Bioavailable diacylhydrazine ligands for modulating the expression of exogenous genes via an ecdysone receptor complex
Document Type and Number:
United States Patent 9255273
The present invention relates to non-steroidal ligands for use in nuclear receptor-based inducible gene expression system, and a method to modulate exogenous gene expression in which an ecdysone receptor complex comprising: a DNA binding domain; a ligand binding domain; a transactivation domain; and a ligand is contacted with a DNA construct comprising: the exogenous gene and a response element; wherein the exogenous gene is under the control of the response element and binding of the DNA binding domain to the response element in the presence of the ligand results in activation or suppression of the gene.
Hormann, Robert Eugene (Elkins Park, PA, US)
Potter, David W. (North Wales, PA, US)
Chortyk, Orestes (Thompson Station, TN, US)
Tice, Colin M. (Elkins Park, PA, US)
Carlson, Glenn Richard (North Wales, PA, US)
Meyer, Andrew (Maple Glen, PA, US)
Opie, Thomas R. (North Wales, PA, US)
Intrexon Corporation (Blacksburg, VA, US)
DETAILED DESCRIPTION OF THE INVENTION
Applicants' invention provides ligands for use with ecdysone receptor-based inducible gene expression system useful for modulating expression of a gene of interest in a host cell. In a particularly desirable embodiment, Applicants' invention provides an inducible gene expression system that has a reduced level of background gene expression and responds to submicromolar concentrations of non-steroidal ligand. Thus, Applicants' ligands and inducible gene expression system and its use in methods of modulating gene, expression in a host cell overcome the limitations of currently available inducible expression systems and provide the skilled artisan with an effective means to control gene expression.
The present invention is useful for applications such as gene therapy, large scale production of proteins and antibodies, cell-based high throughput screening assays, functional genomics, proteomics, metabolomics, and regulation of traits in transgenic organisms, where control of gene expression levels is desirable. An advantage of Applicants' invention is that it provides a means to regulate gene expression and to tailor expression levels to suit the user's requirements.
Polynucleotides encoding extracellular-signal-regulated kinase (ERK) heteropolyligand polypeptides
Document Type and Number:
United States Patent 9255125
The invention relates to kinase inhibitor ligands and polyligands. In particular, the invention relates to ligands and polyligands that modulate ERK activity. The ligands and polyligands are utilized as research tools or as therapeutics. The invention includes linkage of the ligands and polyligands to a cellular localization signal, epitope tag and/or a reporter. The invention also includes polynucleotides encoding the ligands and polyligands.
Reed, Thomas David (Arlington, VA, US)
Intrexon Corporation (Blacksburg, VA, US)
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to ligands and polyligands that are ERK modulators. Various embodiments of ligands and polyligands are represented in SEQ ID NOS:1-108. Polyligands are chimeric ligands comprising two or more monomeric polypeptide ligands. An example of a monomeric ligand is the polypeptide represented by SEQ ID NO:43, wherein Xaa is any amino acid. SEQ ID NO:43 is a selected subsequence of wild-type full length SEQ ID NO:11, wherein the amino acid corresponding to Xaa in the wild-type sequence is a serine or threonine phosphorylatable by ERK. Another example of a monomeric ligand is the polypeptide represented by SEQ ID NO:99. Another example of a monomeric ligand is the polypeptide represented by SEQ ID NO:94. Each of SEQ ID NOS:28-108 represents an individual polypeptide ligand in monomeric form, wherein Xaa is any amino acid. SEQ ID NOS:28-90 are selected examples of subsequences of SEQ ID NOS:9-27, however, other subsequences of SEQ ID NOS:9-27 containing a recognition motif may also be utilized as monomeric ligands. Monomeric ligand subsequences of SEQ ID NOS:9-27 may be wild-type subsequences. Additionally, monomeric ligand subsequences of SEQ ID NOS:9-27 may have the ERK phosphorylatable amino acids replaced by other amino acids. Furthermore, monomeric ligands and polyligands may have at least about 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to a ligand comprising an amino acid sequence in one or more of SEQ ID NOS:28-108. Furthermore, monomeric ligands and polyligands may have at least about 80%, 85%, 90%, 95%, 96%, 97%, 98% and 99% sequence identity to a subsequence of SEQ ID NOS:9-27.
Cellular Immunotherapy Summit at Yale Friday, March 18, 2016
10:10 – 10:45 Bench-to-bedside and back. How T-cell gene therapy has benefited
from a partnership between academia and industry.
Laurence Cooper (MD Anderson Cancer Center/ ZioPharm Oncology)
11:20 – 12:20 Panel Discussion: CAR T-cell therapies: New targets and
Panelists: Renier Brentjens, Marcela Maus, Laurence Cooper, Brian Till
4:10 – 5:05 Panel Discussion: Challenges in translation of immunocellular
therapies and technology transfer
Panelists: Amod Sarnaik, Catherine Bollard, Laurence Cooper, Renier
5 SEC filings yesterday for a total of 414,701 shares bought this quarter.
LIMA, Peru — Scientists are investigating the mysterious die-off of dozens of monkeys in Central America, including the possibility that they have contracted Zika or another virus that could be passed to humans.
In recent months, around 40 howler monkeys have been found dead or dying in the tropical rainforests of Nicaragua. The animals have all had relatively full stomachs and no obvious signs of trauma. Experts fear there may be many more cases that have not been reported to them.
“Wild animals die off all the time, but it is really unusual to see this many deaths in such a short time with no apparent reason,” Kim Williams-Guillen, a conservation PhD who has been researching in Nicaragua’s jungles since 1999, told GlobalPost. “I have never seen anything like it.”
“These deaths are worth investigating not just from a conservation standpoint but from a public health standpoint. It is very important we get to the bottom of this.”
More from GlobalPost: There's a chance Venezuela's Zika outbreak is worse than Brazil's
Primates are highly susceptible to mosquito-borne diseases, and outbreaks among them could be a precursor to the spread of disease among humans, although scientists are careful to warn that this leap remains rare.
Complicating the mystery is the fact that howler monkeys are immune to dengue but are highly vulnerable to yellow fever. Yet Nicaragua has been declared free of that disease for years.
What is less clear is how the primates will respond to Zika and chikungunya, both of which are related to yellow fever and have just arrived in the Western Hemisphere in the last couple of years.
Nicaragua has reported 29 cases of Zika so far. Meanwhile, chikungunya has infected more than 100,000 people across Central America since first arriving there in 2014.
Among the numerous unknowns is whether howler monkeys would even exhibit symptoms if they became infected with either virus.
“It is just not something that has been researched yet, how or whether they would affect primates,” adds Williams-Guillen, who is conservation director at Paso Pacifico, an environmental nonprofit working in Central America’s Pacific jungles.
More from GlobalPost: Why South American parents are hiding their kids from the sun
The group is now coordinating with scientists from the University of California, Davis, to come up with a definitive diagnosis for whatever it is that is killing off the monkeys.
In addition to the possibility of a virus, the researchers will also probe other factors that might be at work, including drought and other environmental variables.
The first challenge is to take hair, skin and other samples from a recently deceased animal and then transport it to Davis in mint condition.
Liliana Cortez Ortiz, a University of Michigan researcher and member of the International Primate Specialist Group of the International Union for the Conservation of Nature, said this kind of unexplained die-off of apparently healthy animals is unusual, but not unprecedented.
“Any instances in which primates are dying from unknown causes is potentially a concern for humans as well,” she added. “We simply don’t know why this is happening and we need to find out.”
Despite their cute appearance and size, typically weighing around 17 to 20 pounds, howler monkeys are actually the loudest land animals on the planet.
That’s because they have large, hard, hollow throats, which they use to project roars that can travel for miles across the jungle. To the untrained ear, they sound more like a big cat than a fluffy monkey.
But now that they are apparently suffering from a mystery disease, they also face a new threat, warns Cortez Ortiz: humans.
“Now that we know they are dying, it is possible that local people may become scared and take matters into their own hands, killing the monkeys deliberately out of fear,” she said.
“It is very important that they message gets out in Nicaragua that that is not the way to handle this, and these monkeys are not a danger to humans.”
May 16-18 2016 in San Diego
13:10 CAR-Engineered Cord Blood NK Cells as a Source of Off-The-Shelf Cellular Therapy
Professor, Department of Stem Cell Transplantation, MD Anderson
Natural killer cells play critical roles in host defense against cancer. Our group is exploring a number of avenues to enhance NK cell function against leukemia. These include:
Novel strategies to expand off-the-shelf cord blood derived NK cells based on their co-culture with genetically-modified leukemic cells that express membrane-bound cytokines and costimulatory moleculesEnsuring reliable expansion and activation of human CB NK cells and these have been implemented in a GMP-grade large-scale setting to support ongoing clinical trials of CB-NK adoptive therapyRedirecting NK cell specificity and enhancing their in vivo persistence, we have done this by successfully transduced expanded CB NK cells with chimeric receptors directed against CD19 (a molecule expressed on lymphoid malignant cells) linked to CD28 and CD3, and IL15 to enhance their in vivo persistence and survival following adoptive transferCAR.CD19.IL15 CB-NK cells exhibited enhanced anti-leukemic activity and in vivo persistence in a nod-SCID gamma null (NSG) mouse model of B lymphoid malignancy
11:40 Therapeutic Implications of Preparing and Administering Innate Immune Cells
CEO, ZIOPHARM Oncology
The immune system can be successfully generated ex vivo for in vivo applications. These laboratory processes encompass, activation, propagation, and genetic manipulation of the biologic product all in compliance with current good manufacturing practice (cGMP) for Phase I/II trials.There is now growing enthusiasm to harness natural killer (NK) cells and T cells expressing gamma/delta TCRs as killer cells for the investigational treatment of malignancyThese effectors belong to the innate immune system implying that the totality of their endogenous recognition events may be sufficient to directly and specifically target cancerous cells and to do so as third party products with implications for off-the-shelf (OTS) therapiesSuch OTS allogeneic cells may be manufactured in advance of patient need and infused on demandThese NK cells and gamma/delta TCR T cells may also serve as a template for genetic manipulation, such as to express CARs and/or TCRs to refine specificity, and to enhance potencyIn my presentation we will explore the therapeutic potential of these two populations of effector cells and how endogenous and genetically modified innate immune cells can be applied under cGMP as adoptive immunotherapy
A leading professor has warned microcephaly - the condition which has seen babies in Brazil born with small heads and damaged brains - may be the "tip of the iceberg" among birth defects linked to the Zika virus.
Albert Ko, an epidemiologist and infectious disease expert at Yale University, said babies born without the condition could suffer other neurological complications that are not necessarily as obvious.
He told the Washington Post that other brain related abnormalities had been linked to the Zika virus outbreak without firm evidence, but that he believes the disease is the probable cause of most.
He said researchers investigating cases of microcephaly in maternity hospitals in Salvador, Brazil, are seeing a "spectrum" of birth defects.
"Many have fairly severe central nervous system lesions," he said.
"There are also a lot of calcium deposits. Those can cause seizures and cause impairment in terms of function for the brain."
Dr Ko also said some of the babies brains are smooth, when they would normally have wrinkles, which suggests they have not developed fully.
A number of newborns also have visual and hearing impairments, he added.
"It seems like microcephaly may just be the tip of the iceberg," warned Dr Ko.
"The preliminary evidence is that [some] babies who don't have microcephaly may also have neurological lesions or birth defects that are not as obvious as microcephaly."
Speaking about how the virus is affecting pregnant women and families, Dr Ko said: "Obviously there's a large amount of fear, especially among pregnant women.
"For many people, the level of anxiety is extremely great. People want a birth. It's one of the greatest pleasures or expressions of love in a person's life.
"For many of the families, it really hasn't hit yet what the future is going to be."
However, he offered a little hope, saying: "Not all the brains are severely compromised. Some of the babies, now one month or two months old, they're feeding, they're growing."
CALLS RUN HOT AS CERUS CORPORATION, ZIOPHARM ONCOLOGY INC. TAKE OFF
Cerus Corporation (CERS) and ZIOPHARM Oncology Inc. (ZIOP) are among the healthcare stocks attracting option traders today
Stocks quoted in this article:
ZIOP | cers
2/9/2016 12:35 PM
A number of healthcare stocks are moving higher today and receiving notable attention in the options pits. Among them are blood safety specialist Cerus Corporation (NASDAQ:CERS) and drugmaker ZIOPHARM Oncology Inc. (NASDAQ:ZIOP). Here's a closer look at the news impacting CERS and ZIOP, and how option traders are responding.
CERS just announced that it's entered into a multi-year agreement with the American Red Cross, which will use the device maker's Intercept blood system to reduce the risk of infection during transfusions. The deal follows a late-January study in which the company's technology effectively inactivated the Zika virus using ultraviolet light. As such, the stock has shot 9.8% higher at $6.25, putting it on pace for its largest single-day gain since April.
In options land, CERS calls are running at 10 times the expected intraday rate. By the numbers, over 8,600 calls have been exchanged compared to just 116 puts. Among the most active strikes is the August 7 call, where it appears a trader sold to open 1,865 contracts, expecting the shares to remain below $7 through August expiration.
Looking at activity among shorter-term option traders, calls are also extremely popular. Specifically, Cerus Corporation's Schaeffer's put/call open interest ratio (SOIR) of 0.10 indicates call open interest outstrips put open interest by a 10-to-1 margin among options expiring in the next three months. What's more, this ratio ranks in the low 14th percentile of its annual range.
Meanwhile, ZIOP is having a rock-solid day after earlier hitting an annual low of $4.56, last seen 2.6% higher at $5.06 as the company prepares to takes the stage at the BIO CEO & Investor Conference at 1 p.m. ET. Also, the company announced that a first patient has been enrolled in an upcoming trial for its advanced lymphoid malignancies treatment.
According to Trade-Alert, one option bull bought to open a block of 17,405 March 8 calls for $0.25 apiece -- or a total of roughly $435,000 (premium paid * number of contracts * 100 shares per contract). In other words, this ambitious bettor is counting on ZIOP toppling $8 -- a 58% premium to current levels, and territory not charted since early January -- by March expiration. Conversely, he may be a short seller hedging against such a sharp rally, given that nearly 45% of the stock's float is sold short.
Today's penchant for call buying is business as usual for ZIOPHARM Oncology Inc. option traders. During the past two weeks at the International Securities Exchange (ISE), Chicago Board Options Exchange (CBOE), and NASDAQ OMX PHLX (PHLX), speculators have bought to open 9.05 calls for each put -- a ratio that ranks in the 73rd percentile of its annual range.
Kenya threatened Tuesday to pull out of this year’s Olympics in Rio, fearing exposure to the Zika virus outbreak in Brazil.
Kipchoge Keino, head of Kenya’s Olympic committee, said Brazil must show it’s controlled the mosquito-borne virus before his nation sends athletes to games in August.
“Obviously, we are not going to risk taking Kenyans there if this Zika virus reaches epidemic levels,” Keino told Reuters.
“They have to assure us that the country is safe enough to take athletes there.”
Kenya took home two gold, four silver and five bronze medals at the 2012 London. The golds were won in the 800-meter and 3,000-meter races.
Kenyan runners also took silver and bronze medals in the women’s and men’s marathons, respectively.
“We have made it clear that unless they clean the venues of this potentially dangerous disease, we will not go there,” said Keino, a former Olympic great himself who took home track gold medals from the 1968 Mexico City and 1972 Munich games.
“But if they assure us that things are in order and there is no risk to participants, mothers, we will go.”
American Olympic officials said they’ve been in contact with US Centers for Disease Control and are monitoring the outbreak.
The USOC has stopped short of threatening a pullout from Rio.
“Team USA looks forward to the Games and we did not, would not and will not prevent athletes from competing for their country should they qualify,” USOC spokesman Patrick Sandusky said on Monday.
new SEC filing today.
A Maharashtra firm is getting ready to find out whether genetically engineered mosquitoes can be a useful tool to check the growth of the insect.
Even as panic spreads worldwide over the Zika virus, harboured by the mosquito species that spreads dengue and chikungunya, a Maharashtra company is getting ready to scale up trials to find out whether genetically engineered mosquitoes can be a useful tool to check the growth of the insect.
Gangabishan Bhikulal Investment and Trading Ltd. (GBIT), a sister company of the Maharashtra Hybrid Company (Mahyco) that first brought Bt cotton to India, has been breeding male mosquitoes. These mosquitoes contain genes which when passed on to its progeny render them unable to mature unless they have access to tetracycline, a compound that is not naturally available in the environment. The idea is that once enough of these laboratory-bred mosquitoes mate with the disease-carrying females in an open environment, they would reduce the region’s mosquito population.
The technology — licensed from Oxitec, a University of Oxford company — is being tested in Malaysia and Brazil, which has seen the highest number of Zika cases. The strain of mosquito, called OX513A, is sourced from Oxitec and introduced into local sites. According to GBIT scientists, international evidence so far shows the strain can reduce the number of mosquitoes in a place by 90 per cent in three or six months.
“About two weeks ago, we got permission to conduct larger trials but still within the laboratory,” said Usha Barwale Zehr, Chief Technology Officer, Mahyco. “Depending on our findings, we will conduct experiments in villages of at least three States.” The key element being investigated is whether female mosquitoes do indeed choose to mate with the genetically altered males over normal ones.
Ms. Barwale said such tests would progress quickly as the life span of the Aedes aegypti mosquito was 15 days and the company expected the government’s permission to start larger trials later this year.
Last week, Bharat Biotech, a Hyderabad-based vaccine maker, said it had two promising vaccine candidates to contain Zika, but would require a vigorous push by the Indian government.
GBIT’s S.K. Dasgupta, who is leading the trials, told The Hindu that the company was following guidelines specified by the Bio-safety Unit of the Department of Biotechnology. “This is a first of its kind experiment, and there are WHO [World Health Organisation] guidelines that have been adapted by India. There will be some similarities to how GM crops are evaluated,” he said.
Scientists are making shocking claims the Zika virus could set evolution back two million years.
Genetic mutations caused by the pathogen may become embedded in human DNA, and human brains will shrink, according to The Express.
The report will be published in the Journal of Astrobiology and Outreach, whose author claims the virus is evolving, as evidenced in the new cases linked to sexual transmission.
Professor Edward Steele believes the human brain has doubled over the past two million years, and may and may be reversed by the virus.
Last week, a British biotech company stated their beliefs the virus could be controlled if millions of genetically modified mosquitoes were released. The Brazilian Health Ministry said they will consider letting Oxitec to release the insects, according to The Telegraph.
But genetically modified mosquitoes were already released in Brazil a few years ago – before the dramatic increase in cases of microcephaly, which has been linked to the virus. It was reported recently by TRUNEWS.
The virus, which was just recently burst onto the headlines, was discovered in 1947 in Africa. Because of the increase in babies born with small brains in Brazil, many dramatic responses have been made by governments.
Several Latin American officials have urged women not to get pregnant, as reported by TRUNEWS. In Brazil there will be massive sprayings of chemicals to kill the mosquitoes.
Athletes have been advised by the Unites States Olympic Committee not to attend the games, scheduled for this summer in Rio, if they are fearful of the virus.
Puerto Rico is to receive $250 million in federal funds to fight an increase in Zika cases after the governor declared a public health emergency.
The U.S. territory's representative in Congress says the money will be used in part to help boost health services provided to pregnant women. Pedro Pierluisi said Monday that the money also will be used for prevention and detection.
The island has 22 confirmed cases of the mosquito-borne virus. Among them is a pregnant woman in her first trimester and a man who developed a temporary paralysis condition known as Guillain-Barre. Researchers have tentatively linked the virus to birth defects.