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Success achieved with the first-in-class oral anti-cancer drug, Inobrodib, by CellCentric and Sygnature Discovery.

An integrated project team at Sygnature Discovery worked collaboratively to design, synthesise, and support the pre-clinical development of Inobrodib, a new, first-in-class oral anti-cancer drug being developed by CellCentric.

What are Androgens?

Androgens are ‘male hormones’ including testosterone and dihydrotestosterone. They carry out their actions through a receptor called Androgen Receptor (AR), which is expressed on many cell types and therefore plays crucial roles in the development and function of many systems in the body including the reproductive, musculoskeletal, immune, and cardiovascular. Owing to the diverse function of the AR in different cells, defects in its mediation have been implicated in the development and ‘drug-resistance’ of some cancers in the prostate, bladder, liver, kidney, and lung.

How Inobrodib works

What Inobrodib does is it binds to two proteins that are needed for the activation of AR. The targeted blockage of Cyclic adenosine monophosphate Response Element Binding protein (CREB-binding protein, CBP) and E1A-associated protein p300 (p300) means that the growth of cancers in AR-positive cells could be inhibited.

This is a major breakthrough because the proliferation of many cancer cells that rely on AR/P300/CBP activation such as in prostate, lymphomas, and lung, bladder, and breast cancers may effectively be inhibited.
Top of it all, Inobrodib can be taken orally!

Congratulations to the team at Sygnature Discovery and CellCentric!

December 16, 2022

FDA Approves First-ever Drug That Can Delay Onset of Type 1 Diabetes

Introduction

Tzield (teplizumab-mzwv) has been approved by the US Food and Drug Administration to delay the onset of type 1 diabetes in people aged 8 years and older who are at high risk for developing the condition.

What is type 1 diabetes?

Type 1 diabetes is a disease that develops when the immune system attacks and destroys the cells that make insulin. People who have been diagnosed with type 1 diabetes must monitor their blood sugar levels frequently throughout the day and must administer insulin shots or wear an insulin pump to survive. Although type 1 diabetes can manifest at any age, it is typically detected in children and young people. Although the majority of people with type 1 diabetes do not have a family history, having a parent, brother, or sister with the disease increases a person’s risk.

How the drug works

It is believed to work by reducing the body’s unintended attack on its own cells that make insulin. Protecting these cells is aimed at giving people more time until they require insulin to control their disease.

Tzield attaches to specific immune system cells and delays type 1 diabetes from progressing to stage 3. Tzield could inhibit the immune cells that attack the cells that produce insulin (pancreatic beta cells) while boosting the number of cells that help control the immune response.

Administration

Tzield is administered by intravenous infusion once daily for 14 consecutive days.

Side effects, Warnings and Precautions

Tzield’s most common side effects include rash, headache, and decreased levels of certain white blood cells. The use of Tzield is accompanied by warnings and precautions, including the need to administer all age-appropriate vaccinations prior to starting Tzield and to avoid using live, inactivated, and mRNA vaccines concurrently with Tzield. Other risks and side effects include the need to premedicate and monitor for symptoms of Cytokine Release Syndrome; risk of serious infections; decreased levels of a type of white blood cell called lymphocytes; as well of risk of hypersensitivity reactions.

November 18, 2022

WOMAN CURED OF HIV

According to a presentation at the Conference on Retroviruses and Opportunistic Infections (CROI) on Tuesday 15th February, a woman with HIV who got a cord blood stem cell transplant to treat acute myeloid leukemia has had no detectable HIV levels for 14 months despite stopping antiretroviral medication (ART). This is the third documented case of HIV remission following a stem cell transplant. The study which was led by Yvonne Bryson, M.D., of the University of California Los Angeles, and Deborah Persaud, M.D., of Johns Hopkins University in Baltimore, was conducted by the International Maternal Pediatric Adolescent AIDS Clinical Trial Network (IMPAACT) P1107 observational study.

The IMPAACT P1107 study, which began in 2015, was a U.S.-based observational study that aimed to describe the outcomes of up to 25 HIV-positive people who received a CCR5Δ32/Δ32 cord blood stem cell transplant for the treatment of cancer, hematopoietic illness, or some other underlying disease. As a result of the genetic mutation CCR5Δ32/Δ32, missing cells lack CCR5 co-receptors, which is what HIV uses to infect cells.

Scientists theorize that persons with HIV establish an HIV-resistant immune system by eliminating cancerous immune cells with chemotherapy and then transplanting stem cells with the CCR5 genetic mutation.

The case presented at the CROI meeting features a woman of mixed race origin who had been on antiretroviral therapy (ART) for four years when she was diagnosed with acute myeloid leukemia. After chemotherapy, she was able to attain remission from acute myeloid leukemia. The participant’s HIV was well-controlled yet detectable before the stem cell transplant. In 2017, she received a donation of CCR5Δ32/Δ32 cord blood stem cells from a relative, along with adult donor cells (called haplo cells). She engrafted with 100 percent cord blood cells at day 100 after the stem cell transplant and had no detectable HIV. The patient stopped using ART 37 months after the transplant.

Two examples of HIV remission following a stem cell transplant had previously been reported. The first, a Caucasian male known as the “Berlin patient,” had HIV remission for 12 years and was declared HIV-free; he died of leukemia in September 2020. For more than 30 months, the “London patient” (a Latino man) has been HIV-free. According to the study team, this third case of HIV remission suggests that CCR5Δ32/Δ32 cord stem cell transplantation should be considered to achieve HIV remission and cure in persons living with HIV who need such a transplant for other conditions.

Source: NIH

February 17, 2022

LESSONS OF 2021 NOBEL PRIZE

Bring 2021 Nobel Prizes into the classroom!

From receptors for temperature and contact to organocatalysis. A compassionate voice of the consequences of colonialism to efforts to protect freedom of expression. Understanding complex frameworks to new bits of knowledge about the work market. Now you can show your students the accomplishments granted the current year’s Nobel Prizes in a straightforward manner.

Choose a lesson that covers all of the rewards for 2021 or a session that focuses on a single prize category. They can be found here: https://bit.ly/3macaqm

November 9, 2021

WHO APPROVES HISTORIC RTS,S MALARIA VACCINE

The World Health Organization (WHO) recommends that children in Sub-Saharan Africa and other places with moderate to high Plasmodium falciparum malaria transmission get the RTS,S /AS01 (RTS,S) malaria vaccine. The proposal is based on the outcomes of a trial program that has touched over 800,000 children in Ghana, Kenya, and Malawi since 2019.

The mortality rate of malaria is over 500,000 people each year in Africa, with about half of them being children. The new vaccine isn’t flawless, but experts believe it will help turn the tide.

“This is a historic moment. The long-awaited malaria vaccine for children is a breakthrough for science, child health and malaria control,” said WHO Director-General Dr Tedros Adhanom Ghebreyesus. “Using this vaccine on top of existing tools to prevent malaria could save tens of thousands of young lives each year.”

Malaria kills over half a million people per year, almost entirely in Sub-Saharan Africa, including 260,000 children under the age of five. GlaxoSmithKline’s new vaccine stimulates a child’s immune system to fight Plasmodium falciparum, the deadliest of the five malaria infections and the most common in Africa.

The vaccine was approved by the World Health Organization on Wednesday, the first stage in a procedure that should lead to widespread distribution in low-income countries.

Having a safe, moderately effective, and ready-to-distribute malaria vaccine is “a historic event,” said Dr. Pedro Alonso, director of the World Health Organization’s Global Malaria Programme.

The vaccine, also known as Mosquirix, is not only a novelty against malaria, but also the first to be developed against any parasitic disease. Parasites are much more complex than viruses or bacteria, and the search for a malaria vaccine has been going on for a hundred years.

“It’s a huge jump from the science perspective to have a first-generation vaccine against a human parasite,” Dr. Alonso said.

The vaccine, RTS,S, produced by UK pharmaceutical firm GSK, reduced hospitalizations for severe malaria by 30% in a pilot study in Ghana, Kenya, and Malawi. Between 2001 and 2015, the Bill and Melinda Gates Foundation provided catalytic financing for the late-stage development of RTS,S.

The RTS,S vaccine is the first and only one to demonstrate such promising outcomes, but because it must be given in three doses, one month apart, with a fourth dose a year later, the WHO needed to observe how it functioned in a “real-world” context before approving it. The pilot study will be continued in the three pilot nations in order to determine the additional value of the fourth vaccination dose and to assess the long-term impact on child mortality.

A recent study revealed that using the vaccine in conjunction with preventative medicines given to children during high-transmission seasons was far more successful than using either strategy alone in preventing severe illness, hospitalization, and death.

In the context of comprehensive malaria control, WHO advises that the RTS,S/AS01 malaria vaccine be administered to prevent P. falciparum malaria in children residing in WHO-defined moderate to high transmission areas. The RTS,S/AS01 malaria vaccine should be given to children starting at the age of 5 months on a four-dose regimen to reduce malaria illness and burden.

Sources: WHO

Sky news

The New York Times

October 7, 2021

U.S DUO DAVID JULIUS AND ARDEM PATAPOUTIAN AWARDED THE 2021 NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE

The Nobel Assembly at the Karolinska Institutet decided on 04/10/2021 to award the 2021 Nobel Prize in Physiology or Medicine jointly to David Julius and Ardem Patapoutian “for their discoveries of receptors for temperature and touch.”

Our ability to sense heat, cold and touch is essential for survival and underpins our interaction with the world around us. In our daily lives we take these sensations for granted, but how are nerve impulses initiated so that temperature and pressure can be perceived? This question has been solved by this year’s Nobel Prize laureates.

David Julius utilised capsaicin, a pungent compound from chilli peppers that induces a burning sensation, to identify a sensor in the nerve endings of the skin that responds to heat. Ardem Patapoutian used pressure-sensitive cells to discover a novel class of sensors that respond to mechanical stimuli in the skin and internal organs.

The groundbreaking discoveries of the TRPV1, TRPM8 and Piezo channels by this year’s Nobel Prize laureates David Julius and Ardem Patapoutian have allowed us to understand how heat, cold and mechanical force can initiate the nerve impulses that allow us to perceive and adapt to the world around us.

The TRP channels are central for our ability to perceive temperature. The Piezo2 channel endows us with the sense of touch and the ability to feel the position and movement of our body parts. TRP and Piezo channels also contribute to numerous additional physiological functions that depend on sensing temperature or mechanical stimuli. Intensive ongoing research originating from this year’s Nobel Prize awarded discoveries focuses on elucidating their functions in a variety of physiological processes. This knowledge is being used to develop treatments for a wide range of disease conditions, including chronic pain.

David Julius – awarded the 2021 Nobel Prize in Physiology or Medicine – used capsaicin from chilli peppers to identify TRPV1, an ion channel activated by painful heat.

In the latter part of the 1990’s, Julius at the University of California, San Francisco, USA, saw the possibility for major advances by analysing how the chemical compound capsaicin causes the burning sensation we feel when we come into contact with chilli peppers.

Capsaicin was already known to activate nerve cells causing pain sensations, but how this chemical actually exerted this function was an unsolved riddle. Julius and his co-workers created a library of millions of DNA fragments corresponding to genes that are expressed in the sensory neurons which can react to pain, heat, and touch. Julius and colleagues hypothesised that the library would include a DNA fragment encoding the protein capable of reacting to capsaicin. They expressed individual genes from this collection in cultured cells that normally do not react to capsaicin. After a laborious search, a single gene was identified that was able to make cells capsaicin sensitive (see figure). The gene for capsaicin sensing had been found!

Further experiments revealed that the identified gene encoded a novel ion channel protein and this newly discovered capsaicin receptor was later named TRPV1. When Julius investigated the protein’s ability to respond to heat, he realised that he had discovered a heat-sensing receptor that is activated at temperatures perceived as painful (see figure).

The discovery of TRPV1 was a major breakthrough leading the way to the unravelling of additional temperature-sensing receptors. Independently of one another, both Julius and his co-laureate Ardem Patapoutian used the chemical substance menthol to identify TRPM8, a receptor that was shown to be activated by cold. Additional ion channels related to TRPV1 and TRPM8 were identified and found to be activated by a range of different temperatures. Many laboratories pursued research programs to investigate the roles of these channels in thermal sensation by using genetically manipulated mice that lacked these newly discovered genes. Julius’ discovery of TRPV1 was the breakthrough that allowed us to understand how differences in temperature can induce electrical signals in the nervous system.

Ardem Patapoutian, awarded the 2021 Nobel Prize in Physiology or Medicine, used pressure-sensitive cells to discover a novel class of sensors that respond to mechanical stimuli in the skin and internal organs. Patapoutian and his collaborators first identified a cell line that gave off a measurable electric signal when individual cells were poked with a micropipette. It was assumed that the receptor activated by mechanical force is an ion channel and in a next step 72 candidate genes encoding possible receptors were identified. These genes were inactivated one by one to discover the gene responsible for mechanosensitivity in the studied cells. After an arduous search, Patapoutian and his co-workers succeeded in identifying a single gene whose silencing rendered the cells insensitive to poking with the micropipette.

A new and entirely unknown mechanosensitive ion channel had been discovered and was given the name Piezo1, after the Greek word for pressure. Through its similarity to Piezo1, a second gene was discovered and named Piezo2. Sensory neurons were found to express high levels of Piezo2 and further studies firmly established that Piezo1 and Piezo2 are ion channels that are directly activated by the exertion of pressure on cell membranes (see figure below).

The breakthrough by Patapoutian led to a series of papers from his and other groups, demonstrating that the Piezo2 ion channel is essential for the sense of touch. Moreover, Piezo2 was shown to play a key role in the critically important sensing of body position and motion, known as proprioception. In further work, Piezo1 and Piezo2 channels have been shown to regulate additional important physiological processes including blood pressure, respiration and urinary bladder control.

Source: The Nobel Committee for Physiology or Medicine

October 5, 2021

Missing Dopamine Restored in Children With Atypical Brain Disorder by Gene Therapy

A girl who has lived 8 years of her life with a very uncommon genetic brain disease that made her unable to talk or walk, got enrolled in a clinical trial whose results suggests the course of such inherited disorders can be altered by gene therapy, even after many years.

The patient had AADC deficiency, a disorder that prevents the brain from making dopamine and serotonin, which are important molecules that enable brain cells to communicate. Innocuous viruses carrying healthy copies of the AADC gene were injected by researchers into her brain so cells would make a missing enzyme. The patient—and six other children in the trial— within months, recovered the ability to generate dopamine, researchers report this week in Nature Communications. Many of the participants of the trials, as a result, can walk on their own—and talk with support—for the first time. The results also propose the brain has an unexpected capability to build new connections when a missing enzyme is reinstated.

Source: Science Magazine

July 19, 2021

Category: News