Craniofacial region of a 13-day old mouse embryo by transmitted light microscopy. Credit: Craig Rhodes and Kenneth Yamada, National Institute of Dental and Craniofacial Research, National Institutes of Health
A team of researchers have found evidence of mouse and human germline cells that suggest they can reset their biological age.
As animals age, cell divisions run into replication errors and other external factors (such as exposure to pollutants) lead to gradual decay in cell quality; all of this is part of the natural ageing process. Eventually, cells become senescent and no longer able to divide in response to injury or wear and tear. In a new effort to understand this, researchers have found evidence that shows germline cells have a mechanism to effectively reset this process, enabling offspring to reset their ageing clocks.
Germline cells pass on genetic material from parent to offspring during the reproductive process. For many years, scientists have wondered why these cells do not inherit the age of their parents. And for many years, they assumed that the cells were ageless, but recent work has shown that they do, in fact, age. So that raised the question of how offspring are able to begin their lives with fresh cells.
To find out, the researchers at Brigham and Women’s Hospital and Harvard Medical School used molecular clocks to track the ageing process of mouse embryos. These clocks measure epigenetic changes in cells, and using them, the researchers continuously compare the biological age of embryos (apparent age based on reactions to epigenetic changes) with their chronological age. They found that the biological age of the mouse embryos remained constant through initial cell division after an egg was fertilised. However, about a week later, after embryo implantation in the uterus, the biological age of the embryos dropped. Some mechanism, it seems, had reset the biological age of the embryo back to zero.
Turning to human embryos, the team was unable to track ageing in human embryos because ethics rules forbid such research, but they still managed evidence suggesting that human embryos also reset their clocks. They plan to continue seeking the mechanism behind the reset process. The team’s findings were published in the journal Science Advances.
Journal information: Csaba Kerepesi et al, Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging, Science Advances (2021). DOI: 10.1126/sciadv.abg6082
Chromosomes prepared from a malignant glioblastoma visualized by spectral karyotyping (SKY) reveal an enormous degree of chromosomal instability — a hallmark of cancer. Credit: Thomas Ried, NCI Center for Cancer Research, National Cancer Institute, National Institutes of Health
Researchers have used a new machine learning and protein profiling system to identify vulnerabilities in glioblastomas and to assess immune checkpoint blockade treatment effectiveness.
Neoadjuvant immune checkpoint blockade (ICB) is a promising treatment for melanoma and other cancer types, and has recently been shown to provide a modest survival benefit for patients with recurrent glioblastoma. To improve the treatment efficacy, researchers are looking for vulnerabilities in surgically removed glioblastoma tissues, but this has been difficult due to the vast differences within the tumours and between patients.
To tackle this problem, researchers at Institute for Systems Biology (ISB) and their collaborators developed a new way to study tumours. The method builds mathematical models using machine learning-based image analysis and multiplex spatial protein profiling of microscopic compartments in the tumour.
The team used this approach to analyse and compare tumour tissues gathered from 13 patients with recurrent glioblastoma and 23 patients with high-risk melanoma. Both groups had been treated with neoadjuvant ICB. Using melanoma to guide the interpretation of glioblastoma analyses, they were able to identify the proteins that correlate with tumour-killing T cells, tumour growth, and immune cell-cell interactions.
Co-lead author Dr Yue Lu described the research : “This work reveals similarities shared between glioblastoma and melanoma, immunosuppressive factors that are unique to the glioblastoma microenvironment, and potential co-targets for enhancing the efficacy of neoadjuvant immune checkpoint blockade.”
“This framework can be used to uncover pathophysiological and molecular features that determine the effectiveness of immunotherapies,” added Dr Alphonsus Ng, co-lead author of the paper.
ISB, UCLA and MD Anderson collaborated on the study, the findings of which were published in Nature Communications. Brain cancer represents one of the toughest settings for immunotherapy success. Collaboration between scientists and clinicians provides a great opportunity for improving patient care and achieving a deep understanding of cancer immunotherapy.
“We believe that the integrated biological, clinical and methodological insights derived from comparing two classes of tumors widely seen as at the opposite ends of the spectrum with respect to immunotherapy treatments should be of interest to broad scientific and clinical audiences,” said corresponding author and ISB President, Dr Jim Heath.
Journal information: Yue Lu et al, Resolution of tissue signatures of therapy response in patients with recurrent GBM treated with neoadjuvant anti-PD1, Nature Communications (2021). DOI: 10.1038/s41467-021-24293-4
An intravenous CRISPR gene editing infusion lowered levels of a disease-causing protein in vivo for the first time in humans, according to interim findings from a phase I trial.
Hereditary (ATTR) amyloidosis is a rare, rapidly progressive disease caused by a mutation in the serum transthyretin (TTR) gene that results in the buildup of misfolded transthyretin and leads to the formation of amyloid deposits in the heart, gastrointestinal tract, and peripheral nerves. Life expectancy is about 3 to 15 years after the onset of neuropathy. Researchers used the DNA-editing tool CRISPR-Cas9 to inactivate the TTR gene in liver cells to prevent misfolded TTR protein from being produced. The liver produces almost all circulating TTR.
The treatment reduced TTR by 87% in three people with hereditary transthyretin (ATTR) amyloidosis with polyneuropathy. The findings were published in the New England Journal of Medicine.
“This is the first successful demonstration of therapeutic gene editing within patients’ bodies, making it a watershed moment in modern medicine,” noted Kiran Musunuru, MD, PhD, MPH, director of the Genetic and Epigenetic Origins of Disease Program at the University of Pennsylvania in Philadelphia, who was not involved with the study.
“The investigators used lipid nanoparticle technology — the same technology used in COVID mRNA vaccines — to deliver CRISPR into the liver, with the goal of turning down a gene responsible for hereditary ATTR amyloidosis,” Dr Musunuru told MedPage Today.
“What was astonishing about this first-in-human study is not just that the treatment worked, but that it worked extremely well in patients, in one case turning off the disease gene close to 100%. It’s like launching a rocket ship in the hope of just getting into orbit, but making it all the way to the moon on the first try.”
Previously, other studies have removed blood stem cells from people with sickle cell anaemia and beta-thalassemia, editing them using CRISPR, and infusing them back into patients. In a trial of people with inherited blindness, a subretinal injection also has delivered CRISPR treatment. Towever, the findings of NTLA-2001 represent the “first-ever clinical data suggesting that we can precisely edit target cells within the body to treat genetic disease with a single intravenous infusion of CRISPR,” noted John Leonard, MD, president and CEO of Intellia Therapeutics, which co-sponsored the trial with Regeneron Pharmaceuticals.
“Solving the challenge of targeted delivery of CRISPR-Cas9 to the liver, as we have with NTLA-2001, also unlocks the door to treating a wide array of other genetic diseases with our modular platform, and we intend to move quickly to advance and expand our pipeline,” said Dr Leonard in a statement.
NTLA-2001 is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system. It consists of a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR.
The ongoing phase I study looked at safety and pharmacodynamic effects of single doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy. Half received 0.1 mg/kg, the other received 0.3 mg/kg. Three patients had a p.T80A mutation, two a p.S97Y mutation, and one a p.H110D mutation. Three patients received no prior therapy; three previously had received diflunisal.
Dose-dependent reductions in serum TTR were seen from treatment with NTLA-2001. At day 28, mean serum TTR levels declined by 52% in the 0.1 mg/kg group and by 87% in the 0.3 mg/kg group. No serious adverse events were recorded.
Two treatments for hereditary ATTR amyloidosis nerve pain won FDA approval in 2018: patisiran (Onpattro), an RNA interference drug, and inotersen (Tegsedi), an RNA-targeting drug that reduces the production of TTR protein.
The NTLA-2001 study could have profound clinical implications, noted Joel Buxbaum, MD, of Scripps Research Institute in La Jolla, California, who was not involved with the study. “If, as the authors surmise, the effect is permanent, and without off-target effects when studied in a much larger patient population, it would be a significant improvement [over] current therapies for this class of disorders, at least with respect to frequency of therapy,” he said.
“However, all that depends on the clinical effect of long-term suppression of hepatic TTR synthesis,” Buxbaum told MedPage Today. “In the published studies of the various currently available ATTR therapeutics, approximately one-third of subjects have little or no clinical response, regardless of the degree of suppression of circulating protein levels, suggesting that while diminishing the supply side for TTR aggregation is likely to be necessary for clinical responsiveness, it may not be sufficient for optimal or profound therapeutic efficacy.”
After phase I studies are complete, the company plans to move forward to pivotal studies for both polyneuropathy and cardiomyopathy manifestations of ATTR amyloidosis.
Journal information: Gillmore JD, et al “CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis” N Engl J Med 2021; DOI: 10.1056/NEJMoa2107454.
Upgrading face masks to filtering face piece (FFP3) respirators for healthcare workers on COVID wards produced a dramatic reduction in hospital acquired SARS-CoV-2 infections, according to a preliminary study published in the BMJ.
For most of 2020, Cambridge University Hospitals NHS Foundation Trust followed national guidance that healthcare workers should use fluid resistant surgical masks as respiratory protective equipment unless aerosol generating procedures (AGPs) were being carried out when FFP3 respirators were advised.
From the pandemic’s outset, the trust has been regularly screening its healthcare workers for SARS-CoV-2 even when asymptomatic. They found that healthcare workers on “red” COVID wards had a greater infection risk than staff on “green” wards, even with protective equipment. So in December 2020 the trust implemented a change in policy so that staff on red wards wore FFP3 masks instead of fluid resistant surgical masks. The FFP3 standard requires that masks filter 99% of all particles measuring up to 0.6 μm.
The study was carried out at Addenbrooke’s Hospital in Cambridge. Before the change in policy, cases among staff were higher on COVID versus non-COVID wards in seven out of eight weeks analysed. Following the change in protective equipment the incidence of infection on the two types of ward was similar. Of 609 positive results over the eight week study period, 169 were included in the study. Healthcare workers who were not ward based or worked between different wards were excluded, as were, non-clinical staff, and staff working in critical care areas.
The researchers developed a simple mathematical model to quantify the risk of infection for healthcare workers. This found that the risk of direct infection from working on a red ward prior to the policy change was 47 times greater than the corresponding risk from working on a green ward. While almost all cases on green wards were likely caused by community-acquired infection, cases on red wards at the beginning the study period were attributed mainly to direct, ward-based exposure.
The model also suggested that the introduction of FFP3 respirators provided 100% protection (confidence interval 31.3%, 100%) protection against direct, ward based covid infection.
Study author Chris Illingworth, from the MRC Biostatistics Unit at the University of Cambridge, said: “Before the face masks were upgraded, the majority of infections among healthcare workers on the COVID wards were likely because of direct exposure to patients with COVID. Once FFP3 respirators were introduced, the number of cases attributed to exposure on COVID wards dropped dramatically—in fact, our model suggests that FFP3 respirators may have cut ward based infection to zero.”
Michael Weekes from the department of medicine at the University of Cambridge added: “Our data suggest there’s an urgent need to look at the PPE offered to healthcare workers on the frontline. Upgrading the equipment so that FFP3 masks are offered to all healthcare workers caring for patients with COVID could reduce the number of infections, keep more hospital staff safe, and remove some of the burden on already stretched healthcare services caused by absence of key staff because of illness.”
