Cholesterol-related heart disease remains the leading cause of death worldwide, and while doctors have more tools than ever to treat it, many patients still can’t achieve safe cholesterol levels or can’t tolerate the side effects of available medications. Researchers at the University of California (UC), San Diego, School of Medicine have now uncovered a hidden biological pathway, dependent on a protein known as Ral, which explains why high-cholesterol diets steadily chip away at our body’s ability to clear harmful low-density lipoprotein (LDL) cholesterol from the blood. The team‘s preclinical study, including tests in mice, also identified a drug candidate already proven safe in humans that could potentially target the pathway.

“We’ve known for a long time that a high-cholesterol diet reduces the liver’s ability to clear cholesterol from the blood, but we didn’t fully understand why,” said Alan Saltiel, PhD, professor of medicine at UC San Diego School of Medicine and director of the UC San Diego/UCLA Diabetes Research Center. “This new discovery explains a critical piece of that puzzle.” Saltiel is senior author of the researchers’ published paper in Nature, titled “Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover,” in which they concluded, “Together, our findings reveal a Ral-dependent signalling pathway as a key regulator of LDLR turnover and cholesterol homeostasis.”

Disruptions in cholesterol homeostasis are closely linked to an increased risk of atherosclerosis and cardiovascular disease (CVD), the authors wrote. “Elevated low-density lipoprotein cholesterol (LDL-C) significantly contributes to CVD by promoting the formation of atherosclerotic plaques in arteries.”

The liver is the main organ involved in removing cholesterol from the blood so it can be broken down and used elsewhere. This is done through LDL receptors (LDLRs), which sit on the surface of liver cells and act like docking stations, grabbing LDL cholesterol from the bloodstream and pulling it inside the cell for processing. “LDLRs have a crucial role in the uptake of LDL-C from the circulation by hepatocytes,” the investigators continued. The more LDL receptors on liver cells, the more cholesterol gets cleared from the blood, which is why most cholesterol-lowering drugs, such as statins or PCSK9 inhibitors, work by preserving or increasing the number of these receptors. However, the team noted, such treatments have their limitations. “The molecular switches that coordinate LDLR trafficking and turnover in response to nutritional cues, including high dietary cholesterol, remain poorly defined.”

The new research, carried out in mice and in human cells, reveals a previously unknown mechanism that quietly works against the cholesterol removal process, slowly reducing the number of LDL receptors and contributing to high blood cholesterol. The team found that this process begins when a protein called Ral—which Saltiel has previously studied in fat cells—is activated by high dietary cholesterol. “We describe here a previously unrecognized role for Ral signaling in orchestrating LDLR cellular trafficking and lysosomal routing in hepatocytes under chronic cholesterol stress,” the team stated.

Their studies showed that the more Ral is activated, the fewer LDL receptors remain available to clear cholesterol from the blood. This depletion process ultimately relies on a lysosomal protease enzyme called cathepsin A (CTSA). They further explained, “Ral engages the endocytic RalBP1–REPS1 complex to promote LDLR internalization and lysosomal routing, where LDLR is degraded by the lysosomal protease cathepsin A (CTSA).”

The researchers also found that blocking CTSA with a selective small molecule inhibitor (SAR164653) was enough to stabilize LDL receptors and dramatically lower circulating LDL cholesterol in mice. “Pharmacological inhibition of CTSA activity increases hepatic LDLR function and improves cholesterol clearance, offering a potential new therapeutic strategy for hypercholesterolaemia and cardiovascular disease,” they stated.

“There’s still a real need for new cholesterol-lowering options, since some people can’t get to safe levels even with the drugs we have now,” said Saltiel. “This new pathway we discovered is completely separate from anything that existing drugs target, so it gives us a new opportunity to fill that gap.”

After a fundamental biological breakthrough, it typically takes significant additional research to find drugs that target it. However, in this case, a CTSA inhibitor has already been through the early stages of drug development, with the initial goal of treating heart failure. While it was eventually shelved for strategic reasons, the drug had previously advanced to a Phase I clinical trial, where it was successfully tested for safety.

This discovery suggests that the investigational drug is already ready for testing in a Phase II trial for high cholesterol. “Luckily, there’s an experimental drug sitting on the shelf that’s already been shown to be safe in humans,” said Saltiel. “We hope to test whether this might be effective by conducting a clinical trial, which could potentially bring a new treatment option to patients much sooner than would have been expected.”

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The world’s first in-human embryonic stem cell-derived clinical trial for Huntington’s disease has launched at UCI Health, the clinical arm of the University of California, Irvine. The Phase Ib/IIa trial will evaluate the safety of hNSC-01 neural stem cells derived from embryonic stem cells delivered to the brain by a specialized neurological mapping and targeting stereotactic system.

Huntington’s disease is a fatal, progressive genetic disorder that gradually destroys brain cells. It usually begins between the ages of 35 and 50 with symptoms that include involuntary movements, difficulty thinking and planning daily tasks, and mood changes such as depression. If successful, this therapy could prolong independent living and significantly reduce long-term care costs.

“This clinical trial highlights the important role that an interdisciplinary academic and clinical team together with the HD families, plays in advancing medicine,” said Leslie M. Thompson, PhD, professor of psychiatry and human behavior at UC Irvine. “We are grateful to our patients and their incredible families for their bravery to provide hope for others with very few options.”

The first patient received the intervention at UCI Health Irvine (home to Orange County’s first adult bone marrow/stem cell transplant and cellular therapy program) in May. A second patient is scheduled to receive the intervention in July.

“The first patient intervention went very well. To date, they haven’t reported any serious adverse events,” said Ravi Rajmohan, MD, UCI Health neurologist. “This trial may help us move one step closer to a future with available treatments that could potentially slow the progression of Huntington’s disease.”

The therapy, hNSC-01, uses pluripotent neural stem cells derived from embryonic stem cells, which were manufactured through the UC Davis GMP facility. In animal studies, the cells have been shown to protect existing brain cells, replace lost cells, rebuild impaired brain circuits, release helpful proteins, such as brain-derived neurotrophic factor (BDNF), and reduce harmful protein accumulations that damage brain cells. The stem cells were also shown to be safe over long periods in mice.

The clinical trial will enroll 21 people ages 18 to 65 with early-stage Huntington’s disease. Twelve participants will be enrolled into a Phase Ib dose-escalation group and nine in a Phase IIa expansion group.

The stem cells are implanted during a roughly six-hour surgical procedure done under general anesthesia. While lying face down in an MRI scanner, the patient receives stem cells implanted directly into the striatum deep in the brain, using a purchased proprietary therapy-enabling platform for navigation and surgical delivery. Damage to the striatum, which is responsible for motor control, decision-making, motivation and more, causes Huntington’s disease symptoms. Subjects will be closely monitored for safety as well as preliminary signs of potential benefit.

The clinical trial is made possible by a $12 million grant from the California Institute of Regenerative Medicine (CIRM), and the trial is coordinated through the UC Irvine Alpha Clinic.

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The pharmaceutical giants behind the monumentally successful weight loss drugs Wegovy and Mounjaro have been teasing an expansion into other aesthetic fields like hair loss or skin care. 

Now, one of them is making a move, investing in a small startup developing a medication to spur hair growth, and potentially also treat endometriosis. 

On Wednesday, Absci announced that it raised $100 million from a group led by Eli Lilly. Lilly brought the lion’s share of the funding, handing over $40 million in exchange for equity in Absci, which is publicly traded on the Nasdaq. 

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