Day: November 14, 2023

Cholesterol Discovery could Lead to New Therapies to Prevent Cardiovascular Disease

Source: CC0

Researchers at the University of Leicester have discovered the mechanism by which cholesterol in the diet is absorbed into cells. This discovery, which has just been published in the journal Science opens up new opportunities for therapeutic intervention to control cholesterol uptake that could complement other therapies and potentially save lives.

The research, conducted with colleagues from the USA, China and Australia, has shown that two proteins (called Aster B and Aster C) play a key role in transporting cholesterol from the membrane of the cells lining our intestine to the internal compartment where it is modified prior to circulation.

Funding came from the Leducq Foundation which awarded $6 million to eight laboratories across the USA and Europe for collaborative research into how cholesterol is transported in our bodies.

University of Leicester researchers from the Institute of Structural and Chemical Biology, used their expertise to reveal how Ezetimibe, a cholesterol lowering drug, blocks the ability of Aster B and C to transport cholesterol.

Professor John Schwabe, Director of the Institute for Structural and Chemical Biology, said: “This breakthrough is the result of a long-lasting collaboration and forms part of an international effort to identify ways in which we can combat cardiovascular disease and stroke. A better understanding of important areas of cholesterol absorption and metabolism and, particularly, how cholesterol moves within cells and tissues is essential. This knowledge will allow us to design new drugs and therapies that target specific proteins involved in these pathways to combat most pressing public health problems such as heart attacks and stroke.

Professor Schwabe added: “If we can prevent some cholesterol from being absorbed into our cells, we may ultimately be able to prevent individuals from having high cholesterol and cut down their risks of heart attack and stroke and therefore potentially save lives.

“The Leducq team of experts have different expertise that is used to target the problem at different levels and following different approaches. In addition to target cholesterol absorption, we are trying to identify how cholesterol metabolism and transport affect cholesterol levels and atherosclerotic disease. Cholesterol transporters are essential to regulate blood cholesterol levels therefore we are testing small molecules that influence the function of these transporters in order to develop drugs that ultimately lower the risk for heart attack and stroke.”

Postdoctoral Researcher, Dr Beatriz Romartinez-Alonso, added: “This has been a great project to work on – discovering new science highly relevant to human health.”

Source: University of Leicester

Obinutuzumab Reduces Lupus Kidney Flareups and Preserves Function

Photo by Robina Weermeijer on Unsplash

In a post hoc analysis of the phase 2 NOBILITY trial, researchers found that treatment with obinutuzumab was superior to placebo for preserving kidney function and preventing flares in patients with lupus nephritis, a kidney condition associated with the autoimmune disease lupus.

Obinutuzumab is a recombinant, humanised type II anti-CD20 IgG1 monoclonal antibody glycoengineered to enhance antibody-dependent cell-mediated cytotoxicity and phagocytosis.

In the analysis, which is published in Arthritis & Rheumatology, compared with standard-of-care treatment alone, the addition of obinutuzumab to lupus nephritis treatment reduced the risk of developing a composite outcome of death, fall in kidney function, or treatment failure by 60%. Adding obinutuzumab also reduced the risk of lupus nephritis relapses by 57% and significantly decreased the rate of decline in kidney function over the trial’s two years duration.    

Overall, 38% of obinutuzumab-treated patients compared with 16% of placebo-treated patients achieved a complete remission of lupus nephritis by week 76, with the need for fewer glucocorticoids.   

“These data are really important because the ultimate goal of lupus nephritis therapy is to preserve kidney survival so patients never have to face the need for dialysis or transplantation because their kidneys failed,” said corresponding author Brad Rovin, MD, of Ohio State University Wexner Medical Center. “The addition of obinutuzumab to standard lupus nephritis therapy may increase the likelihood of achieving this goal.”

Source: Wiley

Experimental Drug Slashes Levels of Lipoprotein(a) by 94% in Early Trial

Image by Scientific Animations, CC4.0

Findings from a phase 1 trial reported by a Cleveland Clinic physician show that a single dose of an experimental therapy produced greater than 94% reductions in blood levels of lipoprotein(a), a key cardiovascular risk driver, with the results lasting for nearly a year. 

The findings were presented at the American Heart Association’s Scientific Sessions 2023 and simultaneously published in the Journal of the American Medical Association.  

Lipoprotein(a), or Lp(a), is made in the liver and has similarities to low-density lipoprotein (LDL). Unlike other types of cholesterol particles, Lp(a) levels are 80–90% genetically determined. The structure of the Lp(a) particle causes atherosclerosis, which greatly increases the risk of heart attacks and strokes. 

Although effective therapies exist to reduce the risk of heart disease by lowering LDL cholesterol and other lipids, currently there are no approved drug treatments to lower Lp(a). Since Lp(a) levels are genetically determined, lifestyle changes such as diet or exercise have no effect. 

In the trial, participants who received an injection of lepodisiran had lipoprotein(a) levels reduced by the top dose as much as 96% within two weeks and maintained levels more than 94% below baseline for 48 weeks. The drug is a small interfering RNA (siRNA) therapeutic that blocks the messenger RNA needed to manufacture a key component of lipoprotein(a) in the liver. 

The findings add lepodisiran to the growing list of therapies that could be promising treatments for atherosclerotic cardiovascular diseases in people with high levels of Lp(a), which is estimated to affect a fifth of the global population.   

“These results showed that this therapy was well tolerated and produced very long-duration reductions in Lp(a), an important risk factor that leads to heart attack, stroke and aortic stenosis,” said lead author Steven Nissen, MD, Chief Academic Officer of the Heart, Vascular & Thoracic Institute at Cleveland Clinic.  

In the trial, researchers enrolled 48 patients in the US and Singapore, average age 47. Investigators studied six different dosages and a placebo, which were all administered as injections. Participants were monitored for up to 48 weeks after administration.   

Maximum Lp(a) plasma concentrations were reduced by 49% from baseline levels for the 4mg dose and up to 96% for the 608mg dose vs a 5% decrease for the placebo. No safety issues were observed, and the only tolerability issue was mild injection site reactions. 

“Despite the strong evidence of the importance of elevated Lp(a) as a risk factor for heart disease, effective treatment has been elusive,” commented Dr Nissen. “This approach to treatment gives hope to the 20% of the world’s population who have elevated Lp(a) levels.” 

A phase 2 trial studying lepodisiran is currently underway. The trial was sponsored by Eli Lilly and Company (Lilly), the company developing lepodisiran. 

Source: Cleveland Clinic

H3D’s Pioneering Research Adds Hope to the Fight against Malaria 

Members of the University of Cape Town’s Holistic Drug Discovery and Development Centre H3D

A formidable disease that has plagued humanity for centuries, malaria has exacted a heavy toll on human lives, disrupting communities and hindering socio-economic progress across some of the most vulnerable regions of the world, particularly the African continent.  

With its stealthy transmission through the bites of infected mosquitoes, malaria has earned the dubious reputation of being one of the deadliest vector-borne diseases on the planet. So much so that the World Health Organization’s World Malaria Report reveals that malaria cases are on the rise, with instances rising from 245 million cases in 2020 to over 247 million a year later1

With an estimated 619,000 people succumbing to the disease in 20211, it remains a defining challenge for global healthcare systems. However, through the unyielding persistence and spirit of medical innovation and scientific ingenuity exemplified by research facilities such as the University of Cape Town’s Holistic Drug Discovery and Development Centre (H3D), solutions to mitigate the severity of malaria are on the horizon.  

“As the first and only integrated drug discovery platform on the African continent, H3D’s mission is to discover and develop innovative life-saving medicines for diseases that predominantly affect African patients,” explains Bada Pharasi, CEO of the Innovative Pharmaceutical Association of South Africa (IPASA).

H3D’s focus on building Africa-specific models aims to improve treatment outcomes in African patients and to educate and train a critical mass of skilled African-based drug discovery scientists. H3D’s scientific output and research model includes attracting international investment in local innovative pharmaceutical research and development (R&D) across the African continent to address the disproportionately high global disease burden. Importantly, H3D targets critical infectious diseases, including tuberculosis, antibiotic-resistant microbial diseases, and malaria. 

“Given the vulnerability of many of the African populations, the continent accounted for 95% of malaria cases and 96% of malaria deaths in 20211. Accordingly, continued antimalarial drug research and development, such as the studies conducted by H3D, is important to prevent and treat the millions of cases that arise each year, all of which have consequences on both the health and socioeconomic development of the continent,” adds Pharasi.

Since the official launch of H3D’s programs in April 2011, there have been notable advances in innovative drug discovery projects. The centre has demonstrated a strong track record with multiple chemical series discovered and being progressed at H3D in each stage of the drug development pipeline.

A significant achievement reached by H3D was the discovery of the malaria clinical candidate, MMV390048, which reached phase II human trials in African patients. This was the first ever small molecule clinical candidate, for any disease, researched on African soil by an African drug discovery research unit. 

According to Dr Candice Soares de Melo, Chief Investigator at H3D, the centre’s current anti-malarial programmes will focus on the identification of quality leads suitable for optimisation and candidate selection as potential agents for the treatment of uncomplicated Plasmodium falciparum malaria, ideally with additional activity against liver-stage parasites to offer protection and prevent relapses (in case of malaria caused by the species Plasmodium vivax), as well as blocking the transmission of the disease. 

“A critical component of the research conducted at H3D is to develop medicines that are safe and sufficiently tolerated to be given to the widest range of recipients, including infants and pregnant women,” says Soares de Melo.

Besides the potential benefits of providing a new cure for malaria, H3D serves as a catalyst for training scientists in infectious disease research and influencing the R&D environment in Africa.  As part of its partnership with the South African Medical Research Council, H3D has worked to mentor and develop scientists at other African universities, including those at Historically Disadvantaged Institutions (HDIs) within South Africa. 

Furthermore, apart from strengthening drug discovery innovation at UCT, the centre has also taken a lead role in partnership with the Bill & Melinda Gates Foundation in catalysing drug discovery across sub-Saharan Africa, with upwards of 16 university research groups working on malaria and tuberculosis drug discovery. 

“An example of this is the Phase 1 clinical trial for the H3D clinical candidate MMV390048, which was carried out at the UCT Division of Clinical Pharmacology,” adds Soares de Melo. 

Another is the MATRIX independent special project, which has the potential to transform local drug manufacturing across the continent. Funded by the United States Agency for International Development (USAID), the project aims to pilot cost-effective local manufacture of antiretroviral Active Pharmaceutical Ingredients using flow reactor technology.

“Should Africa intend on a path to self-sufficiency, it’s important to drive continued investment in health innovations developed for and by Africa.

“We support the research efforts of H3D, and strongly believe that now is the time to take a deliberate and systematic approach to develop new capabilities, transfer technologies, leverage partnerships and networks, and train scientists, all while delivering on drug discovery projects to help address the continent’s, and the world’s, greatest health challenges,” concludes Pharasi.

For more information, visit https://h3d.uct.ac.za/ or contact Candice Soares de Melo at candice.soaresdemelo@uct.ac.za.

Sex-specific DNA Fragment Explains Lupus’s Prevalence in Women

A woman with Systemic Lupus Erythematosus. Source: Wikimedia CC0

The autoimmune condition lupus occurs in women at a rate nine times higher than in men. Some of the factors that cause the disease’s high prevalence in women have eluded discovery, but in a new study published in the Journal of Clinical Investigation Insight, Johns Hopkins Medicine researcher investigated the immune system processes in lupus and the X chromosome, and uncovered answers about the disease’s frequency in females.

A number of dysregulated genetic and biological pathways contribute to the development of lupus and its varied symptoms of muscle and joint pain, skin rashes, kidney problems and other complications throughout the body. One such pathway involves a protein in the immune system called toll-like receptor 7 (TLR7), which, in lupus, reacts to the body’s own RNA, molecules that act as messengers of genetic information. TLR7’s reaction to RNA triggers an immune response that damages healthy tissue.

In the full article, researchers honed in on this TLR7 immune response in lupus, looking specifically at how a piece of genetic material only found in women, known as X-inactive specific transcript (XIST), could trigger TLR7’s immune system response. XIST is a type of RNA that plays a crucial role in inactivating one of the two X chromosomes found in female cells so that females do not have imbalanced gene expression.

“XIST has previously been implicated in autoimmunity, but more as something that could prevent autoimmune conditions like lupus, rather than drive the disease’s development,” says study author and lead researcher Erika Darrah, PhD. “Our findings show the opposite, that XIST actually plays a role in promoting autoimmunity – increasing the susceptibility to lupus and its severity in women.”

The research team first tested whether XIST could bind to TLR7 and initiate the receptor’s immune response using cellular experiments. They observed that XIST could strongly bind to TLR7 and trigger the production of molecules called interferons, an immune system protein seen at high levels in lupus that contributes to tissue damage in this disease. Rather than protect from TLR7 and interferon’s negative effects on the body, these tests illustrated that XIST drove the process of an overactive immune response and therefore contributed to lupus development.

“XIST has now taken on a different role, an alarm signal related to autoimmunity,” says study author Brendan Antiochos, MD. “The immune system activation through XIST and TLR7 is female-specific, helping explain the observation that lupus is so much more common in women compared to men.”

To further study XIST’s role in lupus, researchers also examined XIST levels in patients from two lupus cohorts. The team tested blood samples from patients at the Johns Hopkins Lupus Center for XIST levels, and also used publicly available data from another study that showed XIST and interferon levels in white blood cells taken from the kidneys of people with lupus. They assessed that not only did the levels of XIST in the kidney correlate with higher interferon levels, but also, those with more XIST in their blood cells experienced greater disease severity and worsened lupus symptoms.

Darrah and Antiochos say these findings may implicate XIST in other autoimmune conditions that are more often seen in women, and that more research should be conducted to investigate this female-specific process.

Researchers also say that understanding XIST’s role in lupus development may lead to creative therapies that target the XIST-TLR7 pathway, as well as offer an additional explanation for patients who may wonder about the origins of their disease.

Source: Johns Hopkins Medicine