Scientists make a major breakthrough to treat fibrotic diseases that cause organ failure

Researchers from Duke-NUS Medical School (Duke-NUS) and the National Heart Centre Singapore (NHCS) have discovered that a critical protein, known as interleukin 11 (IL11) is responsible for fibrosis and causes organ damage. While it is surprising that the importance of IL11 has been overlooked and misunderstood for so long, it has now been very clearly demonstrated by this work.

A protein known as transforming growth factor beta 12 (“TGFB1”) has long been known as the major cause of fibrosis and scarring of body organs, but treatments based on switching off the protein have severe side effects. The scientists discovered that IL11, is even more important than TGFB1 for fibrosis and that IL11 is a much better drug target than TGFB1.

Fibrosis is the formation of excessive connective tissue, causing scarring and failure of bodily organs and the skin. It is a very common cause of cardiovascular and renal disease, where excessive connective tissue destroys the structure and function of the organ with scar tissue. Compared to other Asians, American, and Europeans, Singaporeans have a higher prevalence of coronary artery disease, hypertension, and diabetes, the three most common diseases that lead to heart failure. In addition, kidney failure is an epidemic in Singapore and around the world. Fibrosis of the heart and kidney eventually leads to heart and kidney failure, thus this breakthrough discovery — that inhibiting IL11 can prevent heart and kidney fibrosis — has the potential to transform the treatment of millions of people around the world.

The international team, led by Professor Stuart Cook, Tanoto Foundation Professor of Cardiovascular Medicine, along with Assistant Professor Sebastian Schäfer, both from NHCS and Duke-NUS’ Programme in Cardiovascular and Metabolic Disorders, carried out the translational research to identify the key drivers of chronic fibrotic disease in heart, kidney, and other tissues. The team also includes researchers from Harvard University and University of California, San Diego/UCSD (USA), Max Delbrück Center for Molecular Medicine/MDC-Berlin (Germany), London Institute of Medical Sciences/MRC-LMS and Imperial College London (the UK), and the University of Melbourne (Australia).

“Fibrotic diseases represent a major cause of illness and death around the world. The discovery that IL11 is a critical fibrotic factor represents a breakthrough for the field and for drug development. It is an incredibly exciting discovery,” explained the study’s senior author, Professor Cook, who is also Director, National Heart Research Institute Singapore.

“Currently, more than 225 million people worldwide suffer from heart and kidney failure and there is no treatment to prevent fibrosis. The team is at the stage of developing first-in-class therapies to inhibit IL11 and this offers hope to patients with heart and kidney disease,” shared Professor Terrance Chua, Medical Director, National Heart Centre Singapore.

“This therapeutic target for fibrotic diseases of the heart, kidney and other organs may be exactly what we need to fill the unmet pressing clinical gap for preventing fibrosis in patients. We are proud to announce that the suite of intellectual property arising from this research has been licensed to a newly launched Singapore-funded biotechnology start-up Enleofen Bio Pte Ltd, which is co-founded by Professor Cook and Assistant Professor Schäfer,” said Professor Thomas Coffman, Dean of Duke-NUS Medical School.

Drugs, Diseases and Proteins: New Archive Helps Precision Medicine, Drug Development

UNM Cancer Center Scientist co-leads international drug targets effort to create open-source archive for drug discovery, development, and safety

Most aspirin users don’t know what aspirin does to make you feel better. Most doctors and scientists didn’t know, either, until recently. In fact, scientists know how only a handful of drugs really work and they know that drugs can have different effects on different people. That’s why Tudor Oprea, MD, PhD, wished for database that could tell him a drug’s chemical structure, its molecular biology activity and the diseases it is used to treat. Now, after a 20-year effort, Oprea and his collaborators from the UK-based European Bioinformatics Institute in Hinxton and from the Institute for Cancer Research in London have created the beginnings of that archive. They recently published their work in the journal Nature Reviews Drug Discovery.

“This is a landmark paper,” says David Schade, MD, a Distinguished Professor at The University of New Mexico School of Medicine, who oversees clinical research in the Department of Internal Medicine. “Diseases that were not treatable 10 years ago are now treatable,” he says. “That’s because of new medications that have been developed and approved by the Food and Drug Administration.”

But while new drugs have saved lives, they can also complicate treatment. Schade explains that doctors often use more than one drug to treat diabetes, for example. They must make sure those drugs work together and that no dangerous side effects result they’re when combined. “What we want to do,” says Schade, “is hit multiple targets that are causing the disease.” And Oprea’s archive will help doctors to do just that, he says.

Olivier Rixe, MD, PhD, agrees. Rixe oversees all clinical research at the UNM Comprehensive Cancer Center. “At the end of the day,” he says, “it’s for the benefit of the patients because we will be better able to tailor the way we treat their cancer.” Rixe also plans to use Oprea’s archive to speed the process of drug discovery and development at UNM Cancer Center. “We can use this type of data to better align drug development with the characteristics of the patients.”

Oprea, now a Professor at the UNM Cancer Center, started the drug database 20 years ago when he was a drug developer. He archived drug targets, which are molecules that drugs act on to make the cell change its behavior. He later expanded his list to include properties of the drugs themselves and any information about how they acted on their targets. While it sounds simple, creating this type of repository proved far from easy. “It was pretty hard to get here,” Oprea says.

To develop the information, Oprea and his international collaborators had to mine data from all over the world. They correctly mapped the drugs’ molecular structures. They searched for data on the diseases the drugs helped to treat. They collected data on the drugs’ effects on humans and animals. They also listed what scientists had learned about how the drugs reacted with the proteins in cells.

In all, they cataloged 893 drug targets linked to Mode of Action, which is how drugs exert their therapeutic effect at the molecular level, and 1,578 drugs approved by the United States Food and Drug Administration. The information, which has gaps, is now publicly available through a system that Oprea’s research team at UNM developed, called DrugCentral. DrugCentral resides at UNM and Oprea is building his team to be experts in drug discovery. “This type of expertise is rare,” he says. “We are one of the teams that has it.”

Creating the drug targets database unearthed some interesting details. The collaborators used the database to compare drug targets with the Sanger Institute’s list of genes shown to be important in developing cancer. They found that only 38 molecular targets for cancer overlapped with the important cancer genes. “That’s not a lot,” Oprea says, “but the question is, can we treat cancers by blocking the cancer gene drivers? We don’t know that yet.” This effort will help in finding the answer. Oprea hopes that others will contribute their information to grow the drug knowledge for everyone to use.

Researchers Encouraged by Continued Signs of Tolerability and Disease Modification in Gene Therapy Trial for Sanfilippo Syndrome

Researchers from Abeona Therapeutics Inc, a clinical-stage biopharmaceutical company focused on developing therapies for life-threatening rare genetic diseases, provided, an update on clinical results through 30 days post-injection for the completed low-dose cohort (n=3) in the ongoing Phase 1/2 trial for ABO-102 (AAV-SGSH) at the Orphan Drugs & Rare Disease Conference (London, UK). The first-in-man clinical trial utilizes a single intravenous injection of AAV gene therapy for subjects with MPS IIIA (Sanfilippo syndrome type A), a rare autosomal recessive disease affecting every cell and organ in the body causing neurocognitive decline, speech loss, loss of mobility, and premature death in children.

The ongoing Phase 1/2 study is designed to evaluate safety and preliminary indications of efficacy of ABO-102 in subjects suffering from MPS IIIA. Observations 30 days post-injection for the low dose cohort demonstrated:

• ABO-102 is well-tolerated in subjects injected with the low dose of 5E13 vp/kg ABO-102 with no treatment related adverse events or serious adverse events (SAEs). Following favorable review of the safety data by the independent Data Safety Monitoring Board (DSMB), enrollment in the high dose cohort has commenced.

• In the natural history evaluating MPS III subjects it was shown that urine and cerebral spinal fluid GAG (heparan sulfate or “HS”) are significantly elevated in the subject population as a symptom of disease pathology.

• All subjects in the lose dose cohort experienced reductions from baseline in both urinary HS and CSF. At 30 days post-injection, urinary HS reduction was 57.6% +/- 8.2%. Reduction in CSF HS was 25.6% +/- 0.8%, suggesting that ABO-102 crossed the blood brain barrier after intravenous administration.

• The natural history study in 25 subjects with MPS III (Truxal et. al., 2016, Mol. Genet. Metab.) demonstrated that subjects had increased liver and spleen volumes averaging 116% and 88%, respectively, at baseline that did not change over a year of follow up.

• All three subjects demonstrated significant reductions in liver volume (17.1% +/- 1.9%), and spleen volume (17.6% +/- 7.1%) from baseline, as measured by MRI at 30 days post-injection.

Per the design of the clinical trial, subjects in the low-dose cohort received a single, intravenous injection of AB0-102 to deliver the AAV viral vector systematically throughout the body to introduce a corrective copy of the gene that underlies the cause of the MPS IIIA disease. Subjects were evaluated at multiple time points over the initial 30 days post-injection for safety assessments and initial signals of biopotency, which suggest that ABO-102 successfully reached target tissues throughout the body, including the central nervous system, to reduce GAG content that underlies the lysosomal storage pathology central to Sanfilippo syndrome type A (MPSIIIA).

“We remain encouraged by continued signs of tolerability and by early signals demonstrating reduced urinary and CSF GAG,” stated Kevin M. Flanigan, MD, principal investigator with the Center for Gene Therapy at Nationwide Children’s Hospital and Professor of Pediatrics and Neurology at The Ohio State University College of Medicine. “Additionally, we are informed by the natural history study that subjects with MPS IIIA experience hepatosplenomegaly, and are pleased by observations in the low dose cohort of significant reductions in liver and spleen volumes 30 days post-injection as measured by MRI.”

A more complete analysis of these data will be presented from the low-dose cohort and initial high dose cohort at a scientific conference in the first quarter of 2017. The Data Safety Monitoring Board has approved dose escalation of the high dose cohort this quarter.

“The data demonstrate an early and robust systemic delivery of ABO-102, and the reductions in CNS and urinary GAG support our approach for intravenous delivery of ABO-102 for subjects with Sanfilippo syndromes,” stated Timothy J. Miller, Ph. D, President and CEO of Abeona Therapeutics. “We are excited about early biomarker signals in this trial, including the reductions in liver and spleen volumes. Positive impact on hepatosplenomegaly has been an important measure historically in other clinical programs in the lysosomal storage disease space.”
Abeona’s MPS IIIA program, ABO-102, has been granted Orphan Product Designation in the USA and received the Rare Pediatric Disease Designation, and recently announced Orphan Drug Designation has been granted in the European Union.

About ABO-102 (AAV-SGSH): ABO-102 is an adeno-associated viral (AAV)-based gene therapy for subjects with MPS IIIA (Sanfilippo syndrome), that is delivered as a one-time intravenous injection. ABO-102 delivers a functioning, corrective copy of the SGSH gene to cells of the central nervous system (CNS) and other organs with the goal of correcting the underlying deficits caused by the inborn genetic errors that are the cause the disease. ABO-102 has been well tolerated through 30-day post-injection in subjects injected with the low-dose (n=3). The clinical study is supported by neurocognitive evaluations, biochemical assessments and MRI data generated in a 25-subject MPS III Natural History Study, also conducted at Nationwide Children’s Hospital, where subjects continued through one-year of follow up assessments.

Sanfilippo syndromes (or mucopolysaccharidosis (MPS) type III): a group of four inherited genetic diseases each caused by a single gene defect, described as type A, B, C or D, which cause enzyme deficiencies that result in the abnormal accumulation of glycosaminoglycans (GAGs, or sugars) in body tissues. MPS III is a lysosomal storage disease, a group of rare inborn errors of metabolism resulting from deficiency in normal lysosomal function. The incidence of MPS III (all four types combined) is estimated to be 1 in 70,000 births. Mucopolysaccharides are long chains of sugar molecule used in the building of connective tissues in the body. There is a continuous process in the body of replacing used materials and breaking them down for disposal. Children with MPS III are missing an enzyme which is essential in breaking down the used mucopolysaccharides called heparan sulfate. The partially broken down mucopolysaccharides remain stored in cells in the body causing progressive damage. In MPS III, the predominant symptoms occur due to accumulation within the central nervous system (CNS), including the brain and spinal cord, resulting in cognitive decline, motor dysfunction, and eventual death. Importantly, there is no cure for MPS III and treatments are largely supportive care.

Vesicles That Trap Amyloid Appear to Also Contribute to Alzheimer’s Disease

Vesicles, fluid-filled sacs that brain cells make to trap amyloid, a hallmark of Alzheimer’s, appear to also contribute to the disease, scientists report.

Reducing the production of these vesicles, called exosomes, could help reduce the amount of amyloid and lipid that accumulates, slow disease progression and help protect cognition, scientists at the Medical College of Georgia at Augusta University report in The Journal of Neuroscience.

When confronted with amyloid, astrocytes, plentiful brain cells that support neurons, start making exosomes, to capture and neutralize it, said Dr. Erhard Bieberich, neuroscientist in the MCG Department of Neuroscience and Regenerative Medicine and the study’s corresponding author.

“If you swarm astrocytes with amyloid, you trigger an aggressive response,” he said. Happy astrocytes, on the other hand, don’t make exosomes.

Not unlike a landfill, the real problems begin when the biological sacs get piled too high. In such volume and close proximity to neurons, exosomes begin to interfere with communication and nutrition, neurons stop functioning well and eventually begin to die, a scenario that fits with disease progression, Bieberich said.

MCG scientists followed the process in an animal model with several genetic mutations found in types of Alzheimer’s that tend to run in families and make brain plaques early in life. One mouse group also was genetically programmed to make a nonfunctional form of the enzyme neutral sphingomyelinase-2. Amyloid also activates this enzyme, which converts another lipid, called sphingomyelin, into ceramide, a component of the brain cell membrane known to be significantly elevated in Alzheimer’s. In fact, with disease, the brain has two to three times more of the lipid known for its skin-softening ability.

The MCG scientists found exosomes made by astrocytes accelerated the formation of beta amyloid and blocked its clearance in their animal model of Alzheimer’s. Male mice, which were also sphingomyelinase-deficient, developed fewer plaques and exosomes, produced less ceramide and performed better in cognitive testing.

For reasons that are unclear, female mice did not reap similar benefits, said Bieberich, noting that Alzheimer’s tends to be more aggressive in women. His earlier work has shown that female mice have higher levels of antibodies in response to the elevated ceramide levels that further contribute to the disease.

His new work is the first evidence that mice whose brain cells don’t make as many exosomes are somewhat protected from the excessive plaque accumulation that is the hallmark of Alzheimer’s. It is also an indicator that drugs that inhibit exosome secretion may be an effective Alzheimer’s therapy, Bieberich said. Current strategies to prevent plaque formation, have been unsuccessful, the researchers write.

“We show clearly that sphingomyelinase is causative here in making ceramide, making exosomes and in making plaques,” Bieberich said. He and his teams already are testing different drugs given to patients for reasons other than Alzheimer’s that may also inhibit sphingomyelinase and ultimately ceramide and exosome production.

Inside the brain, ceramide is an important component of the cell membrane, but too much starts collecting in the exosomes, combining with the amyloid to form a disruptive and eventually deadly aggregate. In fact, MCG scientists could see the ceramide and amyloid clustered together in the brains of mice without sphingomyelinase suppression, further implicating a close association.

In a scenario that seems to go full circle, Bieberich has mounting evidence that in Alzheimer’s, there is a shorter, “bad” form of ceramide coating the antennae of astrocytes. Normally, antennae help astrocytes focus on taking care of neurons. But the shorter version that he believes contributes to disease has astrocytes giving up their caretaker role, spending their energy on themselves and starting to divide.

Bieberich and his team already are looking for other exosome triggers such as inflammation-producing immune cells called cytokines as well as physical trauma. Ceramide levels have been proposed as an early Alzheimer’s biomarker as has evidence of amyloid-positive exosomes in the blood.

How Do You Kill a Malaria Parasite? Clog It with Cholesterol

Drexel University scientists have discovered an unusual mechanism for how two new antimalarial drugs operate: They give the parasite’s skin a boost in cholesterol, making it unable to traverse the narrow labyrinths of the human bloodstream. The drugs also seem to trick the parasite into reproducing prematurely.

Malaria is a mosquito-borne disease caused by Plasmodium parasites. After a person is bitten, the parasite invades the victim’s red blood cells. There, it eventually divides into daughter parasites, which continue to destroy each red blood cell they infect.

There are several drugs under development that interrupt this life cycle, including a class of compounds discovered in 2014 by Akhil Vaidya, PhD, a professor at Drexel University College of Medicine. In their 2014 study, Vaidya and his research team found that these drugs increase levels of sodium within the parasites’ cells, causing them to swell and erupt.

However, in a new study, published recently in PLOS Pathogens, the researchers have revealed that this sodium increase actually triggers a more complex cascade of events, eventually changing the parasite’s outer membrane and also tricking it into early reproduction, which renders the parasite inert.

“Nobody suspected something like this to be the mode of action,” said Vaidya, who also directs Drexel’s Center for Molecular Parasitology. “The mechanism is a lot more complicated and interesting than we originally thought.”

In this study, the scientists focused on two small-molecule drugs, one of which is undergoing clinical trials. Despite very different molecular structures, both drugs initially increase sodium within the parasite and subsequently kill the pathogen. Until now, scientists have not understood why the increase in sodium concentration leads to the malaria parasite’s demise.

To explore this question, the researchers first tested the properties of the Plasmodium plasma membrane — or the parasite’s outer skin — before and after exposure to antimalarial drugs. The Plasmodium membrane is unusual, because it contains very low levels of cholesterol, a major lipid component of most other membranes, including those of human red blood cells.

The Drexel scientists hypothesized that the low cholesterol content permits greater flexibility for the parasite to travel through the human bloodstream and to withstand the stress of blood circulation. They propose that the sodium increase, caused by the antimalarial drugs, somehow interferes with that elasticity.

The researchers used a cholesterol-dependent detergent to detect the presence of lipids in the parasite membrane. They found that indeed both drug treatments appeared to add a significant amount of cholesterol to the Plasmodium plasma membrane.

“We believe that the cholesterol makes the parasite rigid, and then the parasite can no longer pass through very small spaces in the bloodstream,” Vaidya said, adding that the parasite cannot continue its lifecycle if it cannot enter red blood cells.

Just two hours after treatment, the scientists also saw that many of the parasites showed fragmented nuclei and interior membranes, which are the precursors to cell division. But these changes happened without any sign that the parasite’s genome had multiplied — a step that is necessary for a cell to divide and survive.

The researchers hypothesize that sodium influx is a normal step during the malaria parasite’s division. The antimalarial drugs prematurely induce this signaling event, and the parasite begins dividing before it should.

“The parasite is not ready to divide yet, so it can not survive. It is like premature delivery of an infant,” Vaidya said. “This whole cascade of events is triggered by these drug treatments.”

Malaria is the world’s deadliest parasitic disease. It kills more than 300,000 people per year, according to the World Health Organization, and affects up to 300 million.

One of the biggest challenges for treating malaria is drug resistance. The drugs that are currently available are quickly losing their potency, so researchers are scrambling to develop stronger treatments.

By understanding exactly how new drug candidates stop malaria, Vaidya and his team aim to reveal more about the parasite’s vulnerabilities. This, they hope, will eventually lead to the creation of more effective drugs against the disease. Vaidya noted that the best defense against malaria will always be a combination of treatments.