Gene therapy for sickle cell disease treatment brings hope to patients – The Washington Post

April 28, 2023 at 3:13 p.m. EDT

DACULA, Ga. For as long as he can remember, Jimi Olaghere felt he was destined to be a father. Its so true in my soul, he told his wife, Amanda, when they struggled to get pregnant. But when they were finally expecting a baby boy in 2019, joy was tinged with despair.

For 34 years, sickle cell disease had been hammering Jimis body and stealthily shredding his ambitions. He knew it would come for his dream of being a dad, too.

Inside Jimi, normally pliable, disc-shaped red blood cells deformed into rigid crescents. Those microscopic sickle-shaped cells clumped together, unleashing a cascade of damage. Pain was a constant, but about once a month it erupted into pure agony like glass had shattered inside his veins and shards were sawing back and forth.

How would monthly trips to the emergency room to manage his pain work with a newborn baby? Could he keep up with a toddler when everyday pain could keep him stuck in bed all day? Would he even live long enough to try?

I knew sickle cell would win that battle as well, Jimi said. It won everything with my career, with education, with everything I wanted to do.

Then, midway through Amandas pregnancy, the couple read an article about Victoria Gray, a woman whose genes had been experimentally edited to treat her sickle cell disease. It was still too soon to know exactly how well it worked, but Jimi wanted in.

After decades of neglect, stigma and underfunding, sickle cell is getting the equivalent of the red carpet treatment in science. Its the target of a competitive biotech race, with scientists and companies using a crop of cutting-edge tools to try to cure the debilitating illness.

The first gene therapies for sickle cell, including one based on the buzzy, Nobel Prize-winning technique called CRISPR, will be reviewed by regulators this year, and companies are preparing to launch the medicines if they get the green light. That puts the country at the cusp of two frontiers: a new era in treating a tragically overlooked disease, and the beginning of what could be a CRISPR revolution in medicine.

Its a dramatic about-face for sickle cell patients, who have often felt abandoned by the medical system. The rare disease afflicts about 100,000 people in the United States, most of them Black. Racism at both the institutional and interpersonal level has stymied funding and alienated patients, who are often treated as drug-seekers when they show up in emergency rooms in acute pain.

Of course theres skepticism. This is a disease thats been left to just succumb to the health-care system for so long, and suddenly this influx of money and parties and pharmaceutical companies [and] a whole staff of White folks want to come in and ask us about our disease, said Ashley Valentine, president of Sick Cells, a patient advocacy group that she founded with her brother Marqus, who died of a hemorrhagic stroke at age 36.

There are risks and unknowns with any new technology; one doctor told Jimi the magnitude of the challenge was comparable with landing on the moon for the first time. But the doctors, patients and others eager for sickle cell treatments say that turning gene editing into a viable therapy, then finding ways to make it widely accessible, will help carve a path for others to follow.

The hope, said Valentine, is that if the feds and governments and society can figure this out with sickle cell, they can figure this out with other diseases.

Decades before Jimi was born, chemist Linus Pauling discovered the root of the problem in sickle cell disease: an atypical form of the oxygen-carrying hemoglobin protein inside red blood cells. He dubbed sickle cell the first molecular disease a new paradigm that would shape biomedical research for decades.

Hard scientific work would fill in the rest of the story. The human genetic code is a string of 3 billion letters, each representing one of four molecular building blocks. Atypical hemoglobin is the result of a misspelling in one gene a T where there should be an A. People with just one copy of the altered gene have sickle cell trait. They live without major health symptoms, and even have an advantage: better protection against malaria. But people with two copies can experience devastating symptoms and die decades early.

Jimis parents had sickle cell trait. So did an older sister. But he had sickle cell disease. As a child growing up in Nigeria, it was hard to keep up with his friends energy levels. The pain episodes would arrive at night, or after tough exertion. His parents used menthol rubs and over-the-counter painkillers to try to ease his discomfort, which was so intense he would pass out.

Eventually, Jimi moved to live with relatives in New Jersey so that he could take advantage of better medical care. At a sickle cell support group, Jimi began to understand how deeply the disease infiltrated every aspect of daily life. It wasnt just hospitalizations and pain. A girl shared that she would eat random objects a condition called pica that often accompanies the disease. He recognized his own tendency to scrounge chalk and rubbish to eat, which had always made him feel as if he were going crazy.

The disease often gets worse as patients get older, which tragically coincides with a medical cliff in the U.S. health-care system. Children have parents and pediatric hematologists who are devoted to managing their disease. As adults, they have to coordinate their own care and are often treated very differently. Most people who have the disease in the United States are Black, and they are often met with suspicion and hostility, not compassion when they show up in the emergency room in excruciating pain.

As he got older, Jimis pain episodes became so frequent that they bled together in his memory. One time, his fever spiked so high that he lost consciousness. Jimi woke up in the intensive care unit a day later, disappointed to still be alive.

There became a point of my life I stopped going to the emergency room and started medicating at home, Jimi said. I was just so embarrassed.

He suffered a heart attack in his 20s. He developed blood clots in his lungs. His hips sometimes ache because parts of the bone tissue in his joints died because of lack of oxygen delivery.

Until recently, there werent many treatments for sickle cell disease. A bone-marrow transplant could cure it by providing patients with marrow that made normal hemoglobin, but a suitable match from a sibling could be found for only about 1 in every 5 patients. Then theres hydroxyurea, the first and only drug that was approved to treat sickle cell until 2017; three drugs have been approved since then. Hydroxyurea helps keep red blood cells from sickling, or deforming into a sickle shape, by increasing levels of a type of fetal hemoglobin that is switched off after birth.

Research into the disease gave scientists two main avenues for gene therapy. One would be to replace the gene or correct the genetic typo to restore normal hemoglobin production. Another would be to get the body to start pumping out fetal hemoglobin again.

The ideas were straightforward, but progress was slow. The field was underfunded, in part because the Black population historically lacks access to the intergenerational wealth, influence and privilege that fuels private philanthropy for rare-disease research. Even at the federal level, other rare diseases that cut short peoples life spans such as the lung disease cystic fibrosis received triple the funding per person until the gap began to narrow in 2017.

Theres huge underinvestment, said Stuart Orkin, an expert in the field and professor of pediatrics at Harvard Medical School and the Dana-Farber Cancer Institute. The NIH probably wouldnt like me to say this, but one of the goals of the National Heart, Lung and Blood Institute is to cure sickle cell disease. They certainly have not put the kind of resources into it that would be required.

Gary Gibbons, director of the NHLBI, pointed to data showing that federal funding for sickle cell research has doubled since 2010, and he highlighted the Cure Sickle Cell Initiative that was launched in 2018. NHLBI is committed to improving the care and long-term survival for children and adults with sickle cell disease in the U.S. as well as other parts of the world, Gibbons said.

A turning point occurred when sickle cell became an attractive target for companies to invest in as new gene therapy techniques reached prime time and better understanding of the disease clarified the best therapeutic strategies.

Fifteen years ago, scientists pinpointed a gene called BCL11A that worked like a dimmer switch, controlling the amount of fetal hemoglobin the body produced. When scientists shut it off, fetal hemoglobin expression turned back on. In 2011, Orkins lab showed that it was possible to reverse sickle cell disease in mice by flicking the BCL11A switch.

At the same time, a growing array of gene therapy techniques gave scientists tools to flip genetic switches or insert new genes kicking off a flurry of competing sickle cell cures. CRISPR, discovered in 2012, is being used to edit a key region of the BCL11A gene to turn fetal hemoglobin back on. Other approaches use a harmless virus as a kind of Trojan horse to insert a new version of the hemoglobin gene that resists sickling into a patients stem cells. Yet another uses a specialized RNA molecule to silence BCL11A.

After years of little progress, there wasnt just one way to treat sickle cell there were many.

I have wanted to see this succeed for 40 years, said Francis Collins, the former NIH director whose postdoctoral research in the early 1980s was on sickle cell. I thought wed be lucky if in my lifetime, if we achieved even a single cure of someone for sickle cell disease.

Out of nowhere, I could tell it was gone

For most of his life, Jimi had a hard time envisioning the future. How many times had people told him he wouldnt live to see his 20th or 30th birthday? On his first date with Amanda, when they were in their early 20s, he put down the menu and told her he had sickle cell, and that he understood if that was a dealbreaker.

Im super competitive, and I said, Ill take it on, Amanda recalled, laughing. She went home and began Googling to learn more about the disease.

To manage Jimis sickle cell, the couple forged a powerful partnership. They could handle anything together. But with a baby on the way, the stakes changed.

I thought I was going to die, Jimi said. I thought, I cant leave my wife with a son and not be here for them.

In November 2019, Jimi and Amanda flew to Nashville to meet with Haydar Frangoul, the pediatric hematologist leading a trial of a CRISPR gene therapy for sickle cell disease at Sarah Cannon Research Institute. They learned shortly after Christmas that Jimi qualified for the trial. Their son, Sebastian, had just been born. It felt like a gift.

From start to finish, Jimis treatment would take the better part of a year. First, his stem cells needed to be collected from his blood. This required long car trips to Nashville and being hooked up to a machine for hours at a time. Once the researchers collected enough stem cells, they edited the cells to disable the BCL11A switch. Then the cells needed to be carefully checked for quality.

Jimi also needed chemotherapy to kill off existing cells in his bone marrow so that his edited stem cells would have room to engraft and grow. His hair fell out and he developed painful sores in his mouth.

Amanda, Jimi and baby Sebastian lived in the hospital for weeks, juggling remote work and the haze of starting their new family life. They set up a playpen in the hospital room. The nurses and doctors became like a second family. Jimi continued to run his e-commerce business from his hospital bed, while Amanda worked remotely, sometimes rushing to a nearby hotel room to do conference calls. Sebastian often napped next to his dad.

When Jimis body was ready to receive the cells, the nurses brought three syringes into the room. Another participant in the trial had warned him: It will smell like creamed corn. Sure enough, the room filled with the aroma, due to a preservative used to freeze the cells. His parents watched through a live feed from Nigeria.

Jimi came home at the end of November 2020. As his new edited cells began pumping out fetal hemoglobin, he felt the disease depart.

I had lived 35 years with this disease that sometimes I consider a companion, and out of nowhere I could tell it had gone or was in the process of leaving. We were enmeshed together, and I could feel it detangling, Jimi said.

A year went by, and Jimi had no pain crises.

We can plan in the future like decades in the future now, Amanda said. They got pregnant again using in vitro fertilization, this time with twins.

Carry your cure with you

Jimi is one of 31 participants whose results have been made public in the sickle cell trial run by Vertex Pharmaceuticals and CRISPR Therapeutics. None have had pain crises since their treatment, according to data through February 2022, though at that time, only 11 patients had been followed for at least a year. The companies just finished submitting data to regulators, and the Food and Drug Administration is expected to make a decision on whether to approve the therapy as soon as this year. The therapy is also being tested in the related blood disease beta thalassemia.

Another trial run by Massachusetts-based company Bluebird Bio uses a different gene therapy approach. A patients stem cells are removed, then a virus inserts a gene into them that codes for a non-sickling version of beta-globin, a component of hemoglobin. Bluebird has treated 50 sickle cell patients, six of whom have been followed for six years, and submitted its data to regulators in April. The company has announced it could roll out the therapy in 2024.

The beauty of gene editing for sickle cell is that it takes a lot of the luck out of the equation. People dont have to count on finding a bone marrow match. They also dont have to worry about a dangerous complication that can occur when cells transplanted from another person attack the recipients own tissues.

You carry your cure with you, basically, the Sarah Cannon Research Institutes Frangoul said.

But the challenges of turning an intensive therapy into an accessible medicine are formidable. For instance, chemotherapy is not only time-intensive and unpleasant, but it also causes infertility, meaning patients must have the ability to put their lives on hold for the treatment and have the time and resources to make long-term plans about future reproductive choices.

The first gene therapies for sickle cell will be a turning point, but it will take years and many millions of dollars to reach even a fraction of the patients who could benefit. Jimi did not have to pay for his treatment because it was part of a clinical trial, and the companies have not yet announced the price tag. A draft report by the Institute for Clinical and Economic Review, a nonprofit that examines whether drugs merit their prices, found that charging $2 million per treatment could be cost-effective for patients with severe disease, leading to health gains and lifetime opportunities.

Already, the success of the front-runners is winnowing out competition, as some companies drop their sickle cell gene therapy programs. The trend disappoints scientists who worry that a winner-takes-all model will leave important scientific questions unsettled about which approach is superior.

Jimi says he feels like hes cured, though he knows it isnt the correct word. Frangoul will follow Jimi and other patients for 15 years to track their health and monitor them for side effects.

Two patients in Bluebirds trial developed acute myeloid leukemia and died; extensive studies found that the cases were not likely to be related to the insertion of the new gene.

If both of the therapies being submitted are approved, they probably will be limited to severely ill people at first. Vertex officials estimate there are about 25,000 people in the United States in that category, and they have outlined plans to partner with 50 treatment centers in the United States and 25 in Europe.

Im excited but I dont expect to see my job different two years from now because we have a gene therapy, said John J. Strouse, a hematologist at Duke University School of Medicine who treats adult sickle cell patients.

Frangoul said the questions of access and insurance coverage already worry him. He recalled the early days of bone marrow transplants to treat sickle cell, when he would write appeal after appeal to insurers to try to get the novel procedure covered.

Jennifer Doudna, the biochemist at the University of California at Berkeley who shared the Nobel Prize for discovering CRISPR, said that she anticipates feeling sheer joy when the first CRISPR therapy is approved, but also urgency.

A nonprofit she founded, the Innovative Genomics Institute, is working on a different CRISPR therapy to correct the genetic typo in sickle cell disease. Institute leaders also hope to pioneer a less-conventional business model in which creative partnerships between industry, government, academia and nonprofits could lead to new ways to price very expensive drugs for rare diseases.

I think its going to make me feel even more motivated, Doudna said. People need this therapy, right? And people cant pay millions of dollars for it.

After Jimis treatment, he had a different kind of crisis: Who am I without sickle cell?

After a lifetime of constant pain, it was disconcerting to have none. He felt guilty for not being elated that he was finally well, but he mourned the years of lost potential that he had spent as a prisoner of sickle cell.

The physical toll of the disease sickle cell itself doesnt compare to the emotional vacuum it creates, he said.

At the same time, he looks at his life now with a bit of wonder.

He stands a little taller, and he no longer wears glasses to obscure his eyes, which were severely jaundiced because of the disease. After years of being unable to sleep at night because of pain and taking naps during the day, he wakes up at 4:30 a.m. feeling like he chugged a Red Bull. He meditates, works, then wakes his twin daughters, Eloise and Willow, and gives them breakfast. The soundtrack in his household is kid-friendly songs and discussions of dinosaurs.

To me, it still feels special the amount of energy I have, he said.

The story doesnt end with him. Some of Jimis relatives in Nigeria have sickle cell disease. Three of Jimis children are carriers of the sickle cell trait. He wants to make sure other people with sickle cell have the opportunity to free themselves from the disease not only the patients in the United States, but also the 20 million people in the rest of the world, many of them in sub-Saharan Africa, India and the Middle East.

Extending gene therapies to more populations will require big leaps in science. A major quest is on to invent ways to deliver gene therapies without an intensive bone marrow transplant. And Jimi wants people in the next generation, regardless of where they live, to have the opportunity to grow up without the shadow of illness.

If by Gods grace we cure 100,000 people [in the United States], thats not even a fraction of the people that actually suffer with the disease in West Africa, India and all those regions where its quite prevalent, Jimi said. Most of my advocacy is shining a light to all of these places that are still in the background for now.

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Gene therapy for sickle cell disease treatment brings hope to patients - The Washington Post

Alzheimer’s: Study pinpoints key role of glucose in brain activity – Medical News Today

The brain requires large amounts of energy to function. Glucose is the primary fuel for neurons. While the adult brain accounts for 20-25% of glucose consumption, developing brains may require an even higher quantity.

How glucose is processed in the brain, however, has remained unknown. Some have suggested that glucose may be metabolized by supporter glial cells and then exported to neurons.

More recent studies suggest that neurons may be able to process glucose on their own. It has been difficult to determine whether this is the case due to difficulties in isolating neurons from glial cells for study.

Understanding how glucose is metabolized for energy in the brain could pave the way for new treatments for conditions linked to glucose uptake, such as Alzheimers disease (AD) and Parkinsons disease (PD).

Recently, researchers conducted cell and mouse studies to assess how glucose is metabolized by neurons.

They found two proteins that make it possible for neurons to metabolize glucose themselves both in cell cultures and in animal models.

Dr. Charles Munyon, a functional neurosurgeon with Novant Health in Charlotte, North Carolina, who was not involved in the study, told Medical News Today:

These findings appear to settle a long-standing controversy fairly definitively, and the study is elegantly designed. While it is still not clear what proportion of neuronal energy comes from direct glucose metabolism, we can be certain that the answer is not negligible.

The study was published in Cell Reports.

For the study, the researchers used induced pluripotent stem cells (iPSCs) to generate human neurons. They then added the neurons to a labeled form of glucose. In doing so, they found that neurons were able to break down glucose into smaller metabolites.

Next, the researchers removed two key proteins for importing and metabolizing glucose from the neurons using CRISPR gene editing. Removing either of these proteins impaired the breakdown of glucose in the human neurons.

This, noted the researchers, means that human neurons indeed metabolized glucose.

The researchers next wanted to see whether the findings translated to animal models. To do so, they engineered neurons in mice to lack the same two key proteins for glucose import and metabolism.

The mice that lacked one of the proteins showed normal memory and learning at 3 months of age, but at 7 months they showed severe learning and memory deficits. For the other tested protein, while both female and male mice had normal memory at three and seven months old, they noted that femalesbut not malesdeveloped learning and memory loss by 12 months.

The researchers noted that further studies are needed to understand what may explain the sex differences.

Lastly, they investigated how neurons adapt when glucose is not available as an energy source. They found that neurons use other energy sources, such as a related sugar molecule, galactose, which was less efficient than glucose as an energy source for the neurons.

The researchers concluded that neurons metabolize glucose by themselves and that they require glucose metabolism for normal function.

When asked about the studys limitations, Dr. James Rini, a neurologist at Ochsner Health, who was also not involved in the study, told MNT that as the study was conducted in mice and in a lab setting, it remains unclear if the findings apply to humans and real-life settings too.

He added that the method used to measure glucose metabolism may not capture the full picture of how neurons metabolize glucose in the brain.

[Furthermore], the study only looked at one aspect of brain functionhow neurons metabolize glucoseand did not investigate other factors that may contribute to brain function, such as the role of other nutrients or neural signaling pathways, he explained.

MNT also spoke with Dr. Fahmeed Hyder, professor of Biomedical Engineering at Yale School of Medicine, who was not involved in the study, about the studys implications. He noted that the study adds a well-established line of experimental evidence suggesting that neurons metabolize glucose on demand.

When asked about the studys implications, Dr Rini added:

Direct glucose metabolism pathway may be a new target for therapeutic interventions in brain diseases. For example, if researchers can find ways to enhance glucose uptake or utilization by neurons, it may be possible to improve brain function in people with neurological disorders such as AD and PD.

There have been multiple trials already that have suggested this, CTAD 2022 data suggests Januvia may be neuroprotective in AD, he explained.

Dr. Charles Munyon noted, however, that there is no evidence that the findings will impact therapeutics for AD or PD.

While it is true that glucose metabolism decreases in these conditions, this is a secondary effect due to accumulation of amyloid/tau or alpha-synuclein, he said.

In summation, from a basic science standpoint, this is a well-designed study that answered a long-standing question. In terms of how this will likely impact medical treatment, I dont see a significant impact coming at all, he concluded.

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Alzheimer's: Study pinpoints key role of glucose in brain activity - Medical News Today

Reprogramming Fibroblasts in Vivo for Heart Repair – Lifespan.io News

Scientists from Duke University have found a way to make adult fibroblasts differentiate into cardiomyocytes, which might help develop better heart attack treatments [1].

Myocardial infarction, or heart attack, is a leading cause of death and disability. It happens when the blood flow to a part of the heart gets blocked, often by a blood clot, leading to cell death and necrosis [2]. When the blood flow is restored, the healing is similar to that of flesh wounds. Fibroblasts recruited to the area produce a lot of intracellular matrix elements, which results in the formation of stiff scar tissue. This decreases the hearts efficiency, negatively affecting future lifespan and healthspan.

This imperfect repair process reflects the changes we undergo after birth. Fibroblasts are multipotent cells that can differentiate into other cell types, such as adipocytes, chondrocytes, and cardiomyocytes, the heart muscle cells. This process is effective in fetuses and newborns, which is why cuts on a newborns skin often heal perfectly without leaving any scar tissue. However, after a fairly short time, fibroblasts become less inclined to differentiate, preferring to produce the extracellular matrix instead.

Scientists have been looking for ways to trick adult fibroblasts into behaving immaturely, differentiating into myocytes to heal myocardial infarction more effectively [3]. However, attempts at direct fibroblasts to myocytes reprogramming in vivo have been hampered by low reprogramming efficiency. Apparently, its hard to teach old fibroblasts new tricks.

In this new study, the researchers attempted to identify the changes in fibroblasts after birth and how these changes could be manipulated for therapeutic benefits. First, they isolated cardiac fibroblasts from neonatal and adult mice. All fibroblasts were identically passaged: that is, they had undergone roughly the same number of divisions, which made them of a similar cellular age. The fibroblasts were then transfected with a cocktail of four micro-RNAs (miRNAs) that had been shown by previous research to induce reprogramming of fibroblasts into cardiomyocytes, albeit with low efficacy.

Reprogramming worked well in neonatal, but not adult, fibroblasts. The researchers looked at transcription factors that were expressed differently in those two types of fibroblasts and then made several more attempts at reprogramming, each time adding a siRNA (short interfering RNA) to silence one of the candidate factors. Silencing Epas1, which was highly expressed in adult but not neonatal fibroblasts, seemed to work best, robustly increasing the number of reprogramming events in the culture. Conversely, overexpressing Epas1 in neonatal fibroblasts resulted in them losing their remarkable differentiation capacity.

To test their new insights, the researchers inflicted myocardial infarction on mice, and then delivered the reprogramming miRNA combo and the Epas1-blocking siRNA directly into the infarction border zone. Two months after the injury, no new cardiomyocytes appeared in mice that received sham treatment. In mice who received only the reprogramming cocktail, few reprogramming events occurred. However, in the mice that also received Epas1-blocking siRNA, about 20% of resident cardiomyocytes turned out to be former fibroblasts. The treatment also significantly improved cardiac function.

The authors hypothesized about the event that triggers the expression of Epas1 and moves myofibroblasts towards their adult differentiated phenotype. They suggest that this cue might be oxygen deprivation during birth, since low oxygen levels are known to induce Epas1 expression [4]. The researchers mention that low oxygen levels during birth might also be the stimulus behind cardiomyocyte cell cycle exit (adult cardiomyocytes are largely non-proliferative).

The researchers note that while they chose Epas1, which yielded good results, other transcription factors might be at play as well. Targeting several factors at once might lead to even better outcomes. For RNA delivery, the researchers used exosomes, a type of extracellular vesicles used by cells for communication. This method of delivery was popularized by recent COVID-19 vaccines that use it to deliver their RNA cargo.

Regaining the impressive regenerative abilities that we lose soon after birth might be the key to staving off numerous deadly diseases. This research underscores how pliable cell fate can be, and that we might be able to manipulate it to produce new differentiated cells in environments that normally do not allow this. Direct reprogramming of fibroblasts in vivo can also be used outside of the cardiac context, such as in producing new cartilage.

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[1] Sun, H., Pratt, R. E., Dzau, V. J., & Hodgkinson, C. P. (2023). Neonatal and adult cardiac fibroblasts exhibit inherent differences in cardiac regenerative capacity. Journal of Biological Chemistry, 104694.

[2] Ojha, N., & Dhamoon, A. S. (2021). Myocardial infarction. In StatPearls [Internet]. StatPearls Publishing.

[3] Chen, Y., Yang, Z., Zhao, Z. A., & Shen, Z. (2017). Direct reprogramming of fibroblasts into cardiomyocytes. Stem cell research & therapy, 8, 1-8.

[4] Peng, J., Zhang, L., Drysdale, L., & Fong, G. H. (2000). The transcription factor EPAS-1/hypoxia-inducible factor 2 plays an important role in vascular remodeling. Proceedings of the National Academy of Sciences, 97(15), 8386-8391.

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Reprogramming Fibroblasts in Vivo for Heart Repair - Lifespan.io News

Melding Data Creates Wider Landscape of Brain Cancer – Cancer Health Treatment News

Brain cancer researchers have a new, panoramic visualization tool to help them navigate the complex disease. Built from several publicly available datasets of gene expression and DNA sequences, the new brain cancer landscape acts like a city-wide map of the disease, carefully assembled from neighborhood maps of different brain tumor subtypes.

As researchers, we can get so focused on comparing like with like that we lose sight of the proverbial forest for focusing too much on the leaves of a single tree, wrote Holland Lab computational biologist Sonali Arora, MS, in the paper describing the tool, published in Scientific Reports in March.

Her new map offers a detailed landscape of molecular alterations in brain tumors that will help cancer researchers move between different subtype neighborhoods, as well as between cancerous and healthy brain tissue. Its the first brain cancer computational visualization tool to combine different molecular datasets from both pediatric and adult brain tumors into one landscape, which will allow researchers to chase down key genes and biological pathways that shape development, tumor growth and treatment response, said Arora, who melded the datasets.

Now you can compare all kinds of things, like the expression of certain genes or pathways you can compare across all tumors types and normal brain, said Fred Hutch brain cancer researcher and Human Biology Division Director Eric Holland, MD, PhD. And thats something that hasnt been done before. Now you can compare and learn about gene expression in one tumor versus another, or one subset versus another.

The computational tool reveals biological processes that are ramped up or down in cancer compared to normal brain tissue. And because it draws on datasets from the U.S. and China, Arora was able to show that while tumors from both regions often share molecular alterations, there is a certain subset of glioma in patients from China that is not seen in the U.S.-based data.

And to enable scientists to explore her brain tumor map in 3D detail, Arora uploaded the landscape to the visualization tool Oncoscape, also developed in the Holland Lab.

Aroras landscape offers a way to visualize both normal and tumor samples and show tumor relationships not available in standard plotting methods, Fred Hutch colleague and cancer stem cell biologist Patrick Paddison, PhD, wrote in an email. Paddison and his team used the tool to help identify genes that are critical for brain tumor cells (but not healthy brain tissue), as well as their biomarkers.

Arora got the idea to build the landscape during the initial COVID-19 pandemic shutdown. She saw an opportunity to give brain cancer researchers a wider view of brain cancer by creating a map that combined data from multiple brain tumor subtypes housed in publicly available data repositories.

These datasets include a spectrum of molecular information, including tumors DNA sequences and the patterns of genes that are turned on and off in tumors. The Cancer Genome Atlas, or TCGA, a National Cancer Institutefunded program, includes samples from adult tumors that span 33 cancer types. Arora combined information from 702 TCGA patients with glioma and 270 patients with tissue samples in the Chinese Glioma Genome Atlas, or CGGA. To allow scientists to easily compare the differences and similarities between adult and childhood brain tumors, she added brain tumor data from the Children Brain Tumor Network, or CBTN. And to help scientists clarify how tumors differ from normal tissue, Arora included molecular information from 1,409 normal brain tissue samples in the Genotype Tissue Expression Project, or GTEx.

She then used a technique called uniform manifold approximation and projection for dimension reduction, or UMAP, to simplify the large, complex data and make it easier to detect key relationships between molecular changes and tumors. Arora also used a computational technique called batch effect correction, which to her knowledge has not been used at this scale before. This strategy helps scientists clear away variation in data that arises because samples are processed under different conditions and see true biological variation.

In Aroras UMAP, brain tumors that share gene expression patterns cluster together in the same subtypes. And like a city map, her landscape shows which subtype neighborhoods are near neighbors, and which are across town. Arora was able to see how biological processes differed between normal tissue and cancer, and between different cancer types, including tumors from adult and pediatric patients.

There are clearly some pathways that are upregulated, Arora noted.

Relationships between tumor types, as well as tumors and key genes and biological processes, quickly jumped out, she said. For the most part, tissue from gliomas taken from patients in the U.S. and China clustered into the same neighborhoods, save for two clusters of glioma subtypes seen in the CGGA but not the TCGA data. Its already known that the same cancer type may manifest differently in different regions around the world, and the new brain tumor landscape could help scientists figure out how and why this occurs for glioma as well, the researchers said.

The UMAP showed that in comparison with normal brain tissue, glioma tumors from adults had higher levels of key cancer-promoting biological processes, including those that promote cell growth and DNA repair. Some pediatric tumors had also ramped up these processes. The UMAP also reveals pathways ramped down in tumors, including some neurotransmitter pathways.

Researchers can use the UMAP to dig deeper into these pathways, and explore individual genes involved at different steps in each biological process, Arora said.

You can visualize the expression of each of those genes over the brain tumor map, she said. By using the UMAP, she was able to see that while a specific process in this case, a type of DNA repair might be elevated in cancer cells, the expression level of individual genes involved in that process might vary, with some remaining the same as in normal brain tissue.

To help researcher examine the relationship between DNA changes and brain tumors, Arora built a smaller UMAP using the samples from TCGA and the CBTN that included DNA sequence information. This gave a window into the range of DNA mutations that can drive cancer, from changes in single DNA letters, to the replication or loss of larger chunks of DNA. Sometimes these changes can cause two genes to be fused together, forming a new Frankengene that may drive cancer by acting differently than either of its parent genes. Aroras UMAP showed that certain gene fusions were more common in specific brain cancer subtypes.

Now youre able to compare a group of tumors amongst each other, Holland said. Thats unusual, he noted: Its far more common for scientists to study and report on one tumor type. These cross-subtype comparisons could help brain cancer researchers discover treatment targets shared by multiple brain tumor types, or those unique to specific subtypes.

Paddison used the UMAP to uncover vulnerabilities or genes and biological processes that cancer cells need but healthy cells dont in different subsets of both adult and childhood brain tumors.

Precision oncology is the tailoring of a cancer patients treatment plan to their tumors unique blend of vulnerabilities. While cancer researchers have made great strides, there remains a lot to discover about the treatment targets lurking within tumors, and how to determine which therapies will provide the greatest benefit to which patients.

Aroras UMAP, combined with Oncoscapes data visualization capabilities, will help further those discoveries, Holland said.

It will make it easier for brain cancer researchers like Paddison to uncover what drives brain tumors, whether its from DNA mutations or large-scale changes in gene expression patterns. Identifying key genes or pathways in the UMAP could help researchers better choose candidate therapies for clinical trials, Holland said.

This type of approach could be used to more precisely place patient tumors in continuum of adult or pediatric brain tumors to better predict outcomes and survival, Paddison said.

Using tumor landscapes, incorporating patient clinical as well as tumor molecular landscapes, to refine diagnosis and treatment is Hollands hope as well.

You could imagine a world where a given tumor is sequenced, and then placed on the landscape. Then your nearest neighbors on the landscape could tell you what your diagnosis actually is, but also what your expected outcome would be, Holland said.

Aroras multi-dataset brain cancer UMAP is to my knowledge, the first pseudo pan-cancer approach to a really interactive way of learning about, and predicting, new tumor behaviors, he said.

This work was supported by the National Institutes of Health, the Jacobs Foundation and the National Science Foundation.

This article was originally published April 10, 2023, by Fred Hutch News Service. It is republished with permission.

Link:
Melding Data Creates Wider Landscape of Brain Cancer - Cancer Health Treatment News

2023-04-24 | OTCPK:BRTXD | Press Release | BioRestorative … – Stockhouse

--Clinical data from safety run-in scheduled to be released in second half of 2023.

MELVILLE, N.Y., April 24, 2023 (GLOBE NEWSWIRE) -- BioRestorative Therapies, Inc. (BioRestorative”, BRTX” or the Company”) (NASDAQ:BRTX), a clinical stage company focused on stem cell-based therapies, today announced that it has completed enrollment for the safety run-in component of its Phase 2 clinical study of BRTX-100 targeting patients suffering from chronic lumbar disc disease (cLDD).

BRTX-100 is the Company’s lead clinical candidate, a novel cell-based therapeutic engineered to target areas of the body that have little blood flow. BRTX-100 is currently being evaluated in connection with a Phase 2 clinical trial to treat cLDD. The trial is prospective, randomized, double-blinded and controlled. The trial will evaluate the safety and preliminary efficacy of a single dose of BRTX-100. A total of up to 99 eligible patients will be randomized at up to 15 clinical sites in the United States to receive either the investigational drug (BRTX-100) or control in a 2:1 fashion.

Lance Alstodt, Chief Executive Officer of BioRestorative Therapies, stated The completion of patient recruitment and enrollment for the safety run-in component of our Phase 2 study of BRTX-100 is a very significant milestone for our company. Positive safety data would enable us to initiate unrestricted enrollment across all of our clinical sites and, of course, establish a strong safety profile for BRTX-100. In addition, we would be able to leverage the BRTX-100 platform across other indications within the body on an investigational basis with potentially a shorter timeline from a regulatory pathway perspective.”

About BioRestorative Therapies, Inc.

BioRestorative Therapies, Inc. (www.biorestorative.com) develops therapeutic products using cell and tissue protocols, primarily involving adult stem cells. Our two core programs, as described below, relate to the treatment of disc/spine disease and metabolic disorders:

Disc/Spine Program (brtxDISC): Our lead cell therapy candidate, BRTX-100, is a product formulated from autologous (or a person’s own) cultured mesenchymal stem cells collected from the patient’s bone marrow. We intend that the product will be used for the non-surgical treatment of painful lumbosacral disc disorders or as a complementary therapeutic to a surgical procedure. The BRTX-100 production process utilizes proprietary technology and involves collecting a patient’s bone marrow, isolating and culturing stem cells from the bone marrow and cryopreserving the cells. In an outpatient procedure, BRTX-100 is to be injected by a physician into the patient’s damaged disc. The treatment is intended for patients whose pain has not been alleviated by non-invasive procedures and who potentially face the prospect of surgery. We have commenced a Phase 2 clinical trial using BRTX-100 to treat chronic lower back pain arising from degenerative disc disease.

Metabolic Program (ThermoStem®): We are developing a cell-based therapy candidate to target obesity and metabolic disorders using brown adipose (fat) derived stem cells to generate brown adipose tissue (BAT”). BAT is intended to mimic naturally occurring brown adipose depots that regulate metabolic homeostasis in humans. Initial preclinical research indicates that increased amounts of brown fat in animals may be responsible for additional caloric burning as well as reduced glucose and lipid levels. Researchers have found that people with higher levels of brown fat may have a reduced risk for obesity and diabetes.

Forward-Looking Statements

This press release contains "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and such forward-looking statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. You are cautioned that such statements are subject to a multitude of risks and uncertainties that could cause future circumstances, events or results to differ materially from those projected in the forward-looking statements as a result of various factors and other risks, including, without limitation, those set forth in the Company's latest Form 10-K filed with the Securities and Exchange Commission. You should consider these factors in evaluating the forward-looking statements included herein, and not place undue reliance on such statements. The forward-looking statements in this release are made as of the date hereof and the Company undertakes no obligation to update such statements.

CONTACT:

Email: ir@biorestorative.com

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2023-04-24 | OTCPK:BRTXD | Press Release | BioRestorative ... - Stockhouse

IVG: Tech that can turn skin cells into babies – NewsBytes

IVG: Tech that can turn skin cells into babies

Apr 24, 2023, 04:46 pm 3 min read

It's amazing what science can do these days. In vitro gametogenesis (IVG) is a remarkable reproductive technology that can create babies from skin cells! It has the potential to change the lives of many who face infertility challenges or can't conceive naturally, including same-sex couples and postmenopausal women. Let's delve into understanding the science behind this game-changing technology for the future of parenthood.

IVG would allow nearly anyone to become a biological parent

This technology can help same-sex couples have children who are biologically related to both parents. It can enable single individuals to procreate without another person's genetic contribution. IVG can also allow groups of more than two individuals to procreate together, resulting in children who are genetically related to all the individuals involved. A game-changer for potential parents, IVG could transform the idea of family.

IVG is not the same as IVF

IVG should not be confused with in vitro fertilization (IVF), which has been helping couples with fertility for decades. While IVF is a well-established process, IVG is a new reproductive technology that is still in the research and development phase.

What's the science behind this assisted reproductive technology?

IVG can produce sperm and egg cells in a lab from almost any adult cell. This is done by using skin and blood cells to reverse engineer a special type of cell called induced pluripotent stem cells (iPSC). iPSCs are adult cells that have been genetically modified to an embryonic state. That means they can be used to produce eggs and sperm for reproduction.

Scientists have made significant strides in the development of IVG

In 2016, Japanese researchers successfully created viable eggs from the skin cells of mice and implanted them into female mice, resulting in healthy baby mice. The mice were healthy and able to have offspring of their own from the grown egg cells. In 2018, another researcher based in Japan was able to grow an early-stage egg from human stem cells derived from blood.

IVG may help preserve endangered species

IVG also has the potential to help protect endangered animal species by creating viable egg and sperm cells from stored tissue samples. This is important for animals with low reproduction rates, as it allows their genetic material to be saved without the need for live animals. It could also be helpful in bringing back extinct species whose tissue samples are preserved by scientists.

The ethical concerns of IVG

The ethics related to IVG are complicated, as it raises concerns about embryo farming and the commodification of reproduction. IVG also has the potential to enable direct gene editing, which could have unknown consequences. And there's a risk of unauthorized use of biological material, like hair or skin cells, to generate embryos, which raises crucial questions about privacy and consent.

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IVG: Tech that can turn skin cells into babies - NewsBytes