New strategy for eye condition could replace injections with eyedrops

 A new compound developed at the University of Illinois Chicago potentially could offer an alternative to injections for the millions of people who suffer from an eye condition that causes blindness.

Wet age-related macular degeneration causes vision loss due to the uncontrolled growth and leakage of blood vessels in the back of the eye. A new paper in Cell Reports Medicine led by UIC researcher Yulia Komarova finds that a small-molecule inhibitor can reverse damage from AMD and promote regenerative and healing processes.

The drug can also be delivered via eyedrops—an improvement over current treatments for AMD, which require repeated injections into the eye.

"The idea was to develop something that can be more patient-friendly and doesn't require a visit to the doctor's office," said Komarova, associate professor of pharmacology at UIC.

Komarova's compound targets a protein called End Binding-3 in endothelial cells, which line the inside of blood vessels. In the new study, the researchers looked at whether inhibiting EB3 function could stop the damaging leakage associated with wet AMD.

Using computational drug design methods, the team developed a small inhibitor that could be delivered externally via eyedrops instead of by injection. They then tested its effectiveness in animal models of wet AMD, finding that twice-daily treatment reduced eye damage within 2 to 3 weeks.

Further investigation found that the inhibitor worked by rolling back aging-related genetic modifications. Aging causes inflammation and hypoxia in the eye that leads to changes in gene expression associated with the cellular effects and symptoms of wet AMD. Komarova and colleagues found that the EB3 inhibitor they developed reversed these epigenetic changes, restoring gene expression to a normal, healthy state.

"We reduce the effects of the stressor on endothelial cells and we improve regenerative processes, accelerating healing," Komarova said. "That can be tremendous for the function of the cells."

Because blood vessel leakage and hypoxic stress also drive many other medical conditions, Komarova's group is interested in testing the inhibitor in models of acute lung injury, diabetic retinopathy, stroke, heart disease and even the general effects of aging on the brain. They're also exploring whether an implantable lens, similar to a contact lens, could deliver the drug to the eye more effectively than eyedrops.

More information: Quinn Lee et al, End binding-3 inhibitor activates regenerative program in age-related macular degeneration, Cell Reports Medicine (2023). DOI: 10.1016/j.xcrm.2023.101223

https://medicalxpress.com/news/2023-10-strategy-eye-condition-eyedrops.html

Vertex Positive, Updated VX-880 Results From Ongoing Phase 1/2 Study in Type 1 Diabetes

 All patients treated with VX-880 in Parts A and B have follow-up data beyond Day 90 and have demonstrated islet cell engraftment and glucose-responsive insulin production -

- All patients showed improvement across all measures of glucose control, including decreases in HbA1c, increases in blood glucose time-in-range, and reduction or elimination of insulin use -

- The two patients with at least 1 year of follow-up met the criteria for the primary endpoint of elimination of severe hypoglycemic events (SHEs) and HbA1c <7.0% -

- VX-880 was generally well tolerated -

- Part C concurrent dosing well underway -

https://www.businesswire.com/news/home/20231003786678/en/

Altered ubiquitin signaling induces hallmarks of sporadic Alzheimer's disease

 New discoveries in the development of Alzheimer's disease in a study led by Professor Michael Glickman and Dr. Inbal Maniv from the Faculty of Biology at the Technion were published in Nature Communications.

Alzheimer's disease was named after the German researcher Dr. Alois Alzheimer, who first described it in 1906. The disease is characterized by the degeneration and death of nerve cells, processes that lead to a progressive impairment of cognitive abilities. It occurs typically in adults over the age of 65, but a small percentage of all Alzheimer's patients are hereditary cases that affect younger patients.

Today, Alzheimer's disease is commonly divided into two types—familial and sporadic. Familial Alzheimer's disease is a rare condition, caused by genetic mutations. By contrast, the underlying mechanism of the more prevalent sporadic Alzheimer's disease is unclear and was the focus of the study conducted by Dr. Maniv and Professor Glickman.

Toxic proteins accumulate in the brains of Alzheimer's patients. The mechanism of accumulation in familial patients is clear because there is an obvious link between the known mutations and the proteins that accumulate. In sporadic Alzheimer's disease, on the other hand, the trigger for protein accumulation is unknown.

As protein experts, Prof. Glickman's research group proposed that the accumulation of toxic proteins in the brain is due to a disruption in the protein clearance mechanism, also known as the ubiquitin-proteasome system. To test their hypothesis, the group established a model system of human neurons, that allowed them to examine the involvement of the ubiquitin system in the development of the disease.

In the published article, they describe their results: damage to the ubiquitin system leads to the accumulation of toxic proteins even in healthy tissue, mimicking the typical Alzheimer's pathology.

To assess the importance of their findings, the researchers went on to engineer an RNA molecule that specifically silences one of the components of the ubiquitin system. Treatment with this molecule ameliorated the pathology in their experimental model. The team proposes that this RNA molecule could serve as a prototype for the development of effective treatments.

The past few years have seen major advancements in the packaging and delivery of bio-active RNA molecules as therapies. With proper modifications and packaging, the interference RNA targeting the component that the team has identified could yield promising results in a clinical setting. This discovery highlights the importance of the ubiquitin system in clearing defective proteins to maintain the cells' health. Disruption in this system could lead to the development of the disease.

The Technion researchers believe that beyond the findings presented in the article, the platform they developed may be used to screen drugs for the treatment and prevention of sporadic Alzheimer's disease. They add that this platform will help reduce animal experiments in the development of new Alzheimer's therapies.

More information: Inbal Maniv et al, Altered ubiquitin signaling induces Alzheimer's disease-like hallmarks in a three-dimensional human neural cell culture model, Nature Communications (2023). DOI: 10.1038/s41467-023-41545-7

https://medicalxpress.com/news/2023-10-protein-experts-ubiquitin-hallmarks-sporadic.html

'Protein mutation creates 'super' T cells with potential to fight off cancer and infections'

 Using laboratory-grown cells from humans and genetically engineered mice, scientists at Johns Hopkins Medicine say they have evidence that modifying a specific protein in immune white blood cells known as CD8+ T cells can make the cells more robust, potentially opening the door for better use of people's own immune system T cells to fight cancer.

The findings were published in the journal JCI-Insight.

"Maximizing the effectiveness of T-cell-based therapies remains a critical challenge," says David Kass, M.D., Abraham and Virginia Weiss Professor of Cardiology at the Johns Hopkins University School of Medicine and senior author of the study. "We've identified a powerful way to boost T cell function, offering a promising avenue for improving cancer immunotherapy and potentially treating a wide range of infectious and other diseases."

Kass and his team emphasize that their experiments to date are preclinical, and will require significant further laboratory-based efforts before they can be applied to human therapies.

For the current study, Kass and his team focused on CD8+ T cells, the circulating immune system "soldiers" responsible for identifying and fighting infections and cancer cells.

A protein called TSC2 (tuberous sclerosis protein 2) can activate or block a molecular pathway that regulates the T cells.

Overall, their experiments show that introducing a mutation in the TSC2 gene acts as a molecular "volume knob" to dial up or down the T cells' regulatory pathway when it's actively responding to immune challenges such as a virus or a cancer antigen. Like a volume knob, there is no change until the music starts—then it is louder.

The researchers found the mutated T cells were acting no differently than normal ones when they were just resting and not being stimulated to attack a target. They only became more active when stimulated. This type of control is relatively new for T cells.

This discovery, Kass says, raises the possibility of enhancing a therapy known as CAR-T, in which T cells are genetically engineered to better recognize a particular cancer. If these T cells also had the mutation in the TSC2 gene, the T cells could be more active against the tumor by multiplying, but could also persist longer, enhancing the T cells' effectiveness to kill cancer.

The scientists also found that the T cells containing the TSC2 mutation could expand in great numbers during the initial immune response, but then could also persist long-term, which differs greatly from other T cells used for therapy.

The T cells with the TSC2 mutation were also better able to multiply and be activated to fight infections and to counter tumors, despite being in an environment that was more acidic or had lower oxygen than their nonmutated counterparts.

"After testing our modified T cells, we found they were better at stopping tumor growth, proliferated more inside the tumor and didn't get tired out as easily," Kass says. "As we continue to unravel the complexities of the immune system, such innovative approaches hold promise for revolutionizing the field of immunotherapy."

In recent years, dozens of immunotherapies with novel drugs and antibodies have come on the market to treat cancer and other diseases, but response rates in patients vary widely, and overall, their optimal effectiveness as a group is only in the 15%–20% range. There is room for improvement, and many ongoing efforts are underway to do this. The new results may ultimately contribute to those efforts.

The researchers plan to do further studies with solid tumors such as lung, liver and colon cancers, which, compared with blood tumors such as leukemia, have been harder to achieve complete success with T cell-based therapies.

More information: Chirag H. Patel et al, TSC2 S1365A mutation potently regulates CD8+T cell function and differentiation improving adoptive cellular cancer therapy, JCI-Insight (2023). DOI: 10.1172/jci.insight.167829 insight.jci.org/articles/view/167829

https://medicalxpress.com/news/2023-10-protein-mutation-super-cells-potential.html

Promising treatment for cancer-related fatigue

 Cancer-related fatigue (CRF) is a debilitating yet all-too-common condition, which can severely affect quality of life for patients undergoing treatment. For those struggling with CRF, there have been no effective pharmaceutical treatments for the constellation of symptoms that together define the syndrome.

In a new study led by Yale Cancer Center researchers at Yale School of Medicine, the team found that a metabolism-targeting drug called dichloroacetate (DCA) helped alleviate CRF in mice, without interfering with cancer treatments. The findings are a pathway for future CRF research that may someday lead to a new therapy for patients.

The results were published in American Journal of Physiology-Endocrinology and Metabolism on Oct. 2.

"This study identifies dichloroacetate, an activator of glucose oxidation, as the first intervention, and particularly the first metabolism-focused intervention, to prevent the whole syndrome of cancer-related fatigue in preclinical models," said senior author Rachel Perry, who is a member of Yale Cancer Center.

Researchers used tumor-bearing mouse models to investigate the effectiveness of DCA in treating cancer-related fatigue for patients living with melanoma. The group found that DCA did not affect the rates of tumor growth or compromise the effectiveness of immunotherapy or chemotherapy in two mouse cancer models. DCA also significantly preserved physical function and motivation in mice with late-stage tumors.

The data suggests that DCA treatment may have several positive effects, including reducing oxidative stress in muscle tissue of tumor-bearing mice. The researchers said DCA could be a practice-changing approach in the future, when used as an adjuvant therapy to treat cancer-related fatigue.

"We hope that this research will provide the bedrock for future clinical trials using dichloroacetate—an FDA-approved drug for another indication (lactic acidosis)—to treat the debilitating syndrome of cancer-related fatigue," said Perry, who is also an assistant professor of medicine (endocrinology) and of cellular and molecular physiology at Yale School of Medicine.

Perry was joined by Yale first author Xinyi Zhang.

More information: Xinyi Zhang et al, Dichloroacetate as a novel pharmaceutical treatment for cancer-related fatigue in melanoma, American Journal of Physiology-Endocrinology and Metabolism (2023). DOI: 10.1152/ajpendo.00105.2023

https://medicalxpress.com/news/2023-10-team-treatment-cancer-related-fatigue.html

Oral lipid nanoparticle drug can prevent development of colitis-associated cancer

 An oral lipid nanoparticle drug prevents tumor development in mice, suggesting this is a promising drug formulation for preventing colitis-associated cancer, according to a study led by researchers in the Institute for Biomedical Sciences at Georgia State University.

The findings published in the journal Pharmaceutics report the oral drug formulation consists of M13-loaded nanoliposomes (M13-NL), also known as lipid nanoparticles. M13 is a promising anti-ulcerative colitis compound.

Patients with inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, have an increased risk of developing colitis-associated cancer, which has been found to be unresponsive to standard chemotherapy regimens. Early diagnosis and treatment of colitis-associated cancer can significantly increase patient survival because drug treatments are most effective in the early stages of cancer progression.

Current IBD drug treatments have severe side effects, depending on the specific medication used, which can include immunosuppression, bone loss, liver toxicity, pancreatitis and blood disorders. A safe and convenient treatment is needed that can effectively target and release drugs to diseased tissue, reduce side effects and improve symptoms. Current treatments don't use effective small-molecule drugs and colon-targeted delivery systems, according to the research study.

Previous studies have found the M13-NL formulation can effectively target the colon and reshape gut microbiota in cultures outside of the organism, generating altered microbial metabolites that can efficiently prevent chronic ulcerative colitis. This study tested the cancer cell uptake ability of the lipid nanoparticle formulation and investigated the potential of the M13-NL formulation to prevent colitis-associated cancer in mice.

"In prior studies, we demonstrated that lipids extracted from ginger-derived nanoparticles can be assembled to target specific parts of the digestive tract and support the efficient oral delivery of small molecules and siRNAs," said Dr. Didier Merlin, senior author of the study, Regents' Professor in the Institute for Biomedical Sciences at Georgia State, and senior research career scientist at the Atlanta Veterans Affairs Medical Center. "The assembled lipid nanoparticles also trigger less toxicity than traditional nanoparticles."

"In this study, we loaded these lipid nanoparticles with M13, which is a promising anti-ulcerative colitis compound, and used the generated M13-nano-liposome as an oral formulation to treat colitis-associated cancer. Our findings demonstrate that oral administration of M13-NL prevents tumor development in mice, suggesting that M13-NL is a promising candidate for preventing colitis-associated cancer in patients with inflammatory bowel disease."

The mice used in this study combine two critical factors involved in colitis-associated cancer development, chronic inflammation and DNA damage. They do not produce the anti-inflammatory cytokine, IL-10, in the colon, so they experience chronic inflammation. The compound azoxymethane (AOM) induces DNA damage in the colon, leading to the development of colorectal tumors.

This allowed the researchers to assess the in vivo efficacy of the long-term oral administration of M13-NL against the development of colitis-associated cancer, the study explained.

Further studies are needed to validate these findings and assess the safety and efficacy of M13-NL through human clinical trials, according to the study.

More information: Dingpei Long et al, Prevention of Colitis-Associated Cancer via Oral Administration of M13-Loaded Lipid Nanoparticles, Pharmaceutics (2023). DOI: 10.3390/pharmaceutics15092331

https://medicalxpress.com/news/2023-10-oral-lipid-nanoparticle-drug-colitis-associated.html

From A to Z: An alternative base modification for mRNA therapeutics

 Messenger RNA (mRNA) technology has become popular in the last few years due to its use in COVID-19 vaccines. This technology has been so groundbreaking that it recently won the 2023 Nobel Prize in medicine "for discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19."

This isn't new technology, however—modified mRNAs have been studied for decades and show significant potential for therapeutic applications. Compared to unmodified mRNAs, modified mRNAs are more stable and have more favorable immunogenic effects.

A team of researchers from the University of Illinois Urbana-Champaign has incorporated a newly discovered base, called base Z (2-aminoadenine), into mRNA to create Z-mRNA that has improved translational capacity, decreased cytotoxicity and drastically reduced immunogenicity compared to unmodified mRNA.

The results from this new research, led by chemical and biomolecular engineering professor Huimin Zhao, former chemical and biomolecular engineering graduate student Meng Zhang (current postdoc at Stanford University), and postdoc Nilmani Singh (Carl R. Woese Institute for Genomic Biology), were recently published in the journal iScience.

"We incorporated base Z into mRNA, and we wondered whether it would perform better than the current modified mRNA vaccine platform," says Zhao.

mRNA is a macromolecule that is transcribed from DNA and contains the instructions for protein production in cells. For use in vaccines, the mRNA is used to encode the antigen that triggers an immune response in human bodies. This way, the body is "trained" to fight off certain viruses and if infected with the real thing, the body can recognize it and produce the necessary antibodies.

Unmodified mRNA contains four bases—A, G, C and U. In this research, base A was replaced with base Z, which can form three hydrogen bonds, a weak bond between two molecules from an attraction of positive and negative charges, with base U (unlike two hydrogen bonds formed between typical A:U pairing). Moreover, base Z differs from other modified bases because it does not come from the human body.

"Traditional wisdom is that modified bases should ideally come from the human body so that any mRNA modified by such a base would mimic mRNA in the human body and bypass immune surveillance," Zhang says.

Despite not naturally existing in the human body, base Z mRNA still demonstrated low immunogenicity—the ability of cells to provoke an immune response and generally considered to be an undesirable physiological response—and reduced cytotoxicity (causing cell death) when tested in cultured cells. While mRNA-based vaccines in general induce lower immune responses, many people still experience some sort of immune reaction.

"Having an mRNA vaccine alternative with less side effects would be a really big deal," says Singh.

To demonstrate the application of their Z-mRNA in vivo, the team developed a Z-mRNA-based COVID-19 vaccine. They tested this Z-mRNA vaccine, alongside the modified mRNA vaccine used by Moderna and Pfizer, in mice, and they found that the Z-mRNA vaccine could induce a substantial and antigen-specific immune response. Although the potency of the Z-mRNA vaccine was not as strong as the current standard, the team believes Z-mRNA could be further improved through systematic engineering efforts.

"The biggest implication of this work is that people don't have to be limited by those modifications that are naturally present in our body, it is possible to choose modifications outside of our body, but that can still give the desired biological effects such as reduced immunogenicity and enhanced translational ability," says Zhang.

"We proved that our new modified mRNA vaccine has reduced cytotoxicity and also minimal immunogenicity, which has been a problem in the past for mRNA-based therapies," says Zhao. "mRNA-based therapeutics are a hot area currently. Not just for vaccine applications, but even for cancer treatments. We want to take advantage of the unique features of Z-containing mRNA for other therapeutic applications."

Huimin Zhao is also an affiliate of the Department of Chemistry, the Department of Biochemistry, and the Department of Bioengineering at UIUC. Other contributors to this work include Mary Elisabeth Ehmann (Department of Chemical and Biomolecular Engineering at the University of Illinois at Urbana-Champaign) and Lining Zheng (Department of Materials Science and Engineering at the University of Illinois at Urbana-Champaign).

More information: Meng Zhang et al, Incorporation of noncanonical base Z yields modified mRNA with minimal immunogenicity and improved translational capacity in mammalian cells, iScience (2023). DOI: 10.1016/j.isci.2023.107739

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