doxycycline, rather than trying to suppress Cre with the drug.

The work lends credence to the idea that gene therapy might alleviate some difficulties associated with autism in people with SHANK3 mutations, researchers say. Further studies could also investigate in how many cells the gene needs to be restored to change behavior, and what would be the safest and most effective stage of development to intervene with a gene therapy.

The impression is you have a quite large window, Novarino says. Thats quite positive.

More:
Reversing SHANK3 mutations in mice mitigates autism-like traits - Spectrum

The frequency with whichspinal muscular atrophy (SMA) is found in newborns may be lower than previously thought, according to one-year data from an SMA screening program in the state of New York.

Based on expected disease frequency, the program anticipated that 20 to 38 of the more than 225,000 newborns screened would have tested positive for the neuromuscular disease, but only eight babies were identified as having SMA.

Results from other state screening programs underway will help to better assess SMAs actual frequency in the U.S., the researchers said.

The study, Implementation of population-based newborn screening reveals low incidence of spinal muscular atrophy, was published in the journal Nature: Genetics in Medicine.

Spinal muscular atrophy is the most common genetic cause of death in infants and children, with an estimated frequency of between 1 in every 6,000 and 1 in every 11,000 births.

In most cases (95%98% of all incidences), it is caused by the complete loss of exon 7 in theSMN1gene, which affects the production of SMN, a protein essential for muscle health. Exons are the sections of a gene that contain instructions for protein production.

The existence of a secondSMNgene, calledSMN2, partly compensates for the loss ofSMN1-produced SMN.Typically, the moreSMN2genecopies a person has, the less severe the disease.

SMA is inherited in anautosomal recessivemanner, meaning a child must acquire two mutated copies of theSMN1 gene one from the father and one from the mother to develop the disease. People with only one defectiveSMN1 copy will not have this disease but will be carriers, meaning they can pass the mutation to their children.

Given the approval of a first SMA treatment Spinraza, by Biogen in late 2016, the findings of a pilot SMA newborn screening study in New York state, and the importance of early detection and treatment in preventing lifelong disability, SMA was added to theU.S. Recommended Uniform Screening Panel(RUSP) for newborns in 2018.

As of March, 19 states were screening all newborns for SMA, and others either had legislation pending or were running pilot screening programs. To date, none of these states have reported on SMA frequency based on their screening programs.

Newborns are screened for SMA via a genetic test that checks for the absence of exon 7 in both SMN1 copies. In some states, such as New York, the program also includes assessingSMN2 copy number in infants screening positive for SMA.

Researchers looked at data from Oct. 1, 2018, through Sept. 30, 2019 the first full year of the New York states SMA newborn screening program.

Of the 225,093 infants screened, eight carried exon 7 deletions in both copies of SMN1. Three of these babies had two copies of SMN2 (likely to develop SMA type 1, a severe form), three had three copies (likely to develop type 2 or 3 disease), and two had at least four copies (likely to develop SMA type 3 or 4).

All infants were asymptomatic at diagnosis, and seven were treated with Zolgensma (byAveXis,a subsidiary of Novartis) an SMA gene therapy approved in May 2019 including two babies (with two and three SMN2 copies) initially treated with Spinraza.

All continued to show no symptoms of the disease at a last follow-up (ranging from two to 12 months). Oneinfant with at least four SMN2 copies was not treated, and is being carefully monitored long-term for signs predictive of disease onset, the researchers wrote.

None of the parents had reported knowing of a family history of SMA.

The team noted that, based on current SMA incidence estimates, 20 to 38 newborns were expected to screen positive for SMA among newborns in New York, a number far above the eight positive infants found.

The New York program had an SMA frequency of 1 in 28,137 births (range of 1 in every 14,259 to 55,525 births), which was between 2.6 and 4.7 times lower than expected (1 in 6,000 to 11,000 births).

Including data collected through the end of February 15 positive cases among some 314,000 newborns screened the resulting frequency was still low, about 1 in 21,000 births, the team noted.

This low SMA frequency, it added, cannot be solely attributed to the 2%5% of SMA patients missed by newborn screening, due to other SMA-causing mutations than exon 7 deletion.

Instead, this discrepancy is likely due to imprecise or biased estimates (most are based on small European populations that may not be representative of the U.S. population), as well as better informed reproductive decisions such as increased awareness, access to and uptake of carrier screening, genetic counseling, cascade testing, prenatal diagnosis, and advanced reproductive technologies, the researchers wrote.

Longer-term data from this and other screening programs will shed light on the true incidence of SMA in the U.S., they added.

They also recommended strongly that screening programs continue, and expand across states.

SMA newborn screening ensures equity in diagnosis of a common genetic condition in infants, such that affected children of families who cannot or choose not to undergo carrier screening are universally afforded the same benefit of new, life-saving treatments that are most effective when identified prior to symptom onset, the researchers wrote.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.

Total Posts: 85

Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.

Excerpt from:
SMA Less Common Than Expected Among Newborns Screened in NY - SMA News Today

Gene therapy is an experimental treatment that involves introducing genetic material into a persons cells to fight or prevent disease. Researchers are studying gene therapy for a number of diseases, such as severe combined immuno-deficiencies, hemophilia, Parkinsons disease, cancer and even HIV, through a number of different approaches. A gene can be delivered to a cell using a carrier known as a vector. The most common types of vectors used in gene therapy are viruses.

Scope of the Report:This report focuses on the Gene Therapy in global market, especially in North America, Europe, Asia-Pacific, South America, Middle East and Africa. This report categorizes the market based on manufacturers, regions, types and applications.

The report has been compiled through extensive primary research (through interviews, surveys, and observations of seasoned analysts) and secondary research (which entails reputable paid sources, trade journals, and industry body databases). The report also features a complete qualitative and quantitative assessment by analyzing data gathered from industry analysts and market participants across key points within the industrys value chain.

No. Of Pages 130

Report Covers Market Segment by Manufacturers:

Bluebird BioSangamoSpark TherapeuticsDimension TherapeuticsAvalanche BioCelladonVical Inc.Advantagene

Market Segment by Type, covers:

Ex vivoIn Vivo

Market Segment by Applications, can be divided into:

CancerMonogenicInfectious diseaseCardiovascular diseaseOther

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There are 15 Chapters to deeply display the global Gene Therapy market.

Chapter 1: Describe Gene Therapy Introduction, product scope, market overview, market opportunities, market risk, market driving force.

Chapter 13, 14 and 15: Describe Gene Therapy sales channel, distributors, traders, dealers, appendix and data source.

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Gene Therapy Market 2020 Industry Size, Regions,Trends and Top Manufacturers Bluebird Bio, Sangamo, Spark Therapeutics, Dimension Therapeutics,...

Five years ago, as much of pharma began leaving neuroscience, three big-name scientists from Genentech and some A-list investors, including ARCH and Flagship, made a $217 million bet that new genetic insights and a reliance on biomarkers could bring them success. They called it Denali Therapeutics.

Still, Denali faced the problem that neuroscience developers have faced for decades: How do you get a large molecule across the blood-brain barrier, a natural defense evolved precisely to keep them out? Enzyme replacement therapy, for instance, would be a great candidate to treat several neurological disorders, but enzymes cant cross the barrier.

Now, Denali thinks theyve solved the problem, or at least part of it. In a pair of papers published inScience Translational Medicine,the South San Francisco biotech detailed the invention of a new transport vehicle to sneak large molecules past the brains gates. So far, its been used in mice and monkeys, but they wont wait long to bring it to patients: A clinical trial using it to replace an enzyme lost in people with Hunters syndrome is set to begin this year, with proof-of-concept data expected to come before 2021.

The blood-brain barrier consists in part of tightly packed endothelial cells. Since certain molecules, such as insulin, cross the barrier by first binding to receptors on these cells and then being allowed through, scientists have long tried to build antibodies that can similarly bind to these receptors and shuttle across a therapeutic cargo. But the results, over several decades, have been less than transformative.

CEO and founder Ryan Watts has been part of that search since his Genentech days. The research method he and Denalis scientists came up with began with a process called directed evolution in which a protein is induced to mutate repeatedly, until it gives rise to a protein with the qualities you want to build a protein, called an FC fragment, that binds to whats called a transferrin receptor, a node that normally imports iron into the brain. In theory, there are numerous drugs one could then hook onto that Fc fragment, but Denali first tested it with an antibody-targeting enzyme called beta-secretase. The enzyme is linked to the build-up of amyloid plaques in people with Alzheimers, and the researchers showed their vehicle reduced the amount of amyloid in mice and monkeys.

In a second study, the researchers attached an enzyme called iduronate-2-sulfatase, the critical protein that people with Hunters syndrome are missing. Without it, sugars called glycosaminoglycans build up in cells, causing abnormalities in several different organs. Shire gained approval for an enzyme replacement therapy in 2006, but it only works outside the brain (the companys erstwhile efforts to improve cognitive function yielded little promise). Using the transport vehicle, though, Denali was able to get significantly increased brain penetration of the enzyme and reduce the pathology in mice and monkeys.

Denali played up the potential versatility of their approach over other blood-brain-barrier-crossing proposals, such as bispecific antibodies, saying you can attach a greater range of therapies to their vehicle. The company has over a dozen programs including a Parkinsons one now in the clinic but the first test of the vehicle will be later this year, in 16 kids with a rare disease whose worst symptoms remain untreated.

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Denali unveils new way of crossing blood brain barrier as the big neuroscience bet enters its clinical years - Endpoints News

Its reasonableto assume immunotherapies such as PD-1 inhibitors, which unleashthe bodys own immune system to target and destroy cancer, work best in hot tumors that are flooded with immune cells in their microenvironment. But a new study by scientists at the Dana-Farber Cancer Institute found that is not the case in kidney cancer.

The researchers discovered that in advanced clear cell renal cell carcinoma (ccRCC)the most common form of kidney cancertumors that were infiltrated with large numbers of CD8 T cells were less likely to respond to Bristol Myers Squibbs PD-1 inhibitor Opdivo than cold tumors were.

The findings, presented at the American Society of Clinical Oncology virtual event and published in Nature Medicine, provide critical insights that may help predict which patients are more likely to benefit from immuno-oncology agents, the researchers argued.

The Dana-Faber scientists examined 592 tumors collected from three Opdivo kidney cancer clinical trials in an attempt to draw a correlation between patient outcomes and immune and genomic biomarkers. They discovered that kidney cancer deviates from several well-known tenets of cancer treatment. Normally, tumors containing a large number of neoantigensproteins formed as a result of tumor mutations and therefore new to the immune systemare often more susceptible to immunotherapy. But that didnt affect ccRCC responsiveness to Opdivo, the team found.

Perhaps most surprisingly, hot tumors with high levels of CD8 T cells didnt respond well to Opdivo, either. But why?

The researchers found that these hot tumors were depleted of mutated PBRM1 genes, which are often associated with improved survival from PD-1 blockade. Instead, they had more of an unfavorable genetic featurethe loss of a chromosomal segment called 9p21.3. When found within hot tumors, deletion of 9p21.3 was associated with worse clinical benefit and survival after PD-1 treatment.

We believe that these two factors may explain why CD8 T cell infiltration of the tumors did not make them responsive to checkpoint blocker therapy, while other types of cancer that exhibited CD8 T cell infiltration but did not have those chromosomal changes did respond, explained co-authorSachet Shukla, Ph.D., chief of the computational group at the Dana-Farber Translational Immunogenomics Laboratory,in a statement.

RELATED:Could the anti-cancer gene p53 be a target in treating kidney cancer?

The Dana-Farber study offers clues to mechanisms that contribute to response and resistance to PD-1 drugs in ccRCC and possibly other types of tumors as well, the researchers suggested. It can help identify patients most suitable for these immuno-oncology drugs and provide fundamental information to aid in development of rational combination therapies to overcome resistance in the future, said study co-author Toni Choueiri, M.D., director of the Lank Center for Genitourinary Oncology at Dana-Farber.

The presence of high numbers oftumor-infiltrating immune cells isoften linked to better immunotherapy treatment outcomes. Thats why scientists are constantly looking for ways to turn coldtumors hot. In October, a Yale University team described a method for using gene-editing system CRISPR to make tough-to-spot tumors more visible to the immune system.

Another approach aimed at improving immuno-oncology in kidney cancer involves combining immune-boosting treatments. A combo of BMS' Yervoy with Opdivo was approved for first-line treatment of kidney cancer in 2018. In February of this year, the company unveiled new data showing 56% of patients taking the combo in a trial were still alive at 42 months, versus 47% of patients taking Pfizer's Sutent alone.

See more here:
Why 'hot' kidney tumors don't respond to immunotherapy with PD-1 blockers - FierceBiotech

Others at the center, which coordinates research at eight universities, are reviewing past work on drugs that showed potential against the SARS epidemic in 2002 and the MERS outbreak in 2012. Both diseases are also caused by coronaviruses.

At some point, though, scientists at the center and across the country will need to focus on future threats and break new ground.

You can make a lot of movement fast, based on what you know, Satchell said. But at some point, you hit a wall where you have to discover new things.

Andy Mesecar needs a weekend off.

An expert in biochemistry and gene therapy, hes worked seven-day weeks for the last few months, racing to find a drug for patients with COVID-19 while teaching at Purdue University and submitting daily reports to the National Institutes of Health. The center at Northwestern has funded his work since 2018.

Mesecar has a manuscript under review in a scientific journal on how a drug approved to treat hepatitis C could be modified to potentially treat COVID-19. His lab is one of the leading centers studying coronaviruses, and he and his team have dedicated nearly two decades to the research. But that was still not enough to rapidly create an effective therapy specific to COVID-19.

With a background in biochemistry and structural biology, Mesecar started out as an assistant professor at the University of Chicago, studying enzymes that could fight cancer. He got into infectious diseases after the anthrax attacks in the weeks after 9/11. Then, he pivoted to studying enzymes that could be used against SARS when it surfaced in November 2002.

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Everything we did was to predict the next outbreak. Yet scientists werent prepared for COVID-19. Why? - Longview Daily News