RPS27

New research into how cancer develops has uncovered more detail about the importance of the centromere, a region of human DNA that has a critical role in effective cell division. Researchers have identified that loss-of-function mutations in a specific protein complex prevent it from protecting centromere DNA. The resulting centromere instability leads to abnormal cell division, which is a characteristic feature of many cancer cells. These mutations represent a potential target for future cancer treatments, as they make the centromeres in cancerous cells more fragile and sensitive to disturbance. This could allow a carefully targeted drug to destroy these cells without affecting healthy cells where the centromeres remain intact. The study was led by scientists at The Institute of Cancer Research, London, and funded by Cancer Research UK and the Medical Research Council. The findings were published in the journal Nature Communications. In a dividing cell, the centromere holds together the two identical copies of a chromosome – a DNA fibre containing the genetic information for the cell. It also serves as an attachment point for protein complexes that help manage the alignment and segregation of the two chromosomes during cell division. It was already known that centromeres can be vulnerable to structural alterations and even chromosomal breakage. However, for a long time, the limitations of DNA sequencing prevented scientists from fully determining how healthy cells overcome this issue. The high level of repetition in the centromere DNA posed a challenge by making it a very difficult region to map. Fortunately, recent advances in DNA sequencing allowed the team behind the current study to carry out comprehensive mapping of various proteins in this area to look at the impact of mutations, which led to useful findings. The researchers identified part of a protein complex – the PBAF chromatin remodelling complex – as having a key role in stabilising the centromere. The subunit in question, called PBRM1, is often mutated in cancer, and the researchers showed that cells lacking this subunit have structural changes in and around the centromere. Importantly, PBAF is a type of SWI/SNF remodelling complex, and SWI/SNF mutations are present in more than 20 per cent of all cancers. Next, the researchers looked in detail at some of the proteins that provide chromosomes with structural support. They found that these proteins, called histones, were also affected by PBRM1 loss, potentially contributing to abnormal cell division. When centromeres are unable to function correctly and ensure accurate cell division, this can lead to the loss or disruption of genetic information in daughter cells. If these changes involve deleterious defects or allow the cell to continually divide, they can contribute to the development of cancer. In people who already have cancer, these mutations can contribute to drug resistance during treatment and lead to disease progression as the cancerous cells become more transformed. Having identified the mechanism by which centromere function is affected, the researchers wanted to see whether it might be possible to exploit this vulnerability using anti-cancer drugs. They tested an existing type of medication called an MPS1 inhibitor, which affects cell division in cells with perturbations in their centromere structure or function. When they compared the effects of MPS1 inhibition on healthy cells and on cells lacking PBAF, they found that it induced sensitivity in the latter. Dr Karen Lane, joint first author of the study and a Postdoctoral Training Fellow in the Epigenetics and Genome Stability Group at The Institute of Cancer Research (ICR), said: “We are pleased with the findings of this work, which help us understand PBAF better and add to our knowledge of how this complex helps protect against cancer development. “This advance has two main facets. Firstly, it identifies a mechanism by which centromere DNA, which is fragile and tightly regulated, is protected in normal cells. Secondly, it reveals a potential therapeutic vulnerability in cancers with mutations in this protein. “Our work has also generated a lot of publicly available data, including proteomics datasets, RNA-sequencing, mapping PBAF on DNA and pipelines for visualising repetitive sequences such as the centromere. We hope this will help the research community more broadly.” Joint first author Dr Alison Harrod, also a Postdoctoral Training Fellow in the same ICR research group, said: “We were surprised to find such a clear shift in the histone environment around the centromere following PBRM1 loss, highlighting the impact it has on centromere stability. “We plan on following up a few aspects of this project. These include looking at the role of other SWI/SNF complexes in centromere stability and trying to determine how this low level of instability affects cells over time.” Professor Jessica Downs, Deputy Head of the Division of Cell and Molecular Biology at the ICR, said: “This study has implications for the future of cancer treatment. Knowing that PBAF loss leads to a sensitivity to centromere perturbation has potential therapeutic value. Given that more than 20 per cent of cancers have mutations in SWI/SNF, this could represent a therapeutic target. “More importantly, the study uncovered a previously unknown role of the PBAF chromatin remodelling complex, which will allow us to more fully understand the cellular changes present in PBAF-deficient cancer cells.”

REGENXBIO presented results from its ongoing Phase I/II trial of RGX-111, an investigational one-time gene therapy for people with Mucopolysaccharidosis Type I (MPS I). REGENXBIO presented results Wednesday from its ongoing Phase I/II trial of RGX-111, an investigational one-time gene therapy for people with Mucopolysaccharidosis Type I (MPS I). The data, presented at the 18 th annual WORLD Symposium , represented six patients diagnosed with severe MPS I who were treated with RGX-111. Mucopolysaccharidosis Type I is a rare, genetic condition that can affect many parts of the body. The condition stems from a mutation in the IDUA gene which provides instructions for producing an enzyme that is involved in the breakdown of large sugar molecules. In people with MPS I, the gene reduces or completely eliminates the enzymes needed for the breakdown of large sugar molecules, leading to the accumulation of these molecules in cells called lysosomes, whose function is to digest and recycle molecules. The lysosomes become enlarged, causing significant issues in multiple organs including decline in central nervous system (CNS) functioning. Signs and symptoms of MPS I appear during childhood, and it is a progressively debilitating disorder. Most commonly, people with MPS I experience frequent upper respiratory infections, sleep apnea, hydrocephalus or buildup of fluid in the brain, ear infections and hearing loss, heart valve abnormalities and joint deformities. People with the severe form of the disease experience significant declines in intellectual functioning. Children with severe disease have a shortened lifespan, sometimes only living into late childhood. REGENXBIO reported that RGX-111 was well-tolerated in patients, showing encouraging continued neurodevelopment and biomarker activity in the central nervous system, meeting the primary and secondary endpoints of the trial. Patients also showed encouraging skill acquisition after treatment. No drug-related serious adverse events have been reported. The therapy is designed to deliver the gene that encodes the IDUA enzyme using the adeno-associated virus serotype 9 (AAV9) vector, which has the ability to traverse the blood-brain barrier to target the central nervous system. The drug is intended to provide a permanent source of secreted IDUA beyond the blood-brain barrier, allowing for long-term cross-correction of cells throughout the CNS, which could potentially help prevent the progression of cognitive deficits. “This marks our first data presentation from the Phase I/II trial evaluating RGX-111 as a potential one-time gene therapy delivered directly to the central nervous system for the treatment of severe MPS I. We are encouraged to see that RGX-111 has been well-tolerated with emerging evidence of CNS biomarker activity and improvements in neurodevelopmental function, which suggest biological activity in the CNS following one-time administration of RGX-111,” said REGENXBIO Chief Medical Officer Steve Pakola, M.D. “We also saw emerging evidence of biomarker activity outside of the CNS. We plan to enroll additional patients in the Phase I/II trial and look forward to providing additional updates.” Current treatments for MPS I include hematopoietic stem cell transplant and enzyme replacement therapy with a recombinant form of human IDUA administered intravenously. However, enzyme therapies do not treat CNS manifestations of MPS I. REGENXBIO’s emerging therapeutic would provide a one-time treatment that could potentially alleviate many cognitive concerns that progress throughout the life of a patient.

Every week there are numerous scientific studies published. Here’s a look at some of the more interesting ones. Every week there are numerous scientific studies published. Here’s a look at some of the more interesting ones. Goldilocks and Curing Brain Cancer Goldilocks, most people remember, tasted three types of porridge in order to find the one that was not too hot, not too cold, but just right. Researchers at the University of Minnesota Medical School reported on a “Goldilocks” balance that can control the body’s immune response to brain cancer. They published their research in the journal Advanced Therapeutics . “Our body has armies of white blood cells that help us fight off bacteria, viruses and cancer cells,” said senior author Clark C. Chen , Lyle French Chair in Neurosurgery and Head of the Department of Neurosurgery at the University of Minnesota Medical School. “One of the key reasons why glioblastoma is so aggressive is that it shuts off this immune system.” The researchers injected hollowed silica particles into glioblastoma cells, a particularly virulent form of brain cancer, to help recruit white blood cells. They then treated the tumors with high-intensity focused ultrasound (HIFU). The ultrasounds “blew up” the glass particles, which ruptured the cancer cells, which released particles that attracted the immune cells. By modulating the ultrasound, they could create different temperatures, hence Goldilocks. “Impressively, immunotherapy works only when the ultrasound is adjusted to maintain a stable body temperature as the cancer cells are ruptured,” Chen said. “Temperatures that deviate too much from the body temperature appear to compromise the effectiveness of the white blood cells. This ‘Goldilocks’ aspect of immunotherapy was not previously appreciated.” New Class of Drugs May Fight Chemotherapy Resistance Researchers at The Institute of Cancer Research, London , identified a drug that appears to be effective in cancers that become resistant to chemotherapy. The drug is called BOS172722 and it forces cancer cells to multiply faster, which would seem to be counterintuitive. The drug is an MPS1 inhibitor. MPS1 plays a primary role in controlling chromosome organization during cell division. It makes sure that chromosomes are properly distributed between daughter cells. When inhibited with the new drugs, the cancer cells sped through cell division and resulted in the wrong number of chromosomes, which lead to earlier cell death. Antipsychotics Linked to More Hospital Stays for Alzheimer’s Patients A recent study found that Alzheimer’s patients who received antipsychotics had 11 more hospital days over a two-year period than Alzheimer’s patients not receiving antipsychotics. The research was based on the nationwide register-based MEDALZ cohort in Finland from 2005 to 2011, looking at 70,718 people. Data on antipsychotic use was pulled from the Finnish Prescription Register. It may reflect that patients receiving antipsychotics may have more severe behavioral and psychological symptoms. The Timekeepers of the Gut’s Immune System Researchers identified a new type of immune cell that tracks time in the gut. They are called type 3 innate lymphoid cells (ILC3) and maintain intestine function in a normal, healthy way. These cells strengthen the barrier between gut bacteria and the intestinal cells. These cells can be disrupted by changes to circadian rhythms, such as nightshift work or jet lag, which can affect the gut’s immune system. CRISPR Used to Make Fruit Flies Mimic the Monarch Butterfly Monarch butterflies and some other insects have evolved to allow them to eat milkweed, which is normally toxic. They all have the same mutation that allows them to do so. Researchers have now used CRISPR gene editing to make the same mutations in fruit flies. And yes, the fruit flies gained resistance to the milkweed toxin. The reason this is beneficial to insects is that they can eat milkweed without getting sick, but if then eaten by certain animals, they will be toxic to those animals. This research is the first time anyone has recreated an evolutionary mutation resulting in new adaptation to the environment in a multicellular organism. Common Denominator IDed that Triggers Asthma in Favorable Environments In the last 50 years, asthma has increased in industrialized countries related to environmental changes, such as excessive hygiene, ambient air pollution and respiratory viral infections. Researchers have now identified a commonality among these, specific innate immune cells called neutrophils. In all environmental models in mice, the neutrophils found in the lungs caused inflammation that helps allergic responses like asthma. When treated with drugs that prevent neutrophil recruitment, they were protected from disease development. How Gallstones are Formed Although gallstones are in the ten most common reasons for hospital stays, how they are formed was previously unknown. Researchers have now identified the mechanism behind it. By researching a broad range of gallstones in humans collected in museums, and in the bile from pigs, and from patients, they found all gallstones were covered with small amounts of a type of white blood cell called neutrophil granulocytes. They are the body’s first type of defense, attacking bacteria, pathogens and crystals. But while attempting to ingest crystals, which are part of the cause of gallstones, the cells die and cover the crystals with their genetic materials. The nets of genetic materials are neutrophil extracellular traps (NET) and they clump together and form stones. hbspt.forms.create({ portalId: "4413123", formId: "c4dda430-e2b0-4083-86f3-ccce0c1d4479" });