Category Archives: Gene Medicine

Abhinav Achreja, PhD, Research Fellow at the University of Michigan Biomedical Engineering and Deepak Nagrath, Ph.D. Associate Professor of Biomedical Engineering work on ovarian cancer cell research in the bio-engineering lab at the North Campus Research Center (NCRC). Image credit: Marcin Szczepanski, Michigan Engineering

The way that tumor cells enable their uncontrolled growth is also a weakness that can be harnessed to treat cancer, researchers at the University of Michigan and Indiana University have shown.

Their machine-learning algorithm can identify backup genes that only tumor cells are using so that drugs can target cancer precisely.

Most cancer drugs affect normal tissues and cells. However, our strategy allows specific targeting of cancer cells.

The team demonstrated this new precision medicine approach treating ovarian cancer in mice. Moreover, the cellular behavior that exposes these vulnerabilities is common across most forms of cancer, meaning the algorithms could provide better treatment plans for a host of malignancies.

This could revolutionize the precision medicine field because the drug targeting will only affect and kill cancer cells and spare the normal cells, said Deepak Nagrath, a U-M associate professor of biomedical engineering and senior author of the study in Nature Metabolism. Most cancer drugs affect normal tissues and cells. However, our strategy allows specific targeting of cancer cells.

This approach is known as collateral lethalityusing information gleaned from genes that cancer cells discard to find weaknesses. The human body comes with many mechanisms designed to protect against cancer. Cancer cells themselves used to contain suppressor genes that prevent their spread. Those cells however, have a clever strategy for dealing with that; they simply delete a portion of their DNAthe part that includes those suppressor genes.

In doing so, the cells typically lose other genes that are necessary for survival. To avoid death, the cells find a paraloga gene that can serve a similar function. Usually there are one or, possibly, two genes that can step in and perform the same function to keep the cell alive.

What if you could identify the right paralog and target it in a way that shuts down its vital function for the cell?

When a direct replacement for the deleted metabolic gene is not available, our algorithms use a mathematical model of the cancer cells metabolism to predict the paralogous metabolic pathway they might use, said Abhinav Achreja, a U-M research fellow in biomedical engineering and lead author on the research paper. These metabolic pathways are important to the cancer cells and can be targeted selectively.

Study abstract: Metabolic collateral lethal target identification reveals MTHFD2 paralog dependency in ovarian cancer (DOI: 10.1038/s42255-022-00636-3)

Attacking metabolic pathways essentially shuts down the cells energy source. In examining ovarian cancer cells, U-Ms team zeroed in on one gene, UQCR11, that was often deleted along with a suppressor gene. UQCR11 plays a vital role in cell respirationhow cells break down glucose for energy in order to survive.

Disturbances in this process can lead to a major imbalance of an important metabolite, NAD+, in the mitochondria, where respiration takes place. Despite all odds, ovarian cancer cells continue to thrive by relying on their backup plan.

U-Ms algorithm correctly sorted through multiple options and successfully predicted a cell missing UQCR11 would turn to the gene MTHFD2 as its backup supplier of NAD+.

Researchers at the Indiana University School of Medicine helped validate the findings in the lab. This team, led by professor of medicine Xiongbin Lu, developed genetically modified cell and animal models of ovarian cancers with the deletions. Six out of six mice tested showed complete cancer remission.

This research was supported by funding from the National Cancer Institute, Office of the Director for the National Institutes of Health, University of Michigan Precision Health Scholars Award, and Forbes Scholar Award from Forbes Institute of Cancer Discovery.

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Shutting down backup genes leads to cancer remission in mice - University of Michigan News

We can now screen for over 500 different types of [disorders] depending on the company or test you are using, says Dr. Keegan. This gives us the opportunity to prevent the transmission of inherited genetic disorders through the technology available and a simple blood test.

The ACOG recommends considering family history and ethnicity, in addition to the most common genetic conditions, when deciding which mutations to include. Parents may also benefit from genetic counseling, which is a service that helps people understand the results of their tests and make informed decisions throughout the process.

Here are some of the most common conditions identified through genetic carrier screening:

There are currently almost 40,000 children and adults living with cystic fibrosis in the U.S. Cystic fibrosis is a disease that affects the lungs, pancreas and other organs. People who have cystic fibrosis have difficulties breathing. The mutation involved with cystic fibrosis causes a protein to not function correctly, which then causes mucus buildup in multiple organs throughout the body.

About 1 in 7,000 males and about 1 in 11,000 females have fragile X syndrome, the most common cause of inherited intellectual disability. Fragile X is associated with lower than average IQ, developmental delays and other co-occurring health conditions including seizures, autism, hyperactivity, attention difficulties and more.

One in every 6,000 babies is born with spinal muscular atrophy, or SMA, which is a group of genetic disorders that cause a weakening of the muscles. Symptoms may vary, but people with SMA may require physical and occupational therapy, support devices such as wheelchairs or assistance with breathing. Symptoms generally worsen over time and there is no cure.

Although anyone can be a carrier, Tay-Sachs disease is more common for people of Ashkenazi Jewish ancestry, as one in every 27 members of the population is a carrier for the disease. Symptoms may include deafness, blindness, seizures, decreased muscle tone, dementia and others.

It is estimated that approximately 100,000 people in the U.S. have sickle cell disease. This inherited condition is most common in Black or African American people but can affect any race. Sickle cell disease includes a group of red blood cell disorders that can cause acute chest syndrome, anemia, blood clots or infections.

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Genetic Testing Before Pregnancy: What You Need To Know - Forbes

CAMBRIDGE, Mass., Sept. 22, 2022 (GLOBE NEWSWIRE) -- Verve Therapeutics, a clinical-stage biotechnology company pioneering a new approach to the care of cardiovascular disease with single-course gene editing medicines, today announced that management will participate in the following upcoming investor conferences:

Live webcasts will be available in the investor section of the company's website at http://www.vervetx.com and will be archived for 60 days following the presentations.

About Verve Therapeutics Verve Therapeutics, Inc. (Nasdaq: VERV) is a clinical-stage genetic medicines company pioneering a new approach to the care of cardiovascular disease, potentially transforming treatment from chronic management to single-course gene editing medicines. The companys initial two programs VERVE-101 and VERVE-201 target genes that have been extensively validated as targets for lowering low-density lipoprotein cholesterol (LDL-C), a root cause of cardiovascular disease, in order to durably reduce blood LDL-C levels. VERVE-101 is designed to permanently turn off thePCSK9gene in the liver and is being developed initially for heterozygous familial hypercholesterolemia (HeFH) and ultimately to treat atherosclerotic cardiovascular disease (ASCVD) not at goal on oral therapy. VERVE-201 is designed to permanently turn off theANGPTL3gene in the liver and is initially being developed in homozygous familial hypercholesterolemia (HoFH) and ultimately in patients with ASCVD who have not achieved goal LDL-C with oral therapy and a PCSK9 inhibitor. For more information, please visit http://www.VerveTx.com.

Investor ContactJen RobinsonVerve Therapeutics, Inc.jrobinson@vervetx.com

Media ContactAshlea Kosikowski1ABashlea@1abmedia.com

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Verve Therapeutics to Participate in Upcoming Investor Conferences - GlobeNewswire

This week, researchers delivered insights and breakthroughs in regenerative medicine, Long COVID, immuno-oncology and inflammatory diseases.

Epigenetic Treatment Shows Potential in Spinal Cord Regeneration

Researchers reported that activation of the CBP/p300 protein family led to increased axon growth, regenerative signaling and synaptic plasticity in the spinal cord after injury in mice.

The study, led by Imperial College London,used a molecule called TTK21 to activate the genetic program to induce axon regeneration in neurons. During this process, TTK21 changes the epigenetic state by activating the CBP/p300 family of co-activator proteins, effectively leading to increased axon regeneration.

In the study, researchers began treating the mice 12 weeks after severe spinal cord injury and continued for 10 weeks. They found axon sprouting in the spinal cord and retraction of motor neurons above the injury. These changes are believed to have been spurred by increased gene expression related to regeneration, which the researchers attributed to the TTK21 treatment.

The results, while early and limited, are a step toward potential treatments for spinal cord injury.

The next steps will be to enhance the effects of the treatments and trigger the regenerated axons to connect to the rest of the nervous system. The ultimate goal is to enable animals, and eventually people, to regain movement lost from their injuries.

Neurological Consequences Evident in Long-Term COVID Study

In a recent attempt to decode the long-term impacts of COVID-19, researchers built a dataset fromthe national healthcare databases of the US Department of Veterans Affairs.

The study,led by the Clinical Epidemiology Center, Research and Development Service at VA St. Louis Health Care System,included154,068 individuals with COVID-19, 5,638,795 contemporary controls and 5,859,621 historical controls.

Results were published Thursday in Nature Medicine.

Upon examination of the data sets, the researchers noted an increased risk in a series of neurological consequences. These included: ischemic and hemorrhagic strokes, episodic disorders, extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, Guillain-Barr syndrome and encephalitis or encephalopathy.

They estimated a hazard ratio of 1.42 neurological sequelae per thousand COVID-19 cases, and 70.69 burdens per 1,000 cases.

These numbers were not impacted by the severity of the infection or the need for hospitalization. The researchers note the sample set comprised a majority of white men, so further exploration into other demographic groups may be necessary for future studies.

Novo Nordisk and Octagon Unite on Inflammatory R&D

Octagon Therapeutics, a pre-clinical biopharmaceutical focused on autoimmune disease, announced the initiation of a multi-year research collaboration with Novo Nordiskto studypotential treatments for inflammatory diseases.

Octagon will bring its functional target discovery approach and novel chemistry approach, while Novo will contribute its specific disease expertise.

Uli Stilz, vice president of the Bio-Innovation Hub at Novo Nordisk, commented on the synergies.

Combined with our disease understanding in the cardiometabolic space and Octagons approach in targeting specific lymphocyte populations that drive disease progression, it will be exciting to see what therapeutic discoveries the collaboration can lead to, he said.

Regen's RNA/DNA-Based Cancer Immunotherapy

Regen BioPharmaannounced the filing of a provisional patent application for its RNA/DNA-based approach to cancer immunotherapy.

The patent pertains to what Regen believes is the first combination of an immunotherapy and a gene silencing agent in a single drug.

The novel composition acts as a checkpoint inhibitor drug that also silences the genes that regulate T-cells and cancer cells such as NR2F6 and Survivin.

The new drug takes advantage of aptamers - a short RNA or DNA sequence that can also function as an antibody, recognizing specific proteins and binding to them. The proprietary sequence codes for inhibitory RNA, while keeping the aptamer intact on the other side. When it binds to a checkpoint such as PD-1, that RNA is converted within the cell, thus killing it.

Used to target cancer cells, this could lead to better disease control and treatment. There is also hope that this process could be used to activate T cells, improving their immunotherapeutic potential.

Toronto-Based Researchers Uncover Potential Solve for CAR T Toxicities

Allogeneic double-negative (DN) chimeric antigen receptor (CAR)-T cells inhibit tumor growth without off-tumor toxicities, a new study found.

Current CAR-T therapies approved by the FDA in treating blood cancers are limited by their level of toxicity and cost of production. Researchers from the Toronto General Hospital Research Institute, University Health Network, reported a new version of these therapies that did not have these drawbacks.

The researchers found healthy donor-derived allogeneic DNTs as a CAR-T cell therapy platform had high levels of efficacy in both the human and mouse models.

The researchers found the DN CAR-T cells were as effective as previously studied CAR-T cells but did not have the associated toxicity levels. They also come with the advantage of being made from mixed donors and remained effective even after being frozen for long periods of time. This feature could potentially overcome manufacturing challenges in the space.

The authors noted these features make DN CAR-T cellsan attractive off-the-shelf CAR-T cell therapy option.

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Research Roundup: Regenerative Potential, Long COVID Insights, Immuno-Oncology and More - BioSpace

When we are physically active our bones and muscles work together to make them stronger. To maintain bone health, the American College of Sports Medicine recommends a combination of weight-bearing activities 35 times per week and resistance exercise 23 times a week.

Research has shown lifelong exercise to be beneficial for preserving bone health, and a reduction in physical exercise results in bone loss. The CDC advocates regular physical activity to strengthen and maintain muscle and bone, research has shown improving muscle strength can have a moderate effect in relieving joint pain for people with osteoarthritis.

Despite its benefits, modern-day living is associated with a lack of physical activity. According to the World Health Organization, physical inactivity is a serious but insufficiently addressed public health problem with up to 85% of the worlds population leading a sedentary lifestyle.

Inactivity is also associated with an increased risk of chronic disease. The British Heart Foundation attributes more than 5 million deaths worldwide to physical inactivity, which equates to one in nine deaths overall.

Chronic conditions, injury, and aging may mean it is more difficult to undertake physical activity, which can lead to muscle weakening (sarcopenia) and bone loss (osteoporosis).

New research undertaken at Tokyo Medical and Dental University (TMDU) has identified a new drug that can mimic exercise, and promote similar changes in muscle and bone.

The work, led by Professor Tomoki Nakashima, has been published in Bone Research.

In the study, the research team identified a new compound called Locamidazole (LAMZ) as a potential therapeutic drug that can cause similar effects to exercise.

To test the new compound, the researchers administered either 10mg/kg of LAMZ orally once daily, 6mg/kg LAMZ by injection twice daily, or a control solution for 14 days to male mice.

Administration of LAMZ orally and by injection showed changes in both muscle and bone. Researchers noted that the treated mice had wider muscle fibers and increased muscle strength when compared to the non-LAMZ-treated mice.

Endurance was studied using a treadmill device, the LAMZ-treated mice were less fatigued and traveled a longer distance than the non-treated mice.

In an interview with Medical News Today, Dr. Joseph Watso, assistant professor at Florida State University, who was not involved in the study, explained:

It is thought-provoking that while the changes in distance traveled by the animals were small (around 2%), the increases in adjusted maximal muscle strength and muscle fiber width were quite substantial after 14 days of LAMZ administration.

Using gene analysis, the researchers showed that LAMZ increased the number of mitochondriathe powerhouse of the cellin muscle and bone cells. They noted an increase in the expression of the gene for the PGC-1 alpha, a protein known to maintain muscle and bone cells and increase the production of mitochondria.

PCG1a is a known transcriptional coactivator that increases mitochondrial biogenesis. This is an interesting feature of the agent they identified as mitochondrial biogenesis is a hallmark physiological adaption of exercise training, Dr. Watso explained to MNT.

To understand the pathway further, the researchers orally administered LAMZ to mice whilst blocking PGC-1 alpha. They found no increase in muscle strength, indicating the effects of LAMZ on muscle and bone through PGC-1 alpha.

3D images of bone samples generated using Micro-CT showed an increase in bone thickness, density, and bone mineral content, confirming the cell study findings of increased formation and a reduction of bone loss.

We were pleased to find that LAMZ-treated mice exhibited larger muscle fiber width, greater maximal muscle strength, a higher rate of bone formation, and lower bone resorption activity, the studys lead author Takehito Ono commented.

The study has shown that LAMZ can reinforce bone and muscle with no negative effects on surrounding tissues, and can function as a therapeutic drug by reinvigorating muscle and bone via PGC- 1, mimicking physical exercise.

Dr. Watso summarized the findings:

The article provides convincing evidence in animals for an agent with a high potential to improve bone and muscle health. Like most agents evaluated in animals, the key next question is whether those findings will translate to humans. Of course, without any harmful side effects that may not have been observed in the animal studies.

He cautioned that it will be an arduous task to develop one elixir of health to replace the innumerable benefits of regular physical activity and exercise. That said, continued efforts are needed to reduce the incidence of, and burden associated with, preventable diseases.

In certain cases, medication may be the safer option than exercise, but where possible, exercise should be the first consideration for those who have the capability to be physically active, said Dr. Watso.

Despite this, it is certainly worthwhile to continue to examine population-specific risk factors and pathophysiology for potential treatment targets, he added.

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Could a pill to strengthen muscle and bone replace exercise? - Medical News Today

The past decade has witnessed a rapid expansion of genetic tests, including new instruments to inform patients who have been diagnosed with breast cancer about the risk of recurrence and to guide their treatment.

But the clinical significance of many of the inherited mutations that can now be identified remains unclear, and experts are torn on when and how to deploy all the new tests available. Patients are sometimes left paying out-of-pocket for exams that are not yet the standard of care, and even the most up-to-date oncologists may be uncertain how to incorporate the flood of new information into what used to be standard treatment protocols.

A quarter-century ago, Myriad Genetics introduced the first breast cancer genetic test for BRCA mutations, two genes associated with a substantially elevated risk of getting breast cancer, opening the door to a new era in genetic testing. BRCA1 and BRCA2 mutations account for as many as half of all hereditary breast cancers, and people with a problematic mutation on one of those genes have a 45% to 72% chance of developing breast cancer during their lifetimes. They may also be at higher risk for ovarian and other cancers than people without harmful BRCA mutations.

But the clinical significance is murkier for many other genetic tests.

Testing for BRCA1 and BRCA2 genes used to cost thousands of dollars. Now, for a fraction of that, doctors can order multi-gene test panels from commercial labs that look for mutations in dozens of genes. Some direct-to-consumer companies offer screening panels for a few hundred dollars, though their reliability varies.

When Jen Carbary was diagnosed with breast cancer in 2017 at age 44, genetic testing identified a mutation in a gene called PALB2 that significantly increases the risk of developing breast cancer. Guidelines suggest that breast cancer patients with a PALB2 mutation, much like those with BRCA1 and BRCA2 mutations, consider having a mastectomy to reduce the chance of a breast cancer recurrence.

"I wish genetic testing was the standard of care," said Carbary, who owed nothing for the test because her insurer covered the cost.

Carbary, who lives in Sterling Heights, Michigan, said the test results affirmed the decision she had already made to have a double mastectomy and provided important information for family members, including her 21-year-old daughter and 18-year-old son, who will likely be tested in their mid-20s or early 30s.

But some breast cancer experts are concerned that widespread testing may also identify genetic mutations whose impact is unclear, creating anxiety and leading to further testing and to treatment of questionable value that could raise costs for the health care system.

It can also confuse patients.

"It happens a lot, that patients find their way to us after getting confusing results elsewhere," said Dr. Mark Robson, chief of the breast medicine service at Memorial Sloan Kettering Cancer Center in New York City. Robson said the cancer center has a clinical genetics service, staffed by doctors and genetic counselors, that helps people make decisions about how to manage genetic testing results.

For people diagnosed with breast cancer, many professional groups, including the influential National Comprehensive Cancer Network, or NCCN, recommend limiting testing to certain people, including those with high-risk factors, such as a family history of breast cancer; those who are 45 or younger when they're diagnosed; and those with Ashkenazi Jewish ancestry.

But in 2019, the American Society of Breast Surgeons recommended a different approach: Offer genetic testing to all patients who are diagnosed with or have a personal history of breast cancer. The recommendation was controversial.

"The NCCN guidelines [cover] most of the women who needed testing, but we wanted to get them all," said Dr. Eric Manahan, a general surgeon in Dalton, Georgia, and a member of the surgeons group's board of directors.

Mutations on other genes that are associated with breast cancer are much less common than BRCA1 and BRCA2 mutations and generally don't increase the risk of developing breast cancer as much. The cancer-causing impact of these genes may be less clear than that of the BRCA genes, which have been tested for since the mid-1990s.

And the appropriate response to the less common mutations whether to consider a risk-reducing mastectomy or stepped-up screening is often unclear.

"Things get sloppier and sloppier when you look at other genes," said Dr. Steven Katz, a professor of medicine and health management and policy at the University of Michigan. "The risks tend to be lower for different cancers, and less certain and more variable. You might walk away wondering, 'Why'd I have to know that?'"

After people are diagnosed with breast cancer, genetic testing can help inform their decisions about the types of surgery to pursue for example, a high risk of recurrence or a new breast cancer might persuade some to opt for more extensive surgery, such as a double mastectomy. Testing can also provide important information to family members about their potential cancer risk.

(This type of "germline" genetic testing, as it's called, looks at mutations in the genes that people inherit from their parents. It is different from genomic tumor tests that look at specific genes or proteins in the cancer cells and can help doctors understand the rate at which the cancer cells are dividing, for example, and the likelihood of a cancer recurrence.)

Increasingly, germline genetic testing can also help guide other treatment decisions. Some patients with metastatic breast cancer who have BRCA1 or BRCA2 mutations may be good candidates for PARP inhibitors, cancer drugs that target tumors with mutations in those genes.

But genetic testing that uncovers inherited mutations in many other genes yields less clearly actionable information, even though positive results may alarm people.

At Memorial Sloan Kettering, cancer specialists focus on "therapeutic actionability," said Robson. Will testing help someone decide whether she should get a double mastectomy or provide other important guidance? "A policy of testing everyone will identify very few additional BRCA breast mutations but will cost a lot," he said.

As a result, doctors are debating how best to deploy and incorporate new genetic knowledge. Insurers are trying to figure out which to pay for.

There is both underuse of tests that science says are relevant and overuse of tests that experts say provide information that can't be interpreted with any scientific certainty.

The result may be confusion for patients newly diagnosed with breast cancer as they confront the expense of genetic tests and sometimes little guidance on the proper treatment.

Some doctors say the first step is to make sure that the small group of people who would clearly benefit are getting the genetic tests whose meaning is clearly understood. Only 15% of breast cancer patients who met select NCCN testing guidelines for inherited cancer received genetic testing, according to a 2017 study that examined data from a national household health survey between 2005 and 2015.

"I would argue that our focus needs to be on the people who are at high risk for breast cancer that aren't even identified yet," said Dr. Tuya Pal, associate director for cancer health disparities at Vanderbilt-Ingram Cancer Center and vice chair of the NCCN guidelines panel for genetic/familial high-risk assessment of breast, ovarian, and pancreatic cancers.

Patients may fall through the cracks because no one tells them they should be tested. In one analysis, 56% of high-risk breast cancer patients who didn't get genetic testing said their doctors didn't recommend it.

Even if doctors recommend genetic testing, they may lack the expertise to determine which tests people need and how to interpret the results. That's the role of genetic counselors, but their ranks are stretched thin.

The consequences can be serious. In a study of 666 breast cancer patients who received genetic testing, half of those at average risk for inherited cancer got double mastectomies based on test results that found "variants of uncertain significance," which aren't clinically actionable. As many as half of surgeons reported managing such patients the same way as those with cancer-causing mutations.

"The bulk of our research would say that there is still room for improvement in terms of clinicians getting the understanding they need," said Dr. Allison Kurian, director of the women's clinical cancer genetics program at Stanford University and a co-author of the study.

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Genetic Tests Create Opportunities and Confusion for BRCA Patients - Medscape