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Researchers at UC San Diego report that a protein pathway involving Ral and the enzyme CTSA can reduce the liver’s LDL receptors in experiments with mice and human cells. Blocking CTSA lowered circulating LDL in mice, but the drug candidate has not been shown to lower cholesterol in people; researchers say a Phase 2 trial could test its effect.
Researchers at the University of California San Diego have identified a biological pathway that, in experiments with mice and human cells, may help explain how high dietary cholesterol reduces the liver’s ability to clear LDL cholesterol. Blocking an enzyme in the pathway stabilized LDL receptors and sharply lowered circulating LDL in mice, but the approach has not been shown to work in people.
The study, published in Nature, describes a process involving a protein called Ral and an enzyme called cathepsin A, or CTSA. The researchers report that high dietary cholesterol activates Ral, setting off events that reduce the number of LDL receptors available on liver cells. Those receptors capture LDL from the bloodstream so the liver can process it.
When the team used a small-molecule inhibitor to block CTSA, LDL receptors became more stable and circulating LDL fell dramatically in mice. The work also used human cells, but those experiments do not establish that the drug lowers cholesterol in human patients. The findings identify a possible treatment target, not a proven therapy.
The team points to an experimental CTSA inhibitor developed earlier as a potential heart-failure treatment. That program was discontinued for strategic reasons, according to the report, after the medicine had undergone a Phase 1 safety trial. The researchers say its prior testing could allow them to consider moving to a Phase 2 study of effectiveness for high cholesterol. No such trial or results in patients are reported in the available material.
A Possible Route Beyond Current Drugs
The potential relevance is that the pathway is distinct from targets used by current cholesterol medicines, including statins and PCSK9 inhibitors. If the mechanism also operates in people and can be safely blocked, it could eventually offer another option for patients whose LDL remains high despite treatment or who have difficulty taking existing medications.
That possibility remains conditional. The mouse results do not show that the approach will reduce cardiovascular risk, work at a tolerable dose in people, or outperform available drugs. The immediate value of the study is that it points to a biological mechanism and a candidate compound that researchers can investigate further.
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How the Liver Clears LDL
Liver cells use LDL receptors on their surfaces to take LDL cholesterol out of the blood. In general, more available receptors allow the liver to remove more LDL. Statins and PCSK9 inhibitors help maintain or increase receptor availability through mechanisms different from the one described in this study.
The researchers say the new pathway helps explain how a high-cholesterol diet may gradually weaken this clearance system. Senior author Alan Saltiel, a professor of medicine at UC San Diego, said the work addresses a gap in understanding how diet can reduce the liver’s capacity to clear cholesterol. The report does not establish how large this effect is in people or how it varies between individuals.
“This new discovery explains a critical piece of that puzzle.”
— Alan Saltiel, senior author and professor of medicine at UC San Diego
Human Benefits Remain Untested
The central unknown is whether blocking CTSA will lower LDL in people. The report describes mouse and human-cell experiments, plus an earlier Phase 1 safety trial for the candidate drug, but it does not report a trial testing the medicine’s cholesterol-lowering effect in patients.
It is also unclear whether the drug will proceed to Phase 2, when such a study might begin, what dose would be used, and whether it would have side effects or interact with other treatments. The prior safety testing does not by itself show that the drug is safe or effective for long-term cholesterol treatment.
Testing the Candidate in Patients
The next step would be clinical testing to determine whether the CTSA inhibitor reduces LDL in people and to assess its safety for that use. Saltiel and colleagues have said they hope to conduct a trial and believe the compound’s earlier Phase 1 testing may shorten development compared with starting with a new drug.
Until a patient study is announced and reports results, the findings remain an early-stage research development. People taking cholesterol medication should not change treatment based on this study; decisions about care should be discussed with a qualified clinician.
Key Questions
What pathway did the researchers identify?
The study describes a pathway involving Ral and CTSA that may reduce the number of LDL receptors on liver cells after high dietary cholesterol activates the process.
Did blocking CTSA lower cholesterol in people?
No human cholesterol-lowering result is reported. The researchers observed lower circulating LDL in mice; human cells were also used in experiments, which are not a clinical test.
Has the experimental drug already been tested?
The report says the CTSA inhibitor previously underwent a Phase 1 clinical trial that evaluated safety while it was being developed as a possible heart-failure treatment. That does not establish its effectiveness for high cholesterol.
Could this replace statins or PCSK9 inhibitors?
That is not known. The pathway differs from targets used by those medicines, but the candidate has not been shown to lower LDL in patients or compared with existing treatments.
Source: sciencedaily.com
