Nearly 10 years later, the same group of researchers is once again approaching a new breakthrough, this time with the potential to bring the technology to more patients and more clinics, and to revolutionize the treatment options for many neurological and brain diseases.

The team, led by Dr. Kullervo Hynynen, vice president of research and innovation and senior scientist at SRI, as well as the Temerty Chair in Focused Ultrasound Research, has developed a powerful new ultrasound device specifically designed to open the blood-brain barrier to allow helpful agents — such as chemotherapy, antibodies, stem cells or gene therapy to reach the brain. However, unlike the current focused ultrasound device, the new technology operates without the need for real-time MR imaging – a costly hurdle for delivering focused ultrasound to the brain.

At Sunnybrook, focused ultrasound is most commonly used to treat essential tremor, a neurological disease that causes tremors which can severely affect a person’s quality of life. Dr. Nir Lipsman, chief of the Hurvitz Brain Sciences Program, Harquail Chair in Neuromodulation and senior scientist at SRI, explains that the technology used for this indication is called high-intensity focused ultrasound, which uses ultrasound waves to target tissue and create lesions deep within the brain, without the need for a scalpel or incisions.

The new technology in development, meanwhile, is low-intensity focused ultrasound, which Lipsman says, “is used to open the blood-brain barrier and deliver all kinds of therapeutics to the brain.”

The technology behind the low-intensity focused ultrasound is currently undergoing clinical trials at Sunnybrook’s Harquail Centre for Neuromodulation – to be housed within the new Garry Hurvitz Brain Science Centre – and has the potential to provide new treatments and therapies for brain cancers, Alzheimer’s disease, Parkinson’s disease and Amyotrophic Lateral Sclerosis (ALS).

Drs. Hynynen and Lipsman shared some of the latest developments and most promising potential of the next-generation helmet.

Drs. Kullervo Hynynen and Nir Lipsman

How could this next-generation helmet change the way focused ultrasound is used to treat brain diseases?

Lipsman: One of the conditions we are most interested in is brain cancer. Currently, the entire procedure across all of our trials is done inside the MRI for real-time imaging. There are some indications where that’s very important, but there are other indications where real-time imaging may not be as critical. The next-generation helmet means we may be able to do the procedure outside of the MRI environment, saving time and money, and making the procedure more comfortable for patients. The idea is over time to develop a safer, more streamlined, and effective procedures for accessing critical brain circuits, and that’s where the new technology will really shine.

Hynynen: Taking the procedure out of the MRI would make it a more accessible form of treatment. We would do an initial scan of the patient’s head to be able to create a rapid prototype of the helmet that is customized to the patient, and subsequent treatments could be done without real-time imaging. Being out of the MRI means no associated costs, and by bringing costs down it increases capacity significantly.

How is the next-generation helmet different from the existing technology?

Hynynen: The current focused ultrasound technology works really well for precise single ‘dose’ treatments, like treating tremors or what you might think of as ‘surgery’ treatments. But for treating brain cancer or Alzheimer’s, which require multiple treatments, it becomes prohibitive in its current state using real-time MRI. By taking the treatment out of the MRI, we can perform any number of treatments. It’s taking it to the next level – it becomes a real treatment for things like brain cancer and Alzheimer’s.

What would a treatment visit look like for someone using this new technology?

Hynynen: The patient would get the initial MRI scan, and from that a customized helmet would be created. Then, the patient would come in for treatment, get the helmet and transducers on. We would infuse drug and infuse the microbubbles that help us open the blood-brain barrier, and with very controlled modulation we would open the blood-brain barrier to deliver the therapy. The treatment can be precisely customized for each patient to the area of the disease while the intact blood-brain barrier is protecting the rest of the brain.

Lipsman: An aspirational goal would be to do with focused ultrasound what we do in a chemotherapy clinic or a dialysis centre. It would be an outpatient procedure where patients come in, get the procedure, and leave in a more streamlined, comfortable process. Ultimately, we hope to use focused ultrasound at every stage of the brain cancer treatment journey. This can include immediately after surgery, when patients undergo chemotherapy and radiation or it might be at the time of a recurrence, and in order to enhance the effect of other treatments. The idea is to match, as much as possible, novel treatments to our patient’s specific conditions.

This technology development is generously supported by the Weston Family FUS Initiative and our incredible donor community.

The post Behind the Research: How a next-generation helmet could revolutionize focused ultrasound appeared first on Your Health Matters.

In a recently published preclinical study, Dr. Isabelle Aubert, senior scientist at Sunnybrook Research Institute and postdoctoral researcher Dr. Kristiana Xhima successfully used focused ultrasound to non-invasively deliver a therapeutic in the brain, targeting brain cells affected by Alzheimer’s disease and improving cognition.

The study has been published in the journal BRAIN.

This is the first study to demonstrate that repeated focused ultrasound blood-brain barrier modulation in the basal forebrain is safe in the presence of Alzheimer’s pathology, and when combined with a growth factor-related therapeutic, can lead to therapeutic effects. Focused ultrasound harnesses the power of sound waves to transiently open the blood-brain barrier, a protective barrier that prevents toxins or potentially helpful therapeutics in the bloodstream from entering the brain.

This promising research comes at an urgent time. It is estimated that more than 600,000 Canadians are currently living with dementia. According to a recent report from the Alzheimer’s Society of Canada, rates of dementia, including Alzheimer’s disease, are projected to rise to nearly 1 million people in Canada by 2030. Below, Drs. Aubert and Xhima discuss how their breakthrough research is an important advancement on the road to developing effective therapeutic approaches for the disease.

Dr. Aubert and Dr. Xhima

What was the impetus behind your study?

Dr. Aubert: This preclinical study was a follow-up to our previous proof-of-concept study that used MRI-guided focused ultrasound to non-invasively deliver a type of growth factor-related therapeutic (D3) to brain cells called cholinergic neurons, which are important for learning and memory and most vulnerable in Alzheimer’s disease. D3 stimulates important signaling mechanisms in brain cells that are related to the tropomyosin receptor kinase A (TrkA) pathway. The TrkA pathway is critical for neuroprotection, plasticity and survival of cholinergic neurons; engaging it with D3 promotes the resilience of brain cells against Alzheimer’s pathology.

In our first proof-of-concept study, we had found that D3 combined with focused ultrasound efficiently stimulated key survival and neuroprotective pathways, and in the short-term, helped to restore brain cell communication (also known as neurotransmission). Yet for clinical translation and impact, it was critical for us to study whether focused ultrasound combined with D3 could rescue cognitive function – the rationale and goal of the current study.

What did your current study find?

Dr. Xhima: In this preclinical study, we demonstrated the therapeutic potential of D3 in a preclinical model of Alzheimer’s and showed its impact on learning, memory and cognitive flexibility. The D3 therapeutic agent, like many promising therapeutics, does not have the properties required to efficiently cross the blood-brain barrier (BBB) and reach its targets deep in the brain. To overcome this challenge, we coupled the intravenous administration of the therapeutic drug D3 with MR-guided focused ultrasound to non-invasively, locally and transiently increase BBB permeability in key brain regions for the effective delivery of D3 from the blood to the brain.

Following brain delivery of the therapeutic agent with focused ultrasound, performance in cognitive tasks was improved. The treatment of focused ultrasound with the therapeutic D3 led to enhanced neurotransmission in cholinergic neurons, which are highly vulnerable to injury in Alzheimer’s disease. We also observed beneficial effects on brain regeneration – new brain cells were formed in the hippocampus, an area of the brain that plays a major role in learning and memory, and amyloid plaques, common in Alzheimer’s, were reduced in targeted brain areas.

What could these results mean for patients and clinicians in the future?

Dr. Aubert: Although still early-stage, this work is an important and fundamental step in the development of potential treatments for the disease. The results also open the door for many other regenerative agents, that normally do not cross the BBB, to be tested and delivered using this drug-delivery platform. This is the first study to demonstrate that a growth-factor related agent delivered to the basal forebrain and associated cortical and hippocampal areas repeatedly using focused ultrasound BBB modulation is safe and can lead to therapeutic effects in the presence of Alzheimer’s pathology. These results provide a major step forward in terms of drug delivery that can be very promising for clinical translation.

Dr. Xhima: Another key feature of this preclinical research is that we tested focused ultrasound delivery of a TrkA-stimulating agent in the presence of established Alzheimer’s pathology. In contrast to many previous studies, here we showed that this therapeutic approach rescued cognition and improved Alzheimer’s related pathologies once they were already established, similar to how patients would present in the clinic. The beneficial effects of the treatment were also broad with respect to several key systems affected in Alzheimer’s disease. This makes us very hopeful about this therapeutic approach because it certainly represents an important step forward for potential clinical development.

What’s the next step in this work?

Dr. Xhima: The improvements in cognitive function we saw in the preclinical models studied lasted for several weeks, which raises the question: how often will treatment need to be repeated for therapeutic effects that can last over months and years?

Dr. Aubert: In addition to this, we’re interested in taking an exploratory approach to look at other molecular pathways in the brain that could also be affected by this treatment, since our results went beyond what was expected with target engagement on cholinergic neurons alone.

It’s important to note that this research is still at an early stage and has not yet moved to clinical trials. We are hopeful that this fundamental research will translate into the clinic in the near future, as we continue to explore therapeutic options to stop degeneration and promote regeneration in Alzheimer’s disease and dementia.

Hear Dr. Aubert and Dr. Xhima discuss their findings in further scientific detail on the BRAIN podcast, the official podcast of Brain and Brain Communications.

The post Behind the research: New study finds focused ultrasound enhances delivery of brain therapeutic and improves cognition in Alzheimer’s appeared first on Your Health Matters.

These are difficult words for me to say, and difficult words for people to hear.

As a medical oncologist specializing in breast cancer, it’s a conversation I unfortunately have to have with many people each year. The brain is a common area for HER2+ breast cancer to spread. HER2+ means that the cancer cells contain this growth-producing protein.

There are not a lot of treatment options for patients whose breast cancer has spread to the brain. While there’s no cure, we try to manage the disease with radiation, surgery and drug therapies.

Drug therapies that work well to control cancer in other parts of the body don’t work as well in the brain, like Trastuzumab. This antibody therapy is a large molecule that has difficulty passing through the blood-brain barrier. This protective layer of cells around the brain prevents compounds circulating in the bloodstream from entering the brain but it also blocks potentially useful medications such as antibodies, chemotherapy drugs or other treatments for brain conditions.

So while Trastuzumab is really effective at treating cancer in the breast or that has metastasized to other areas, it cannot penetrate the brain easily. It’s frustrating: we know this therapy works well at controlling tumours, we just need to help it get it into the brain.

Soon after I started at Sunnybrook, I learned of research happening with focused ultrasound – using MRI-guided beams of ultrasound to temporarily open the blood-brain barrier. If the blood-brain barrier is opened, a drug like Trastuzumab could potentially more enter the brain more easily and target the tumour. It sounded like a unique way to approach the treatment of cancer that has spread to the brain. Therefore, I began working with Dr. Nir Lipsman and Dr. Maureen Trudeau, who were at the time setting up a trial to examine the safety of this approach for patients with breast cancer that has spread to the brain.

Our recently published study found that this approach is safe. The Trastuzumab was labelled so the research team could actually watch it pass through the blood-brain barrier and go into the brain. Patients were safe, and while these are early results, we saw some shrinkage in tumour size over time.

It feels amazing to be a part of something that’s a world-first and that shows so much potential. It’s a good first step in being able to offer patients with metastatic breast cancer another option for treatment. I’m excited to move into the next phase of this work and expand our trial to look more at how effective this treatment is at improving outcomes for patients with brain metastases.

To the patients involved in this and other clinical trials: Thank you. You put your faith and trust in the scientists, the physicians and the research teams who say “We are really excited about the promise of this treatment.” When it’s an early trial, you might be the very first person. You are so courageous for putting your hand up first. It’s through your courage that we can make life-saving breakthroughs.

Please talk to your doctor about taking part in clinical trials.

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