Gene Therapy Candidate AXO-Lenti-PD Continues to Benefit Parkinson’s Patients in SUNRISE-PD Trial

 JUNE 7, 2019    BY ALICE MELÃO 

A single dose of Axovant’s gene therapy candidate AXO-Lenti-PD continues to improve motor function and has been well-tolerated after six months in two patients with advanced Parkinson’s disease, according to early results of an ongoing Phase 1/2 clinical trial.

“We continue to be encouraged by the consistency of the data and improvements in quality of life seen at six months in the two low-dose cohort patients, as we enroll additional patients in the second cohort of the SUNRISE-PD study,” Gavin Corcoran, chief research and development officer at Axovant, said in a press release.

Patient enrollment is ongoing for up to 30 participants, ages 48–70, who have been diagnosed with idiopathic (of unknown cause) Parkinson’s for at least five years. More information on contacts and trial locations (in Europe) is available here.

AXO-Lenti-PD is a gene therapy that uses a harmless virus-based system to deliver three genes that generate three enzymes — tyrosine hydroxylase, cyclohydrolase 1, and aromatic L-amino acid decarboxylase for the production of dopamine, the brain-signaling molecule that is present in low levels in Parkinson’s patients.

The therapy is administrated surgically directly into the brain to restore dopamine levels and provide long-lasting benefits with a single administration.

“Our patient-focused goal of improving motor function, reducing dyskinesia, lowering the requirement for oral levodopa, and improving quality of life is made possible by the continuous dopamine replacement strategy of AXO-Lenti-PD gene therapy,” Corcoran said.

The SUNRISE-PD (NCT03720418) study consists of two parts. Part A is an open-label, dose-escalation phase in which patients receive one of approximately three escalating doses of the gene therapy. In part B of SUNRISE-PD, patients are then randomized to receive either the selected dose from part A or an imitation surgical procedure (control group). The goal is to test the safety, tolerability, and effectiveness of the potential treatment.

The first two patients enrolled received the lowest dose (4.2×106 transducing units) of AXO-Lenti-PD. In March, Axovant revealed results of three months of follow-up.

Now, at six months of follow-up, the patients experienced an average improvement of 17 points in motor function, as measured using the physician-rated Unified Parkinson’s Disease Rating Scale (UPDRS) Part III, which represents an average 29% change from the beginning of the study.

The patients also showed an average improvement of about 20 points from baseline on the UPDRS Part II (activities of daily living) off score, and an average improvement of 3 points from baseline on the UPDRS Part IV (dealing with complications of therapy) off score. “Off time” is when medication — namely levodopa — is not working optimally, and Parkinson’s motor and non-motor symptoms return.

Treatment with AXO-Lenti-PD also was associated with an average reduction of 21% in levodopa equivalent daily dose — the amount of levodopa with a similar effect as the medication taken — at six months.

Data also revealed a mean 18% improvement in dyskinesia — involuntary, jerky movements — at six months, determined with the Rush Dyskinesia Rating Scale “on time” score, which measures functional disability during activities of daily living while on treatment with levodopa.

According to a patient-recorded diary, both patients experienced an improvement in on time without dyskinesia of 2.7 hours, a reduction in on time with non-troublesome dyskinesias of 2.4 hours, a reduction of on time with troublesome dyskinesia of 1.5 hours, and an increase in off time of 0.9 hours.

In addition, the patients reported significant improvements in their quality of life, achieving a reduction of 32 points (65% improvement) from baseline in the Parkinson’s Disease Questionnaire-39 Summary Index score.

“These data at six months highlight the potential for a clinically meaningful improvement over the currently available standard of care for those patients with moderate to advanced Parkinson’s disease,” Corcoran said.

Three-month data from SUNDRISE-PD patients treated with the second dose of AXO-Lenti-PD is expected to be announced during the fourth quarter of this year.

https://parkinsonsnewstoday.com/2019/06/07/axo-lenti-pd-gene-therapy-showing-potential-sunrise-pd/

Zonisamide with Levodopa May Reduce Risk of Dementia, Other Parkinson’s-related Symptoms, Japanese Study Suggests

 JUNE 7, 2019  BY CATARINA SILVA

Japanese researchers have reported that zonisamide — an antiparkinsonian medicine approved in Japan as a combination therapy with levodopa — may be associated with a lower risk of dementia, insomnia, and gastric ulcers in Parkinson’s disease, compared with other non-levodopa medicines.

Their research was published in the study “Comparison of zonisamide with non-levodopa, anti-Parkinson’s disease drugs in the incidence of Parkinson’s disease-relevant symptoms,” in the Journal of the Neurological Sciences.

Marketed under the name Zonegran in the U.S. for adjunctive therapy in the treatment of partial seizures in adults with epilepsy since 2000, zonisamide has been approved in Japan (where it’s called Trerief) as an antiparkinsonian agent to be used in combination with levodopa therapy.

Parkinson’s patients have low levels of the chemical messenger dopamine in their brains due to disease-specific death of dopaminergic (meaning “dopamine-producing”) neurons. Among other brain functions, sleep, memory, and movement are all affected by the lack of dopamine and, as such, patients often develop insomnia and dementia, along with the hallmark motor symptoms of Parkinson’s disease.

Levodopa (L-DOPA) is the first choice when it comes to effective Parkinson’s motor symptom control, and as the disease progresses, patients typically need to gradually increase their treatment dose for maximum benefit. After that, they might sometimes experience reappearance or worsening of symptoms due to diminishing effects of dopaminergic therapy. Because of this, most patients will require combination therapy at some point.

Although zonisamide’s mechanism of action is not yet fully understood, studies indicate the compound acts by preventing the breakdown of dopamine, increasing its levels in the brain, and relieving Parkinson’s symptoms. Evidence also suggests that the medicine may have neuroprotective effects.

Clinical trials have shown zonisamide significantly alleviates Parkinson’s motor and non-motor symptoms. “However, partly because zonisamide is off-label for PD [Parkinson’s disease] except for in Japan, situations in which it is more suitable than other drugs have not been sufficiently elucidated,” the researchers noted.

For the study, investigators from Ehime University Graduate School of Medicine in Japan sought to evaluate if zonisamide use in Parkinson’s patients, 40 years or older, was associated with the time of onset of Parkinson’s disease-relevant symptoms, mainly mental, autonomic nervous system, movement, and gastric symptoms.

The results were compared to seven other non-levodopa drug classes that are often used when primary therapy is not fully effective (also referred to as second-line therapy).

For this analysis, levodopa was not considered as a comparison drug to zonisamide, as the majority of study participants were taking levodopa together with zonisamide or another second-line medicine.

Patients had to be on levodopa or other antiparkinsonian medicine without having switched to or recently combined use with other drug classes.

Using a set of statistical approaches, the researchers investigated the time it took for a given symptom of interest to occur while participants were on zonisamide, compared with other non-levodopa medications indicated for Parkinson’s disease.

Of the 9,157 studied subjects, those who were on COMT inhibitors, anticholinergics, or amantadine were two to nearly five times more likely to develop dementia. In addition, zonisamide use was found to be associated with a lower risk of developing insomnia and gastric ulcers, compared with three other non-levodopa medicines.

An increased prevalence of gastric ulcers has long been associated with Parkinson’s disease, and they are generally accepted as a symptom experienced by patients.

“Zonisamide also showed significant lower risk in the incidence of orthostatic hypotension, constipation, and limb fracture,” the researchers wrote, adding that the treatment was, however, also associated with a higher risk “in the incidence of depressionand aspiration pneumonia than at least one of the other drug classes.”

Compared with three other classes of medications, zonisamide appears to be associated with a lower risk of developing dementia, insomnia, and gastric ulcers in Parkinson’s disease. However, it was not always the same three-treatment set that was found to be somehow associated with the lowest risk for a given symptom.

Nonetheless, “[t]here may be a potential clinical impact of zonisamide on some of the [Parkinson’s disease]-relevant symptoms,” the authors concluded.

https://parkinsonsnewstoday.com/2019/06/07/zonisamide-in-combination-with-l-dopa-reduces-risk-of-dementia-other-parkinsons-related-conditions-japanese-study-suggests/

Norman artist's paintings help Parkinson's patients communicate emotions

Katie Standlee,  CNHI News Oklahoma  Jun 6, 2019

Norman resident and artist Tim Kenney paints his plein air painting in Steamboat Springs, Colorado in 2018.

NORMAN, Okla. — For individuals with Parkinson's disease, motor fluctuations, also known as "off" times, occur when medications aren't working well and disease symptoms return or intensify.

Some patients struggle with expressing the symptoms they experience during these off periods, but, with a paintbrush in hand, Norman artist Tim Kenney illuminated those symptoms.

In July of 2018 Acorda Therapeutics, Inc. contacted Kenney and asked him to be an artists involved in their Framing OFF Through Art program. Through the program Kenney and two other artists, Julie B. and Anita Kunz, were each paired with two patients diagnosed with Parkinson’s disease and they painted or crafted the individuals' description of their off periods.

The completed program involved patients Steve Peters, Jennifer Parkinson, John Pelchat, Linda Berghoff, Sarah Diaz and Gustavo Pavon.

“Research has consistently shown that off periods are among the most common issues for people living with Parkinson’s disease,” said Dr. Ron Cohen, Acorda’s President and CEO in an Acorda press release. “This re-emergence of Parkinson’s symptoms can occur unexpectedly, up to several times a day, despite daily medication regimens; this causes enormous disruption and distress to the people who experience this.”

Cohen added, each person’s experience with off periods is unique and can be difficult to describe. He said they believe that people with Parkinson’s will be able to see aspects of their experiences with Parkinson’s and off periods in these works of art, and use this as an opportunity to discuss their symptoms with their healthcare team.

“During an off period, where your medication is suddenly not doing its job, and this happens sort of out of nowhere unexpectedly, it can be very traumatic," Dr. Nicole Jarvis, a Norman OB-GYN and founder of The Nicole Jarvis Parkinson’s Research Foundation, said. "It depends on what you’re doing, but not only can it physically impair you from being able to walk or speak, but it is a very frightening feeling to be sort of stuck in a place.”

Jarvis said every patient is different, but when medications are working well, most Parkinson’s patients function fairly normally.

“I won’t say that we are not aware that we have Parkinson’s disease, I myself have Parkinson’s disease so I am always aware of it, but when my medications are working well, I can still function and probably nobody else would even know that I have Parkinson’s disease,” Jarvis said.

When patients are experiencing off periods, Jarvis said, it can be very isolating having the inability to explain the feeling.

“I think that these paintings that Tim did, those patients described to him specifically what they feel like during their off times and he represented that through his art, and to be able to do that it just blows me away that he is just incredibly talented,” Jarvis said.

Kenney said that’s the main goal of this project, showing how a patient feels during off periods and encouraging communication with family and physicians. He said Jarvis is a good friend and learned more from her about off periods before the program began.

His work features a medley of bright colors and uses the color and characteristics of the trees, in both his paintings, to portray the off periods for Diaz and Pavon. Mid-February he interviewed each for about four hours.

All six individuals have a video about each piece of art and their story written out on the Live Well Do Tell webpage.

“It’s been a real honor to work on the Framing OFF program with this company who is trying to create more awareness for Parkinson’s patients to communicate with their physicians and their families,” Kenney said. “The more they communicate with their doctor about every little thing, especially during their off periods, then the physician can help them fine tune their treatment.”

Kenney said this project was unique, because he had never painted feelings before. When he first heard about this project he wasn’t sure how he was going to paint them, but that all changed when he met Diaz and Pavon.

Diaz has been a Parkinson’s patient for 11 years. She was hesitant to disclose her diagnosis and has struggled with family support while taking care of her mom, Kenney said. However, he said she has a positive outlook on life and he wanted to portray that.

“The painting I did for her was the aspen painting with most of the trees dark. There was one light tree and, to me, that signified what Sarah was, which is the light in the darkness,” Kenney said.

Pavon was the same way, Kenney said, in not wanting to share his symptoms with family and physicians when he was first diagnosed.

“He has now learned to go to more groups and he is blooming a little bit and learning how to get back out in the community a little bit more,” Kenney said. “The oak tree was, he has got a real strong family so he is rooted to the ground and the oak tree has lots of roots that are going through the ground.”

Kenney said Pavon’s wife, Marcela Del Bosque, described the tree as his personality with him branching out and blooming more.

Acorda Therapeutics announced on Monday that all six pieces of art are on display at an art gallery inspired by people with Parkinson’s at the 5th World Parkinson Congress this week in Kyoto, Japan. All of the artwork, stories and videos for Framing OFF Through Art can be found at livewelldotell.org under the Framing OFF tab.

https://www.woodwardnews.net/oklahoma/news/norman-artist-s-paintings-help-parkinson-s-patients-communicate-emotions/article_53f44854-2437-59fb-bd45-c3521d0b98c6.html

After Deep Brain Stimulation, He’s Living His Best Life with Parkinson’s

Written by Cathy Cassataon   June 6, 2019

After being diagnosed with Parkinson’s disease at 30 years old, Jim McNasby’s symptoms were getting worse, then he tried deep brain stimulation.

“I share my story because it is one of optimism. I had brain surgery and it worked,” said Jim McNasby. Images via Jim McNasby

In 2000, Jim McNasby was putting his Harvard law degree to work in the litigation group of the cigarette and tobacco company Philip Morris.

“This was a pretty high pressure [job] as you can imagine,” McNasby told Healthline.

The demands of the job were so intense that he chalked up cramping in his feet, curling of his toes, and tremors to anxiety.

“But then I spilled a cup of coffee on myself two days in a row at work and that seemed like a problem,” he said.

After visiting the company doctor, McNasby was hopeful that something acute and treatable was going on. 

“The doctor was looking for every alternative other than Parkinson’s because it was so unlikely that someone would develop Parkinson’s in their late 20s,” McNasby said. “Michael J. Fox had just come out with the early onset Parkinson’s idea and so it was just coming into the public domain.” 

After several months of further testing, McNasby was diagnosed with Parkinson’s disease at 30 years old.

“Parkinson’s usually affects people older than 50. However, it can affect younger people — even children. Between 2 to 10 percent of patients with Parkinson’s are diagnosed before the age of 50,” Dr. Binith Cheeran, medical director of movement disorders at Abbott, told Healthline.

Considering his age and with no family history or knowledge of the disease, the diagnosis came as a shock to McNasby.

“A million things go through your head. Why me? Why now? Surely, there’s a cure,” McNasby said.

The road to treatment and deep brain stimulation

After his diagnosis, McNasby began taking pramipexole, and because his tremors worsened, he was also prescribed amantadine.

While tremors are a cardinal feature of Parkinson’s, Dr. Fiona Gupta, assistant professor of Neurology at the Icahn School of Medicine at Mount Sinai, says slowness of movement, stiffness, and gait imbalance are also signs of the disease.

“However, it is crucial to understand that all patients experience symptoms differently. There are no two people that are exactly alike,” Gupta told Healthline.

“There are also a multitude of non-motor symptoms, including mood related symptoms and premotor symptoms that can predate the cardinal symptoms, which include loss of smell,” she said.

Throughout the years, McNasby has tried different medications to help with his symptoms, including Sinemet, which he stayed on for nearly 15 years.

In 2006, he began taking trihexyphenidyl, which he believes helped stabilize his symptoms until recently. 

In 2017, his symptoms became progressively worse and he was taking 15 pills a day to help manage them. His condition reached a point that required him to step down from his role as general counsel for Marsh.

“When you take medications to deal with your symptoms, your symptoms get more intense in the beginning and you move out of that into feeling great for a while,” McNasby said.

“I went from tremor to dyskinesia, which means I went from shaking to moving in slower involuntary ways like rocking back and forth instead of shaking. Then that would wear off, and my tremor would come back and I’d go through the shakes again,” he said.

Whenever he took medication, he would go through this cycle.

The constant up and down caused him to look into deep brain stimulation (DBS). He heard about the surgery through the Michael J. Fox Foundation, which he became involved with in 2002 as a pro bono legal resource. 

“I mentor about 40 people who are newly diagnosed with Parkinson’s, I speak [at events], and when people call the Fox foundation, they might pass them on to me as a resource,” said McNasby. “I can imagine doing this forever.”

Being involved in the foundation also helps him stay up-to-date on the latest treatments, such as DBS, which according to Cheeran is a well-established treatment for Parkinson’s disease.

During DBS surgery, weak electrical pulses from a pacemaker-like device are delivered by fine wires directly to the affected network in the brain. 

“DBS can be a good treatment option for a person who has suffered with typical Parkinson’s disease for at least four years and has experienced fluctuations in the control of symptoms for at least four months, despite adjustment of medication,” said Cheeran.

The way in which Parkinson’s manifested for McNasby made him a perfect candidate. However, before going ahead with the surgery, he spent time discussing different system options with his neurosurgeon, Dr. Brian Kopell.

“The concept of brain surgery was scary to me, so I addressed my fear through education. I spoke to many individuals with Parkinson’s disease, providers, and researchers, and I ultimately held off until my medications were no longer sufficient… Ironically, I used to be concerned about the ‘permanence’ of the DBS procedure, but now that it’s over, I hope that its effects are permanent,” McNasby said.

Kopell suggested that the Abbott’s Infinity DBS System was the best option for McNasby, and on January 10, February 4, and February 11 of 2019, he underwent three surgeries.

While he missed a few months of work to recover fully, he says he immediately noticed improvement.

“I felt a tremendous difference as soon as it was activated. I could sit up straight and felt steadiness in my hands and legs with a lightness in my movements. It was as if someone had lifted the symptoms from my body,” said McNasby.

“I was euphoric and started walking aggressively and even jogging up and down the halls of the neurology department,” he said. 

As a part of the initial adjustment process, he took a full dose of Sinemet, but the combination “overstimulated” him, causing dyskinesia.

His doctors concluded that he was sensitive to the combination of the electrical current and medication and made a plan to reintroduce the current gradually. 

“About a week after the initial adjustment, I reached a level of stimulation that was like the initial euphoria without any Sinemet at all. I consider that day, March 5, 2019, to be my ‘re-birthday.’ Today, I feel great, and I notice palpable difference in my everyday life,” said McNasby.

“The DBS therapy has given me the ability to feel lighter, move more easily, and be in control. There is a drastic reduction in my tremors and shuffling. My facial expressions have returned, and my posture is better.”

Cheeran says DBS can reduce fluctuations in symptom control and reduce the dependence on complex medication regimes, as was the case with McNasby. 

“However, even 25 years after the treatment was discovered, many people with Parkinson’s remain unaware of this option or are not offered the procedure despite many years of suffering fluctuating symptom control,” said Cheeran.

“Today, I feel great, and I notice palpable difference in my everyday life. The DBS therapy has given me the ability to feel lighter, move more easily, and be in control,” said McNasby.

A hopeful future for those living with Parkinson’s

Both Gupta and Cheeran are hopeful that many new therapies for Parkinson’s are underway.

“The investment in research, particularly in the past decade, has increased our understanding of Parkinson’s by leaps and bounds. This gives us great hope for better treatments in the future. That said, for someone with Parkinson’s today, it is vital to get the right treatment at the right time; delaying treatment does not delay the disease,” said Cheeran. 

He adds that technological advances arrive faster than pharmacological advances. 

“Rapid advances in DBS technology have given doctors even more powerful tools to personalize therapy, and at the same time the technology is robust, low-maintenance, and discreet,” Cheeran noted.

McNasby shares in the message of hope.

“I share my story because it is one of optimism. I had brain surgery and it worked. It was the best medical decision that I have made,” he said. “Anyone with PD should be aware that there are increasing treatment options for PD and that DBS is among them.”

Today, McNasby works at Marsh in a part-time capacity, and continues to volunteer at the Michael J. Fox Foundation. 

In his spare time, he spends his time staying active by working with a physical trainer, taking spin and yoga classes, and going on hikes with his husband and dog.

“If you don’t have a plan or something that you want to do, then your ability to do it decreases. I like my work and find great gratification volunteering,” said McNasby. “I also want to be in the best possible health for my family.”

https://www.healthline.com/health-news/this-man-with-parkinsons-experienced-improvement-after-trying-deep-brain-stimulation#A-hopeful-future-for-those-living-with-Parkinson’s

Parkinson's: New gene therapy shows promise for prevention Published

By Maria Cohut   June 6, 2019

The hallmarks of Parkinson's disease and some forms of dementia include Lewy bodies, toxic aggregates that form in the brain and disrupt neural circuits. Researchers from Osaka University in Japan are now testing a new preventive therapy in a preliminary mouse study.

Researchers from Japan are testing out a new therapeutic approach for the prevention of Parkinson's disease.

According to information from the Parkinson's Foundation, an estimated 1 million people in the United States will have Parkinson's disease by 2020, and approximately 60,000 U.S. adults receive a diagnosis of this condition every year.

Across the world, they add, more than 10 million people live with Parkinson's disease. Even though it is so prevalent, scientists are still unsure what causes it, and doctors only prescribe symptomatic treatments for the management of this condition.

Nevertheless, researchers continue to study its causes and possible preventive therapies. Recently, a team of scientists from the University of Osaka in Japan decided to find out whether targeting a protein called alpha-synuclein, which aggregates into Lewy bodies, could help prevent or reverse Parkinson's disease.

To this purpose, they have tested a new gene therapy in mice with this neurological condition. Their findings, which appear in Scientific Reports, suggest that this new approach is promising and that scientists should take their investigations further.

"Although there are drugs that treat the symptoms associated with [Parkinson's disease], there is no fundamental treatment to control the onset and progression of the disease," notes the study's lead author Takuya Uehara.

"Therefore, we looked at ways to prevent the expression of alpha-synuclein and effectively eliminate the physiological cause of [Parkinson's disease]," Uehara adds.

Implications for Parkinson's and dementia

First, the team designed "mirror" sections of genetic material to match those that correspond to alpha-synuclein. The researchers then used amido-bridging — a technique that employs amino radicals to connect molecules — to stabilize these genetic fragments.

For this reason, they called the new genetic fragments amido-bridged nucleic acid-modified antisense oligonucleotides, or ASOs. These fragments work by binding to their matching genetic sequence, which is messenger RNA (mRNA). The role of mRNA is to help "decode" genetic information, translating it into proteins.

By binding to mRNA, ASOs prevent it from translating the genetic information that encodes alpha-synuclein, the protein that forms Lewy bodies.

The researchers experimented with different ASO variants until they found one that lowered alpha-synuclein mRNA levels by as much as 81%. Finally, the team tested the effectiveness of their new approach in mouse models.

"When we tested the ASO in a mouse model of [Parkinson's disease], we found that it was delivered to the brain without the need for chemical carriers," explains study co-lead author Chi-Jing Choong. In rodents, the novel gene therapy proved effective and promising.

"Further testing showed that the ASO effectively decreased alpha-synuclein production in the mice and significantly reduced the severity of disease symptoms within 27 days of administration," says Choong.

In the future, the researchers aim to continue testing this method. Should their continued efforts prove successful, they hope that the new therapeutic approach could help prevent and treat not just Parkinson's disease but also other neurodegenerative conditions in which Lewy bodies play a key role.

"

Our results showed that gene therapy using alpha-synuclein-targeting ASOs is a promising strategy for the control and prevention of [Parkinson's disease]. We expect that in the future, this method will be used to not only successfully treat [Parkinson's disease], but also dementia caused by alpha-synuclein accumulation.   "Senior author Dr. Hideki Mochizuki" 

https://www.medicalnewstoday.com/articles/325407.php

Ultrasound Method is First to Restore Dopaminergic Pathway in Brain at Early Stages of Parkinson's Disease

June 6, 2019

Columbia biomedical engineers use transcranial ultrasound and intravenously inject microbubbles to open a pathway through the blood-brain barrier for drugs to penetrate and trigger therapeutic effects—FDA has approved their device for clinical trials in Alzheimer’s patients

Credit: Maria Eleni Karakatsani/Columbia Engineering

Upregulation of the dopaminergic pathway following focused ultrasound-facilitated drug delivery The dopaminergic pathway can be downregulated similar to Parkinson’s disease in toxin-based mouse models. Application of focused ultrasound results in increased blood-brain barrier permeability allowing the diffusion of pharmacological agents in the brain. Depending on the number of administrations and the delivery vehicle, the deliverable compounds can have beneficial effects of varying degree.

Credit: Antonios Pouliopoulos /Columbia Engineering 

Portable ultrasound system for targeted and non-invasive blood-brain barrier opening in humans. The system was recently cleared by the FDA for ultrasound treatment of 6 US Alzheimer's disease patients.

Ultrasound Technique First to Restore Dopaminergic Pathway in Brain at Early Stages of Parkinson's Disease 

Columbia biomedical engineers use transcranial ultrasound and intravenously inject microbubbles to open a pathway through the blood-brain barrier for drugs to penetrate and trigger therapeutic effects—FDA has approved their device for clinical trials in Alzheimer’s patients 

Newswise — New York, NY—June 6, 2019—While there are several thousand drugs available to treat a wide range of brain diseases, from depression to schizophrenia, they cannot penetrate the blood-brain barrier (BBB) into the brain. The BBB, which protects the brain from pathogens that may be present in blood, also prevents most drugs from gaining access to the brain  functional tissue, the parenchyma, a well-known challenge to the treatment of all brain diseases including neurodegenerative disorders like Parkinson's disease and Alzheimer’s. 

A team led by Elisa Konofagou, Robert and Margaret Hariri Professor of Biomedical Engineering and Professor of Radiology (Physics) at Columbia Engineering, has been developing a novel technique that could open up new ways to facilitate targeted drug delivery into the brain and enable drugs to treat brain diseases more focally. The researchers used transcranial, focused ultrasound and intravenously injected microbubbles into the BBB to make a localized and transient opening that allows drugs to cross through the BBB reversibly and non-invasively. Focusing on Parkinson’s disease, in collaboration with Serge Przedborski’s group in the department of neurology at Columbia University Irving Medical Center, they discovered that protein delivery and gene delivery across the BBB can partly restore the dopaminergic pathways, the neurons in the brain that are affected in early Parkinson's disease. 

“We found both behavioral and anatomical neuronal improvements in the brain,” says Konofagou, who led the study, published online April 4 by the Journal of Controlled Release, and in print June 10. “This is the first time that anyone has been able to restore a dopaminergic pathway with available drugs at the early stages of Parkinson's disease. We were able to curb the rapid progression of neurodegeneration while improving the neuronal function. We expect our study will open new therapeutic avenues for the early treatment of central nervous system diseases.” 

The team targeted the brain regions involved in early stage Parkinson's and Alzheimer's disease, such as the putamen and hippocampus. The tool they developed for the study is a device that uses a neuronavigation system to direct the treatment in real-time. The U.S. FDA has just assigned the team an Investigational Device Exemption (IDE) to use the device in clinical trials to test its safety in Alzheimer's patients. 

“Neurosurgeons use such systems all the time to guide them for neurosurgery,” says Antonios Pouliopoulos, associate research scientist in Konofagou’s lab who worked on the development of the clinical neuronavigation system. “Our group just replaced the surgical instrument with an ultrasound transducer to perform our non-invasive procedure.” 

Konofagou’s Ultrasound Elasticity and Imaging Laboratory is the only academic lab in the U.S. to receive FDA approval for ultrasound-assisted, blood-brain-barrier opening. Other groups doing similar research either use nanoparticles to facilitate drug delivery or require MRI to guide the procedure. Konofagou’s approach is MRI-independent and does not require any nanoparticles. 

Her device is a single-element transducer that is much smaller, faster, and less expensive than current helmet-shaped, 1024-element transducer systems that use MRI guidance. Because Konofagou’s system is portable, doctors will be able to treat patients anywhere in a hospital and, in the future, even at a patient’s home. Treatment can be completed in less than 30 minutes, compared to three to four hours for MRI-guided therapy, and monitored in real-time, a unique feature of the new device.  The cost is 10 times less than the MRI-guided helmet. The first trial with the device will be with Alzheimer's patients, after which Konofagou plans to work with Parkinson's patients. 

Konafagou recently won a four-year $2.5M NIH grant to use a similar device for deep brain stimulation aiming to unveil the mechanism by which ultrasound excites neurons and to monitor the unveiled mechanism in human subjects. In addition, she will be honored with the 2019 Engineering in Medicine and Biology Society’s Technical Achievement Award in Berlin this July for her “outstanding and pioneering contributions in the field of ultrasound imaging and therapy, and their application and clinical translation to the diagnosis of cardiovascular diseases, tumor diagnosis and treatment as well as brain drug delivery and stimulation.” 

“We all have loved ones with neurodegenerative disorders,” Konofagou adds. “My grandmother has been suffering from dementia for more than five years, so I know first-hand how essential it would be to have a simple device that can be wheeled into the patient's home and offer a higher quality of life, especially for our rapidly aging population. And there are so many deadly diseases like brain tumors that affect people of all ages, with no cure yet in sight. That’s why we want to bring our research so rapidly to the clinic.” 

About the Study 

The study is titled “Amelioration of the nigrostriatal pathway facilitated by ultrasound-mediated neurotrophic delivery in early Parkinson's disease.” 

Authors—all from Columbia University—are: Maria Eleni Karakatsani a,; Shutao Wang a; Gesthimani Samiotaki a; Tara Kugelman a,;Oluyemi O. Olumolade a; Camilo Acosta a; Tao Sun a; Yang Han a; Hermes A.S. Kamimura a; Vernice Jackson-Lewis c, e, f; Serge Przedborski c, d, e, f; Elisa Konofagou a, b, f.a Department of Biomedical Engineeringb Department of Radiologyc Department of Pathology & Cell Biologyd Department of Neurologye Center for Motor Neuron Biology and Diseasef Columbia Translational Neuroscience Initiative 

The study was supported by the National Institutes of Health, (AG038961, EB009041, NS099862, NS072428, and NS107442), the Focused Ultrasound Foundation, the Kavli Institute, and the Kinetics Foundation. 

The authors declare no financial or other conflicts of interest. 

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LINKS:

Paper: https://www.sciencedirect.com/science/article/pii/S0168365919301907?via%3Dihub
DOI: 10.1016/j.jconrel.2019.03.030
http://engineering.columbia.edu/
https://engineering.columbia.edu/faculty/elisa-konofagou
http://orion.bme.columbia.edu/ueil/
https://www.cuimc.columbia.edu/
https://www.journals.elsevier.com/journal-of-controlled-release
https://bme.columbia.edu/

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Columbia Engineering

Columbia Engineering, based in New York City, is one of the top engineering schools in the U.S. and one of the oldest in the nation. Also known as The Fu Foundation School of Engineering and Applied Science, the School expands knowledge and advances technology through the pioneering research of its more than 220 faculty, while educating undergraduate and graduate students in a collaborative environment to become leaders informed by a firm foundation in engineering. The School’s faculty are at the center of the University’s cross-disciplinary research, contributing to the Data Science Institute, Earth Institute, Zuckerman Mind Brain Behavior Institute, Precision Medicine Initiative, and the Columbia Nano Initiative. Guided by its strategic vision, “Columbia Engineering for Humanity,” the School aims to translate ideas into innovations that foster a sustainable, healthy, secure, connected, and creative humanity.

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