Thursday, January 23, 2020

New ray of hope for people living with Parkinson’s disease

A non-invasive technique which could be used later to treat Parkinson’s disease has been discovered by the scientists that helps to successfully target a highly specific group of brain cells which play a key role in the development of the condition.

Parkinson’s disease is a disorder of the central nervous system that affects movement, often including tremors.

The study was published in the journal Neurotherapeutics.

Earlier in 2015, a form of gene therapy was demonstrated by the scientists that could target and stimulate a group of nerve cells affected by the disease, called cholinergic neurons. These cells degenerate as the disease progresses.

With the advent of brain imaging technology, scientists now have discovered that their method, which targets cells that produce specific brain chemicals, can also successfully stimulate another type of neuron through cell-to-cell interactions.

A revelation of clear communication of two major neurotransmitter systems found in the brain, cholinergic neurons and dopaminergic neurons, was found by Dr Ilse Pienaar, Lecturer in Pharmacology at the University of Sussex, along with colleagues at Imperial College London and Invicro.

In Parkinson’s disease dopaminergic neurons produce dopamine, but the levels of which are reduced as neurons deactivate and eventually die. This can cause a number of symptoms, including impaired movement.

The team used a type of gene therapy in a rat model of Parkinson’s, and Dr Pienaar and her colleagues targeted cholinergic neurons, only to realise that a therapeutic knock-on effect was also felt by dopaminergic neurons.

The originally stimulated cell was able to evoke a positive reaction in the receptive cell type, restoring dopaminergic functions.

With both groups of nerve cells stimulated, test subjects were seen to make a complete recovery including showing no more signs of movement and postural impairment.

Dr Ilse Pienaar, senior author of the study said: “When we used brain imaging, we found that as we activated cholinergic neurons, they then interacted directly with dopaminergic neurons.

“This seems to be a knock-on effect so by targeting this one set of neurons, we now know that we are able to also stimulate dopaminergic neurons, effectively restarting the production of dopamine and reducing symptoms,” Dr Ilse added.

“This is really important as it reveals more about how nerve systems in the brain interact, but also that we can successfully target two major systems which are affected by Parkinson’s disease, in a more precise manner.” The disease is currently being managed by drugs, which can become ineffective after five years and also present a number of side effects. But the technique identified could, in future, provide a less invasive and more effective way to treat Parkinson’s patients.


 

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Monday, January 06, 2020

Researchers test novel approach for injecting gene therapy vectors into kidney

A mouse-experiment conducted by the researchers to better understand the ways to treat renal diseases has identified that before gene therapy is implemented to treat, targeted delivery of the therapeutic genes to the kidney should be the 1st necessary step.

In a novel approach devised by a group of scientists, 3 different gene delivery vectors were injected intravenously and directly into the kidneys of mice. 


As the kidney filters out large compounds from the bloodstream, the researchers chose to study the ability to deliver 3 different sized vectors via an intravenous route: small adeno-associated virus (AAV) vectors (25mm), larger adenovirus vectors (100mm) and lentiviral vectors (120mm).


To bypass this filtering mechanism, they also tested 2 different direct injection routed into the kidney and found these to be superior to intravenous injections.


However, some of the vectors were able to leak out of the kidney, creating the possibility for off-target tissue effects.


The potential for direct injections opens new possibilities for treating kidney diseases with gene therapy, but additional improvements are needed.


The great burden of kidney diseases in the U.S. and Europe has yet to be impacted by gene therapy, said one of the researchers.


The researchers have performed an important head-to-head comparison of currently available gene therapy technology, to identify which may best be used to address this important group of diseases.



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Study suggests feasibility of treating encephalopathy with gene therapy

A new study has highlighted that it is feasible to use gene therapy for treating chronic traumatic encephalopathy ( CTE) which is a progressive neurodegenerative disorder.

Researchers demonstrated the effectiveness of the direct delivery of gene therapy by delivering it into the brain of a mouse.


CTE is much more prevalent than was initially realised, and there is currently no therapy available. This new work is potentially ground-breaking as a means to remove the offending Tau phoshoprotein, said the lead researcher.


The disease which is caused by recurrent trauma in the central nervous system, such as those suffered by soldiers, atheletes in contact sports and in accidents, is currently incurable.


Inflammation results in the accumulation of hyperphosphorylated forms of Tau protein (pTau). 


Researchers developed an adeno-associated virus (AAV) vector to deliver an anti-p-Tau antibody to the CNS. They showed that direct delivery of the AAVrh,10anti-p_tau directly into the hippocampus of brain-injured mice was associated with a significant reduction in p-Tau levels across the CNS.

They propose that doses could be scaled up and this strategy could be effective in humans as well.

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Saturday, September 21, 2019

Gene therapy for sickle cell disease steps closer

Researchers have found a way to repair the faulty gene that causes sickle cell disease, which they suggest is a significant step forward in the search for a viable gene therapy.

 In a study,  they report how - using the CRISPR gene-editing tool - they corrected the gene in stem cells from diseased patients and showed they could make red blood cells capable of making functioning hemoglobin. They also transplanted the stem cells into mice and found them thriving in their bone marrow months later.

Sickle cell disease is a group of inherited disorders where red blood cells form abnormal, hard and sticky, crescent, or sickle shapes instead of normal, flexible, disc-like shapes.

The sickle red blood cells stick to vessel walls and cause blockages, slowing the flow of blood and stopping oxygen reaching nearby tissues. This can cause pain and damage to tissue and organs. Also, sickle cells die faster than normal red blood cells, raising risk of anemia, which can also damage organs.

The disease is caused by a single mutation in a gene that codes for a protein chain in hemoglobin - the molecule in red blood cells that carries oxygen. The faulty hemoglobin forms stiff rods within the red cell, making it crescent-shaped.

Sickle cell disease affects millions of people around the world. The number of Americans living with it is not known, but estimates suggest it is around 100,000.

Children born with sickle cell disease in high-income countries typically survive and can go on to live full lives and enjoy most of the activities that other people do. However, in low-income countries, children born with the disease typically die before they reach their fifth birthday.


Gene therapy and the promise of CRISPR

Since its early beginnings in the 1980s, gene therapy has been a holy grail among researchers looking for ways to cure or treat genetic disorders.

CRISPR is a relatively new gene-editing tool that is said to have "triggered a revolution in genome engineering within living systems." Researchers prefer CRISPR to older methods because it is easier and faster.

The technique is a type of molecular scissors that snip out faulty strips of DNA so they can be replaced with corrected versions using other tools.


The senior author of the new study, has been trying ways to target sickle cell genes with gene-editing technology for several years.

He says with the new CRISPR technology, they can work much faster and more effectively, significantly cutting the time of experiments.

"We spent half a dozen years trying to target the beta globin gene using the old technology," he remarks, adding that within a week of trying CRISPR, they had a gene-editing tool that was much better.

For their new study, Prof. Porteus and his team took hematopoietic stem cells from the blood of patients with sickle cell disease and corrected the faulty gene using CRISPR to remove a strip of DNA and a virus to insert the correct version. Hematopoietic stem cells are stem cells that make blood cells.

They concentrated the human hematopoietic stem cells so that 90 percent carried the corrected sickle cell gene and then injected them into young mice.


Proof of concept that gene-editing can repair sickle cell

Prof. Porteus says that the hematopoietic stem cells have the ability to travel from the bloodstream into the bone marrow, where they then "set up shop and start making other blood cells."

Sixteen weeks after the transplant, the researchers found the stem cells were thriving in the mice's bone marrow.

A gene therapy for sickle cell disease would not have to replace all of a patient's sickle cells Prof.  explains. You just need a sufficient amount of normal cells. Patients whose sickle cells are below 30 percent show no symptoms of disease.

The researchers now need to take their discovery through a series of tests so they can investigate the safety aspects of the new gene editing tool.

This is going to be no mean feat - no CRISPR-edited genes have yet been tested for safety or efficacy in human clinical trials. A particular challenge is how to overcome potential so-called "off-target" effects, where the molecular scissors accidentally cut out the wrong piece of DNA.

Prof. Porteus says Stanford is building the infrastructure so they can start to take their findings out of the lab and scale them up into the types of systems that will be needed to create gene therapy for patients.

For now, he and his team can say that their gene-edited human hematopoietic stem cells appear to behave like normal, healthy human hematopoietic stem cells.

They suggest their findings are proof of concept that using gene-editing can repair sickle cell and other blood-borne genetic diseases, such as thalassemia.

    "What we've finally shown is that we can do it. It's not just on the chalkboard. We can take stem cells from a patient and correct the mutation and show that those stem cells turn into red blood cells that no longer make sickled hemoglobin."



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Sunday, May 12, 2019

Genetic therapy heals damage caused by heart attack


Scientists have developed a gene therapy that can induce heart cells to regenerate and repair the damage caused by a heart attack.

Myocardial infarction, more commonly known as a heart attack, caused by the sudden blocking of one of the cardiac coronary arteries, is the main cause of heart failure.
 
The condition affects over 23 million population in the world, according to the WHO.

At present, when a patient survives a heart attack, they are left with permanent structural damage to their heart through the formation of a scar, which can lead to heart failure in the future, according to the researchers.

"It is a very exciting moment for the field. After so many unsuccessful attempts at regenerating the heart using stem cells, which all have failed so far, for the first time we see real cardiac repair in a large animal," said a researcher.

In the study,  researchers delivered a small piece of genetic material, called microRNA-199, to the heart of pigs, after a myocardial infarction which resulted in the almost complete recovery of cardiac function at one month later.

This is the first demonstration that cardiac regeneration can be achieved by administering an effective genetic drug that stimulates cardiac regeneration in a large animal, with heart anatomy and physiology like that of humans.

"It will take some time before we can proceed to clinical trials," the researcher said in a statement.

"We still need to learn how to administer the RNA as a synthetic molecule in large animals and then in patients, but we already know this works well in mice," he said.

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Tuesday, March 19, 2019

A brain circuit can help reverse craving for liquor

Scientists have found that they can reverse the urge to drink alcohol, finds a study, which may open the door to developing drug or gene therapies to control alcohol addiction.

The team  used a laser treatment to temporarily inactivate a specific neuron, which not only reversed alcohol-seeking behaviour but also reduced the physical symptoms of withdrawal.

“This discovery is exciting. It means we have another piece of the puzzle to explain the neural mechanism driving alcohol consumption,” said a researcher.

Although the treatment is far from ready for human use, he believes identifying these neurons opens the door to developing drug therapies or even gene therapies to control alcohol addiction.

For the study, the team tested the role of a subset of neurons in the ensemble, called corticotropin-releasing factor (CRF) neurons. They found these CRF neurons make up 80 per cent of the ensemble.

Rats were surgically implanted with optic fibres aimed to shine light on the CRF neurons — to make them inactive at the flip of a switch.

Once rats were alcohol dependent, the researchers withdrew alcohol, prompting withdrawal symptoms in rats. When they were offered alcohol again, rats drank more than ever. The CeA neuronal ensemble was active, telling rats to drink more.

When the CRF neurons were inactivated, rats immediately returned to their pre-dependent drinking levels. The intense motivation to drink had gone. Inactivating these neurons also reduced the physical symptoms of withdrawal, such as abnormal gait and shaking.

“We were able to characterise, target and manipulate a critical subset of neurons responsible for excessive drinking,” said a researcher.

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Friday, March 01, 2019

Gene therapy can help correct heart rhythm disorder

A novel gene therapyuses an implanted LED device to reset a racing heart immediately and automatically, paving the way for pain-free treatment for patients with heart rhythm disorder.

The therapy detects fast arrhythmias in the atrium of a rat's heart and sends a signal to a LED device placed near the heart. 

"The flash of light from this LED then causes the heart to generate an electric current itself to halt the arrhythmia," said the lead author of the study.


"This is made possible by using gene therapy to introduce specific light-sensitive proteins into the heart. This restores the heart's normal rhythm immediately and automatically," he added.

According to the researchers, this could represent a great improvement on the current way of stopping atrial fibrillation.
 
Atrial fibrillation is the most common heart rhythm disorder in clinical practice. The current treatment, known as cardioversion, is based on administering an electric shock to the heart, which has to be done in the hospital under general anaesthesia because of pain.


For many patients, this is the only treatment to immediately stop atrial fibrillation because drugs or an operation are ineffective.




 "The bio-electronic defibrillator can stop atrial fibrillation without an electrical shock In this way, the heart can be reset in a fully automated manner and at any time," he said recently.
 
"We anticipate that this treatment for atrial fibrillation could improve both the patient's quality of life and their prognosis," he added.

However, considerable research is still needed before a treatment can be arrived at that is suitable for human patients, the researchers noted.


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