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Development of new stem cell type may lead to advances in regenerative medicine

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IMAGE: Drs. Jun Wu, Leqian Yu, Yulei Wei and colleagues isolated a new type of pluripotent stem cell from mice, horses, and humans, named XPSCs, which are capable of generating chimeras…
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Credit: Photo illustration by Leqian Yu

DALLAS – Dec. 3, 2020 – A team led by UT Southwestern has derived a new “intermediate” embryonic stem cell type from multiple species that can contribute to chimeras and create precursors to sperm and eggs in a culture dish.

The findings, published online this week in Cell Stem Cell, could lead to a host of advances in basic biology, regenerative medicine, and reproductive technology.

Cells in early embryos have a range of distinct pluripotency programs, all of which endow the cells to create various tissue types in the body, explains study leader Jun Wu, Ph.D., assistant professor of molecular biology. A wealth of previous research has focused on developing and characterizing “naïve” embryonic stem cells (those about four days post-fertilization in mice) and “primed” epiblast stem cells (about seven days post-fertilization in mice, shortly after the embryo implants into the uterus).

However, says Wu, there’s been little progress in deriving and characterizing pluripotent stem cells (PSCs) that exist between these two stages – largely because researchers have not been able to develop a paradigm for maintaining cells in this intermediate state. Cells in this state have been thought to possess unique properties: the ability to contribute to intraspecies chimeras (organisms that contain a mix of cells from different individuals of the same species) or interspecies chimeras (organisms that contain a mix of cells from different species) and the ability to differentiate into primordial germ cells in culture, the precursors to sperm and eggs.

For this study, the researchers successfully created intermediate PSCs, which they named “XPSCs” from mice, horses, and humans.

Wu says that these results could eventually lead to an array of advances in both basic and applied research. For example, looking at gene activity in XPSCs from different species and interspecies chimeras could help researchers understand which signatures have been conserved through evolution. Examining the communication between cells in chimeras may help scientists identify strategies that could be used to accelerate the development of tissues and organs from stem cells used for transplantation. And using chimera-derived primordial germ cells to create sperm and eggs could aid in preserving endangered animal species and advancing infertility treatments.

“These XPSCs have enormous potential. Our study helps open the door to each of these possibilities,” says Wu, who is a Virginia Murchison Linthicum Scholar in Medical Research.

Wu notes that developing XPSCs presented a special challenge because the conditions that keep naïve PSCs in a stable state are exactly the opposite from those that stabilize primed PSCs. While culture conditions for naïve PSCs must activate a WNT cell-signaling pathway and suppress the FGF and TGF-ß pathways, the conditions to maintain primed PSCs must suppress WNT and activate FGF and TGF-ß.

Aiming for the preferred environment for XPSC derivation, Wu and his

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health

Voters asked to approve $5.5 billion for stem cell research

LOS ANGELES (AP) — The future of California’s first-of-its-kind stem cell research program is in the hands of voters, who will decide whether it deserves a $5.5 billion infusion of borrowed bond money to keep functioning.

A yes vote on Proposition 14 on Tuesday’s ballot would approve such a bond sale, bailing out the California Institute for Regenerative Medicine, which was created by a similar $3 billion bond measure in 2014 but is now nearly broke.

With dozens of clinical trials involving the use of stem cells to treat cancer, Alzheimer’s disease, Parkinson’s disease, paralysis, autoimmune diseases and other conditions underway at universities across California, supporters say it is crucial to keep that money flowing.


“Trials that use human embryonic derived stem cells to treat diabetes, to treat blindness and to treat spinal cord injury, those trials are early but already showing signs of patient benefit,” said professor Larry Goldstein, who directs the stem cell research program at the University of California, San Diego. “Losing those trials would be a terrible tragedy for those patients.”

Opponents say the state simply can’t afford to take on that kind of debt during a pandemic-induced economic crisis. What’s more, they say, there isn’t as much need for California to bankroll stem cell research now that the federal government and private investors have turned their attention to it.

“We built something good, but I think the field has expanded and there’s plenty of money going into research in California now,” said Jeff Sheehy, who sits on the governing board of the California Institute for Regenerative Medicine but says the state can’t afford to borrow more bond money to support it.

When voters approved the initial $3 billion in 2004, President George W. Bush’s administration had banned the use of federal funds for research using newly created human embryonic stem cell lines. The Obama administration lifted that ban in 2009.

Since then, opponents say, the National Institutes of Health has provided $1.5 billion a year in stem cell research money, while private investment in companies doing stem cell research has flowed in.

Supporters say that federal money could stop at any time, noting more than 90 members of Congress recently signed a letter demanding the Trump administration put an end to funding stem cell research.

More than a third of the initial $3 billion was spent to create stem cell research facilities at Stanford, the University of California, Berkeley, and other prestigious California institutions. Much of the rest has gone toward research.

With only about $30 million left, the California Institute for Regenerative Medicine has reduced its staff and stopped funding new studies.

If Proposition 14 passes, at least $1.5 billion would be earmarked for developing treatments for Alzheimer’s, Parkinson’s and other brain-related diseases. Some funds would be used to train California university and college students, and no more 7.5% could be used for administrative costs.

The state Legislative Analyst’s Office estimates that paying off the bonds with interest over 30 years would cost $7.8

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health

California Prop 14 may change lives of sick kids, keep taxpayer funding of stem cell therapy research

Three-year-old Ava was constantly sick. Her gums were inflamed, and every time she got a scraped knee, it turned into a dangerous infection.

Her parents, Alicia and Jon Langenhop, were months pregnant with their third child when they learned that Ava’s constellation of symptoms added up to an extremely rare, inherited disorder of the white blood cells, called leukocyte adhesion deficiency-1. Although antibiotics and antivirals could prolong her life, the disease was considered fatal, usually before kindergarten.

Ava’s primary hope, doctors told the Langenhops, was a bone marrow transplant from someone who was a good match, probably a brother or a sister.

Two-year-old Olivia had inherited the same disease as her big sister. She had been hospitalized with infections, too.

The baby in Alicia’s belly would be the girls’ best hope. Since both parents were carriers of the rare genetic mutation, the new baby, a boy, had a 25% chance of inheriting it, too.

Alicia was still in the hospital last October when they found out baby Landon had the mutation. Around the same time, the couple learned of a research trial in California.

Children Ava, Olivia and Landon Langenhop were diagnosed with an extremely rare, inherited disorder of the white blood cells, called leukocyte adhesion deficiency-1. California Proposition 14, a citizen-initiated ballot measure, authorizes bonds continuing stem cell research.
Children Ava, Olivia and Landon Langenhop were diagnosed with an extremely rare, inherited disorder of the white blood cells, called leukocyte adhesion deficiency-1. California Proposition 14, a citizen-initiated ballot measure, authorizes bonds continuing stem cell research.

Doctors would take each child’s blood cells, fix the mutation and return them. It should be a permanent fix, with less risk than a bone marrow transplant because the healthy cells would be their own, so their bodies wouldn’t reject them as foreign.  

The approach had been tried in only one child, though.

This is the type of research reaching patients nearly two decades after President George W. Bush banned federal funding of stem cell research and 16 years after California residents approved a tax increase on themselves to support research.

Proposition 14 on Tuesday’s ballot asks whether Californians want to continue this work, providing $5.5 billion for stem cell research over the next three decades.

In the early 2000s, stem cell research was controversial because it often required the destruction of human embryos. Though embryonic stem cells remain essential for some therapies, in cases such as the Langenhops’, treatment focuses on manipulating a person’s own cells.

Stem cell science has made tremendous progress, but as in most new fields, the pace remains painstakingly slow. Every treatment has to be the subject of years of trial-and-error research, and many scientific hurdles linger. 

Stem cells have been used to treat rare diseases, such as severe combined immunodeficiency, also known as “bubble boy disease,” and they are being tested in more common conditions such as Parkinson’s disease, macular degeneration, Type 1 diabetes and even heart disease.

“Even if a subset of stuff in the pipeline goes all the way, it will change the world for patients who currently don’t have other good options,” said Sean Morrison, a stem cell biologist in Dallas.

“It’s a pivotal time in the field,” said

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health

Everything you need to know about the $5.5-billion stem cell measure

Scientists are learning more about how to harness stem cells to reverse heart failure, but treatments won't be widely available right away. Above, a stem cell researcher.
Scientists are learning more about how to harness stem cells to reverse heart failure, but treatments won’t be widely available right away. (Dennis Drenner / For The Times)

Proposition 14 would authorize the sale of $5.5 billion in general obligation bonds for the California Institute for Regenerative Medicine, known as CIRM, for stem cell studies and trials.

Here is a rundown of the ballot measure:

The measure

In 2004, voters approved a bond measure to pay for stem cell research.

Now, with the money from that bond running out, supporters of the state’s stem cell agency are asking taxpayers for a new infusion of cash.

With interest, the bond could cost the state $260 million per year, or $7.8 billion over the next 30 years, according to the nonpartisan Legislative Analyst’s Office.

Pro arguments

Proponents of Proposition 14 say the measure will help find new treatments and cures for chronic diseases and conditions, including cancers, spinal cord injuries, Alzheimer’s, Parkinson’s and heart disease. They say the previous bond advanced research and treatments for more than 75 diseases, including two cancer treatments for fatal blood disorders that were approved by the U.S. Food and Drug Administration.

Without new funding to keep the program going, supporters of Proposition 14 say, groundbreaking medical discoveries and lifesaving research will be slowed or stopped.

Anti arguments

Opponents say that the state shouldn’t take on new debt while facing a pandemic-induced deficit and that medical advances attributed to the previous stem cell bond have been overstated. In addition, opponents say CIRM has been hampered by conflicts of interest and too little oversight, neither of which are remedied by the ballot measure.

The campaign to pass the 2004 ballot measure told voters that the bond would save millions of lives and cut healthcare costs by billions. Critics say that’s not been the case to date, although supporters of this year’s measure note that they never intended those results within 16 years. While there is not much organized opposition, some newspaper editorial boards, including those at the Los Angeles Times and San Francisco Chronicle, have opposed it.

Reading list

With Prop. 14, California voters will be asked for more borrowing to keep stem cell research going

Explaining Prop. 14

Times columnist George Skelton assesses Prop. 14

The California stem cell program’s $5.5-billion funding request might be its downfall

California’s stem cell program faces an existential moment — and a chance for reform

When it comes to disease, stem cells are a game-changer, scientists say. This is why

This story originally appeared in Los Angeles Times.

Source Article

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health

Genprex Unveils New Branding for Upcoming Combination Clinical Trials in Non-Small Cell Lung Cancer

New branding will support upcoming combination clinical trials, including the Company’s trial combining REQORSA™ immunogene therapy drug with AstraZeneca’s Tagrisso®, which received FDA Fast Track Designation earlier in 2020

Genprex, Inc. (“Genprex” or the “Company”) (NASDAQ: GNPX), a clinical-stage gene therapy company focused on developing life-changing therapies for patients with cancer and diabetes, today announced the launch of new branding for its upcoming oncology clinical trials combining its lead drug candidate, REQORSA(quaratusugene ozeplasmid), with AstraZeneca’s Tagrisso® (osimertinib), which received U.S. Food and Drug Administration (FDA) Fast Track Designation earlier this year, and for the combination of REQORSA with Merck’s Keytruda® (pembrolizumab), for the treatment of non-small cell lung cancer (NSCLC).

These trials will use the trial brand “Acclaim,” which the Company believes evokes its enthusiasm and the hope these trials represent for NSCLC patients and the oncology community. Acclaim-1 will be used to identify the REQORSA and Tagrisso combination clinical trial, and Acclaim-2 will be used to identify the REQORSA and Keytruda combination clinical trial.

“We are enthusiastically preparing for our upcoming clinical trials and are excited to launch the adoption of this branding,” said Rodney Varner, President and Chief Executive Officer of Genprex. “We believe the Acclaim brand communicates our passion for providing hope to NSCLC patients for important new treatment options in the fight against this devastating disease and aligns us with the clinical, medical and patient communities.”

The trial brand was developed in order to encourage early exposure of the Company’s clinical programs to the broad audience that Genprex’s business addresses, including patients, healthcare practitioners, clinical investigators, investors, employees and others. Genprex plans to initiate the Acclaim-1 clinical trial and the Acclaim 2 clinical trial in the first-half of 2021. Acclaim-1 is a Phase 1/2 clinical trial using a combination of REQORSA with Tagrisso in patients with late stage NSCLC with mutated epidermal growth factor receptors (“EGFRs”) whose disease progressed after treatment with Tagrisso. Acclaim-2 is a Phase 1/2 clinical trial using a combination of REQORSA with Keytruda in NSCLC patients who are low expressors (1 to 49%) of the protein, programmed death-ligand 1 (PD-L1).

About Genprex, Inc.

Genprex, Inc. is a clinical-stage gene therapy company focused on developing potentially life-changing therapies for patients with cancer and diabetes. Genprex’s technologies are designed to administer disease-fighting genes to provide new therapies for large patient populations with cancer and diabetes who currently have limited treatment options. Genprex works with world-class institutions and collaborators to develop drug candidates to further its pipeline of gene therapies in order to provide novel treatment approaches. The Company’s lead product candidate, REQORSA™ (quaratusugene ozeplasmid), is being evaluated as a treatment for non-small cell lung cancer (NSCLC). REQORSA has a multimodal mechanism of action that has been shown to interrupt cell signaling pathways that cause replication and proliferation of cancer cells; re-establish pathways for apoptosis, or programmed cell death, in cancer cells; and modulate the immune response against cancer cells. REQORSA has also

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health

Billions of Dollars for Stem Cell Research Institute On California’s November Ballot

SACRAMENTO, Calif.—In an election year dominated by a chaotic presidential race and splashy statewide ballot initiative campaigns, Californians are being asked to weigh in on the value of stem cell research—again.

Proposition 14 would authorize the state to borrow $5.5 billion to keep financing the California Institute for Regenerative Medicine (CIRM), currently the second-largest funder of stem cell research in the world. Factoring in interest payments, the measure could cost the state roughly $7.8 billion over about 30 years, according to an estimate from the nonpartisan state Legislative Analyst’s Office.

In 2004, voters approved Proposition 71, a $3 billion bond, to be repaid with interest over 30 years. The measure got the state agency up and running and was designed to seed research.

During that first campaign, voters were told research funded by the measure could lead to cures for cancer, Alzheimer’s and other devastating diseases, and that the state could reap millions in royalties from new treatments.

Yet most of those ambitions remain unfulfilled.

“I think the initial promises were a little optimistic,” said Kevin McCormack, CIRM’s senior director of public communications, about how quickly research would yield cures. “You can’t rush this kind of work.”

So advocates are back after 16 years for more research money, and to increase the size of the state agency.

Stem cells hold great potential for medicine because of their ability to develop into different types of cells in the body, and to repair and renew tissue.

When the first bond measure was adopted in 2004, the George W. Bush administration refused to fund stem cell research at the national level because of opposition to the use of one kind of stem cell: human embryonic stem cells. They derive from fertilized eggs, which has made them controversial among politicians who oppose abortion.

Federal funding resumed in 2009, and thus far this year the National Institutes of Health has spent about $321 million on human embryonic stem cell research.

But advocates for Proposition 14 say the ability to do that research is still tenuous. In September, Republican lawmakers sent a letter to President Donald Trump urging him to cut off those funds once again.

The funding from California’s original bond measure was used to create the new state institute and fund grants to conduct research at California hospitals and universities for diseases such as blood cancer and kidney failure. The money has paid for 90 clinical trials.

A 2019 report from the University of Southern California concluded the center has contributed about $10.7 billion to the California economy, which includes hiring, construction and attracting more research dollars to the state. CIRM funds more than 56,500 jobs, more than half of which are considered high-paying.

Despite the campaign promises, just two treatments developed with some help from CIRM have been approved by the Food and Drug Administration in the past 13 years, one for leukemia and one for scarring of the bone marrow.

But it’s a bit of a stretch for the institute to take

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health

Sickle cell anemia: Symptoms, treatment, and causes

Sickle cell disease (SCD) is a group of conditions that cause red blood cells to malfunction. Sickle cell anemia is a type of SCD.

Healthy red blood cells are disc-shaped and flexible, which helps them move through blood vessels and deliver oxygen to the body’s cells.

In sickle cell anemia, these red blood cells are crescent- or sickle-shaped, inflexible, and sticky. These traits make them clump together, blocking blood vessels and impairing blood flow. The sickle cells also die early, resulting in a shortage of red blood cells.

This article outlines the different types of SCD. We also describe the symptoms, causes, and treatment options of sickle cell anemia.

Red blood cells contain a protein called hemoglobin, which delivers oxygen to the body’s cells. In all forms of SCD, the red blood cells have an abnormal type of hemoglobin. Doctors refer to this as sickle hemoglobin or hemoglobin S.

Besides hemoglobin S, there are other abnormal variants of hemoglobin. The type of SCD a person has depends on which abnormal hemoglobin genes they inherit from their parents.

Below are the three most common types of SCD.

Sickle cell anemia

Sickle cell anemia is the most common and severe type of SCD. It develops when a person inherits two hemoglobin S genes — one from each parent.

People with sickle cell anemia become anemic. This means that their body does not produce enough red blood cells to supply sufficient oxygen to their cells.

Sickle-hemoglobin C

Sickle-hemoglobin C is a milder form of SCD. It occurs when a person inherits two different types of abnormal hemoglobin genes: one for hemoglobin S, and one for hemoglobin C.

Hemoglobin C causes milder symptoms than sickle cell anemia. As a result, a person with sickle-hemoglobin C usually has a higher red blood cell count and a reduced risk of developing anemia than someone with sickle cell anemia.

Sickle beta-plus thalassemia

Sickle beta-plus thalassemia occurs when a person inherits one gene for hemoglobin S and one gene for beta thalassemia.

Beta thalassemia is a different type of anemia, and the gene comes in two forms: 0 and +. Those with the 0 variant usually have a more severe illness than those with the + variant.

Less common types

Below are the rarer types of SCD.

Sickle-hemoglobin D

Sickle-hemoglobin D occurs when a person inherits one gene for hemoglobin S and one gene for hemoglobin D. The two genes interact in a way that usually results in mild to moderate anemia. People with one of each gene may also experience bouts of pain.

Sickle-hemoglobin O

Sickle-hemoglobin O occurs when a person inherits one gene for hemoglobin S, and one gene for hemoglobin O. The two genes interact to trigger various symptoms ranging from mild to severe.

People with sickle cell trait (SCT) inherit one sickle cell gene from one parent and one normal gene from the other. A person with SCT can pass the trait on to their offspring. If both parents have SCT, there is a

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health

Ultimovacs Announces Updated Positive Results from Phase I Trial Evaluating Universal Cancer Vaccine, UV1, in Non-Small Cell Lung Cancer

Ultimovacs ASA (“Ultimovacs”, ticker ULTIMO), today announced five-year overall survival data from the Phase I trial evaluating UV1 as maintenance therapy in patients with non-small cell lung cancer. The results confirm achievement of the primary endpoints of safety and tolerability and indicate encouraging initial signals of long-term survival benefit.

“Ultimovacs has established a growing body of clinical data demonstrating a strong safety and tolerability profile for UV1 and a range of preliminary efficacy signals in several cancer indications, all of which supports the further development of our proprietary cancer vaccine candidate,” stated Carlos de Sousa, Chief Executive Officer at Ultimovacs. “The long-term follow-up results announced today demonstrate that treatment with UV1 is safe both at the time of administration and throughout the follow-up period of at least 5 years. Non-small cell lung cancer highly expresses telomerase and remains an indication in great need of new treatment options for patients.”

In the study, a total of 18 non-small cell lung cancer patients whose disease had not progressed after receiving at least 2nd line treatment with chemotherapy were enrolled to receive UV1 monotherapy as maintenance treatment. Outcomes of the study included the safety and tolerability of UV1 as well as initial signs of clinical response. As per the cut-off date of June 2020, every patient in the trial reached at least 60-months of follow-up post treatment with UV1. At the five-years landmark, the Overall Survival (OS) rate was 33% and median Progression Free Survival (mPFS) was 10.7 months. Throughout the follow-up period, none of the patients experienced unexpected safety issues related to UV1. Further, none of the patients alive after 5 years have received other immunotherapy after the vaccination with UV1.

“At the time of the study initiation, there were no checkpoint inhibitors available for treatment of this patient population. For patients that received a second-line of chemotherapy the expected 5-year survival rate was less than 5 percent,” stated Jens Bjørheim, Chief Medical Officer at Ultimovacs. “While our Phase I study is non-randomized and conducted in a small population, it is promising to see that UV1 was safe and well-tolerated and that using UV1 as a maintenance therapy could potentially provide benefit to patients in need of novel approaches.”

Ultimovacs presented 48-months of follow-up data at the Society for Immunotherapy of Cancer’s (SITC) 34th Annual Meeting in November of last year.

About UV1

UV1 is a peptide-based vaccine inducing a specific T cell response against the universal cancer antigen telomerase. UV1 is being developed as a therapeutic cancer vaccine which may serve as a platform for use in combination with other immunotherapy which requires an ongoing T cell response for their mode of action. To date, UV1 has been tested in four phase I clinical trials in a total of 82 patients and maintained a positive safety and tolerability profile as well as encouraging signals of efficacy.

About UV1 Clinical Programs

As a universal cancer vaccine, UV1’s unique mechanism of action has the potential to

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