Target to $34 from $10
Monday, August 21, 2023
Anebulo: Positive Feedback from FDA on Path to Advance Phase 3
Anebulo Pharmaceuticals, Inc. (Nasdaq: ANEB) (the "Company" or "Anebulo"), a clinical-stage biopharmaceutical company developing novel solutions for people suffering from acute cannabinoid intoxication (ACI) and substance abuse, today announced positive feedback from the United States Food and Drug Administration (FDA) following a Type B meeting in July. The FDA indicated that a single well-controlled study of ANEB-001 in ACI patients presenting to the emergency department combined with a larger THC challenge study in volunteers could potentially provide substantial evidence to support a new drug application.
https://finance.yahoo.com/news/anebulo-receives-positive-feedback-fda-120000098.html
Compass: Up to $285 M Private Placement Financing Joined by Leading Healthcare Investors
Transaction led by healthcare specialist investors, TCGX and Aisling Capital
$125 million financing upfront with up to an additional $160 million tied to exercise of warrants
Net proceeds from financing expected to extend cash runway into late 2025
'Viral relicts' in the genome could fuel neurodegeneration
Genetic remnants of viruses that are naturally present in the human genome could affect the development of neurodegenerative diseases. Researchers at DZNE have come to this conclusion based on studies of cell cultures. In their view, such "endogenous retroviruses" could contribute to the spread of aberrant protein aggregates—hallmarks of certain dementias—in the brain. Thus, these viral relicts could be potential targets for therapies. They have reported these findings in the journal Nature Communications.
It has been suspected for some time that viral infections contribute to the genesis and development of neurodegenerative diseases. Laboratory studies by DZNE scientists now suggest a mechanism that, although related to viruses, does not require infection by external pathogens. According to this study, the culprits would be endogenous retroviruses that are naturally present in the human genome.
"During evolution, genes from numerous viruses have accumulated in our DNA. Most of these gene sequences are mutated and normally muted," explained Ina Vorberg, research group leader at DZNE and a professor at the University of Bonn. "However, there is evidence that endogenous retroviruses are activated under certain conditions and contribute to cancer and neurodegenerative diseases. Indeed, proteins or other gene products derived from such retroviruses are found in the blood or tissue of patients."
Experiments with tau aggregates
Vorberg followed this trail together with colleagues from Bonn and Munich. Using cell cultures, the researchers simulated the situation in which human cells produce certain proteins from the envelope of endogenous retroviruses. Specifically, this involved HERV-W and HERV K—both viruses are present in the human genome but are usually dormant. However, studies indicate that HERV-W is activated in multiple sclerosis and HERV-K in the neurological disease amyotrophic lateral sclerosis (ALS) and in frontotemporal dementia (FTD).
Now, Vorberg's team has found that the viral proteins facilitate the transport of so-called tau aggregates from cell to cell. Tau aggregates are tiny protein clumps that occur in the brains of people affected by certain neurodegenerative diseases, including Alzheimer's disease and FTD.
"Certainly, conditions in the brain are much more complex than our cellular model system can replicate them. Nevertheless, our experiments show that endogenous retroviruses can influence the spread of tau aggregates between cells," Vorberg said. "Endogenous retroviruses would thus not be triggers of neurodegeneration, but could fuel the disease process once it is already underway."
Viral transport mediators
The current research and earlier studies by Vorberg's team suggest that viral proteins serve as transport mediators for tau aggregates because they insert into the cell membrane and into the membrane of the so-called extracellular vesicles, which are small fat bubbles that are naturally secreted by cells.
"For the transport of tau aggregates from cell to cell, we see two pathways in particular. Transfer between cells that are in direct contact, and transport within vesicles that act as cargo capsules, so to speak, and pass from one cell to another to eventually merge with it," Vorberg explained.
"In both scenarios, membranes have to fuse. Proteins from the envelope of viruses can promote this process. That's because many viruses are adapted to fuse with host cells. This happens by means of special proteins that viruses carry on their surfaces. If precisely these proteins are incorporated into the cell membrane and the membrane of extracellular vesicles, it is understandable that the tau aggregates then spread more easily."
Starting points for therapy
In the course of the natural aging process, the regulation of genes can change—originally "dormant" endogenous retroviruses could be "awakened" as a result. Indeed, the symptoms of most neurodegenerative diseases do not manifest until older age. This raises two conceivable approaches to therapy.
"On the one hand, one could try to specifically suppress gene expression, that is, to inactivate the endogenous retroviruses again. That would get to the root of the problem," Vorberg said. "But you could also start elsewhere and try to neutralize the viral proteins—for example, with antibodies."
Searching for antibodies
In the opinion of the researchers, it is likely that dementia patients with tau aggregates carry increased amounts of such antibodies. If it were possible to isolate these and reproduce them using biotechnological methods, it might be possible to develop a passive vaccine. Thus, in collaboration with DZNE colleagues in Berlin and Bonn, Vorberg's team aims to specifically search for such antibodies in patients.
In addition, the scientists are considering antiviral drugs. In cell culture, they have already found that such agents can actually stop the spread of protein aggregates. "This is another approach we intend to pursue," said Vorberg.
More information: Shu Liu et al, Reactivated endogenous retroviruses promote protein aggregate spreading, Nature Communications (2023). DOI: 10.1038/s41467-023-40632-z
https://medicalxpress.com/news/2023-08-viral-relicts-genome-fuel-neurodegeneration.html
'Does prior omicron infection shield against future infection? Maybe not'
People may assume that a COVID-19 infection protects them the next time they encounter the virus, but that's not necessarily true.
A new study of 750 vaccinated seniors living in retirement homes and long-term care facilities found that those infected during the first omicron wave were actually more vulnerable to reinfection with a later wave.
"This research highlights the need for continued vigilance and underscores the importance of ongoing preventive measures against COVID-19," said study co-author Dawn Bowdish, an immunologist and associate professor of medicine at McMaster University in Ontario, Canada.
"We must remain cautious and proactive in our approach to protecting public health," she said in a university news release.
Bowdish and her colleagues said the findings underscore the need to consider COVID vaccine boosters this fall.
This should serve as a warning that there are still unknowns about how previous infections will affect susceptibility to the variants now in circulation, said co-author Andrew Costa, an epidemiologist and associate professor in McMaster's Department of Health Research Methods, Evidence and Impact.
"These findings strongly suggest broader research is required to understand whether the wider population shares the same susceptibility as the seniors our group studied," Costa said in the release. "Until we know more, we think it's smart for everyone to protect themselves."
Bowdish said long-term care residents are easier to study because COVID-19 infections were, until recently, monitored more closely. The results may not be the same in the wider population, but it's important to learn more, she said.
The region where the study participants lived has seen four major waves of omicron. Those included the first wave, with omicron BA.1 and BA.2 variants, which caused older adults to be more susceptible to infections in the third wave, which was caused by the omicron BA.5 variant, according to the study.
Researchers were not able to identify which omicron variant a person had, but the initial infections occurred during the BA.1/BA.2 wave, and the reinfections occurred during the summer of 2022 when the BA.5 variant was responsible for the vast majority of infections.
"We found that some individuals had normal immune responses after the first infection, while others had very low levels of protective antibodies, which we believe was one contributing factor to why they got reinfected," Bowdish said.
"Our current vaccine schedules are based on the assumption that having had an infection provides some level of protection to future infections, but our study shows that may not be true for all variants in all people," Bowdish said.
The findings were published Aug. 21 in eClinicalMedicine
More information: Jessica A. Breznik et al, Early Omicron infection is associated with increased reinfection risk in older adults in long-term care and retirement facilities, eClinicalMedicine (2023). DOI: 10.1016/j.eclinm.2023.102148
https://medicalxpress.com/news/2023-08-prior-omicron-infection-shield-future.html
Timing is key in cortisone treatment of inflammation
Whether you have a sports injury, repetitive strain injury or pain in the knee, cortisone preparations are often used to treat acute inflammations. Chronic inflammatory diseases such as asthma, diabetes and chronic inflammatory bowel diseases are also treated with drugs containing cortisone or derived drugs. This is because these drugs usually have a rapid anti-inflammatory effect.
However, there are also drawbacks: Their therapeutic efficacy is often limited in time, as they work very well at the beginning but their beneficial effects decrease over the course of treatment. In addition, there can be serious side effects, including osteoporosis, increased susceptibility to infections, stomach ulcers and metabolic disorders.
"When using these preparations, it's therefore important to limit and optimize their use," says Prof. Oliver Werz, Professor for Pharmaceutical/Medicinal Chemistry at the University of Jena. But when is the optimum treatment window, and when is the use of cortisone preparations contraindicated? Until now, there has not been any clear answer to this question.
In a recent study, Prof. Werz and Dr. Markus Werner of the Institute of Pharmacy, together with other researchers from the University of Jena, Jena University Hospital and Harvard Medical School (U.S.), have now clarified an important biochemical mechanism explaining how cortisone preparations mediate inflammation-resolving effects in human immune cells, thus paving the way for an optimized use of these drugs. The researchers present their results in PNAS.
Cortisone influences enzymes
In the course of an inflammatory reaction, pro-inflammatory immune cells appear first, including M1 macrophages. They produce pro-inflammatory messenger substances (prostaglandins and leukotrienes), which trigger the typical symptoms, such as fever and pain. After a few days, the second phase follows, in which the inflammation subsides. At that point, macrophages of the "M2" type are increasingly active, which produce inflammation-resolving messenger substances (i.e., resolvins).
"In studies on cell cultures, we were able to show that cortisone regulates the activity of certain enzyme genes in the immune cells, which influence the inflammatory process," explains Dr. Werner. In this way, cortisone induces the formation of inflammation-resolving resolvins in M1 macrophages, which appear early, but significantly impairs this function in the M2 macrophages, which appear later.
This effect is regulated by the 15-lipoxygenase enzymes, which occur in two forms in immune cells: 15-lipoxygenase-1 and 15-lipoxygenase-2. "We found that cortisone upregulates 15-lipoxygenase-2 in pro-inflammatory M1 macrophages of the early inflammatory phase. This enzyme catalyzes the formation of resolvins, thereby stopping and resolving inflammatory processes, which is partly responsible for the positive effects of cortisone," says Dr. Werner.
At the same time, the experiments also showed that cortisone suppresses this resolvin formation in inflammation-resolving M2 macrophages, which is important for healing, by virtually "switching off" 15-lipoxygenase-1. "This explains why the use of cortisone in the later phase of inflammatory diseases no longer leads to symptom relief, and can even be counterproductive and inhibit regeneration processes," adds Prof. Werz.
After the researchers had deciphered the mechanisms at the gene regulation level, they proved these effects in further studies on immune cells from patient samples. They included patients at Jena University Hospital with chronic inflammatory diseases, such as Crohn's disease and ulcerative colitis, as well as those with severe acute inflammation caused by COVID-19, who were treated with cortisone preparations. Blood was taken from these patients before and after the administration of the medication and examined with regard to the inflammation parameters and enzyme activities.
"As in the experiments on cell cultures, we were able to detect a clear upregulation of 15-lipoxygenase-2 in the patient groups treated with cortisone," notes Dr. Benjamin Giszas, a doctor at the Clinic for Internal Medicine IV. Giszas supervised the studies as part of his Clinician Scientist project.
According to the researchers, their results imply that treatment of inflammatory diseases could be improved by a time-limited use of cortisone and by new 15-Lipoxygenase-based therapy principles, with fewer cortisone-related side effects.
More information: Rao, Zhigang et al, Glucocorticoids regulate lipid mediator networks by reciprocal modulation of 15-lipoxygenase isoforms affecting inflammation resolution, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2302070120. doi.org/10.1073/pnas.2302070120
https://medicalxpress.com/news/2023-08-key-cortisone-treatment-inflammation.html
KRAS solution method overcomes the undruggable obstacle
Research conducted by Revolution Medicines, California, and Memorial Sloan Kettering Cancer, New York, has developed a method to bypass the undruggable nature of a common oncogene mutation that drives cancer development and resistance to existing therapies.
In a paper, "Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS," published in Science, the team introduces a novel approach for targeting active mutant KRAS, addressing the "undruggable" challenge. A Perspective published in the same journal discusses the team's findings.
KRAS is a notorious cell signaling gene frequently implicated in various cancers, pivotal in driving uncontrolled cell growth and proliferation. KRAS mutations are present in about 25% of tumors and are the driver mutation behind 32% of lung cancers, 40% of colorectal cancers, and 85% of pancreatic cancer cases. KRAS is the most frequently mutated oncogene in humans.
With such an involved role in many cancers, KRAS should be a prime target for therapeutic intervention. The lack of suitable drug-binding sites on the KRAS protein has posed a significant obstacle in developing effective drug treatments, leading to the label "undruggable" being associated with it. Labels like untreatable, undruggable and unknown cause have an increasingly shorter shelf life in modern science.
The team crafted a small molecule, RMC-6291, with a precision-targeted neomorphic binding interface. Researchers strategically engineered RMC-6291 to form a tri-complex with CYPA, a natural cellular chaperone, and a single-point mutation on the KRAS protein. With RMC-6291 at the intersection, the interactions are disrupted, shutting down the signaling pathways driven by KRAS.
Beyond its applicability to the single-point mutation in KRAS, the study highlights the potential this approach strategy has to be extended to other challenging targets. This opens up the possibility of addressing a broader range of oncogenes previously considered beyond the reach of drug development.
As with any novel find or innovative method, more research is needed. A phase 1/1B clinical trial testing RMC-6291 (NCT05462717) is currently underway.
More information: Christopher J. Schulze et al, Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS, Science (2023). DOI: 10.1126/science.adg9652. www.science.org/doi/10.1126/science.adg9652
Jun O. Liu, Targeting cancer with molecular glues, Science (2023). DOI: 10.1126/science.adj1001
https://medicalxpress.com/news/2023-08-kras-solution-method-undruggable-obstacle.html
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