A major hindrance to Parkinson’s disease (PD) treatment is the ability for drugs to “show up” where they are supposed to. The brain is a vulnerable, complex organ and, as such, is protected by a structure known as the blood brain barrier (BBB). The BBB prevents entry of particles from the blood into the brain, unless these particles are granted special “access.” 

One of the latest advances in PD drug delivery uses specialized technology to circumvent the BBB. This novel method is called transcranial focused ultrasound (FUS) and involves using tiny “microbubbles” to bypass the BBB and deliver drugs directly to their target point. FUS delivery is precise, accurate, and involves drug delivery while the patient is in an awake state! This is in contrast to previous PD drug delivery methods which involved invasive neurosurgical approaches. 

In 2018, the Food and Drug Administration (FDA) approved FUS as an available treatment option for Parkinsons and Parkinson-like movement disorders. In this treatment, imaging is used to visualize the brain and then guided ultrasound beams target cells causing disease. 

In the new approach, FUS uses the “microbubbles” to open the BBB allowing the focused ultrasound beams to have a more precise targeting region for sending drugs. This application offers a variety of treatment possibilities including gene therapy to manage PD symptoms or modify disease progression, and immune therapy to recover damaged cells.  

Novel Therapeutics using FUS 

Gene therapy – or the implantation of engineered genes into specific brain regions – is being researched for a host of neurodegenerative diseases including PD. Past gene therapy methods have often employed the use of an invasive deep brain stimulation (DBS). The disadvantage of invasive surgical gene therapy is that certain patients will need to be excluded, including those who have cognitive impairment. 

Gene therapy approaches including one aimed at altering the activity of a specific molecule which converts levodopa to dopamine, and another which helps to improve “off” periods in Parkinson’s have shown promise for treating PD symptoms in a clinical trial setting. Other experimental gene therapy approaches aim to slow the progression of PD by using FUS to bypass the BBB and send drugs that would “rescue” damaged brain cells directly to the specific brain regions involved. 

Another avenue for PD treatment is harnessing the immune system. This approach includes the deployment of immune molecules called antibodies to “attack” poorly folded alpha-synuclein (the hallmark of PD). This targeted immunotherapy faces a similar drawback of not being able to cross the BBB, leading to limited brain penetration of the drug. Utilizing FUS might be the key to enhancing this use of this approach for PD. 

Future Directions  

FUS will literally and figuratively “open doors” for PD treatment options requiring direct drug delivery to the brain. While FUS seems promising, there are some drawbacks. Currently, there has not been enough research conducted to understand exactly how far these molecules will travel once they have crossed the BBB, with the consensus being that the molecules have demonstrated travel distances of up to a few millimeters. The brain regions implicated in PD are relatively large, and more research needs to be done to understand how to tackle wide tissue drug distribution. Another concern is that opening the BBB might pose some considerable long-term risks, including immune system reactions to the entry of foreign molecules into the brain. 

Overall, the use of FUS for targeted drug delivery seems to be a promising avenue for PD therapeutics. Further elucidation of the specific capabilities of FUS including symptom management and disease modification therapies may alter the course of many neurodegenerative diseases including Parkinson’s and offer a safe and reliable method to deliver drugs to the brain. 

To learn more about FUS please visit the Focused Ultrasound Foundation website: https://www.fusfoundation.org/for-patients/ 

Article Source: (LeWitt PA, Lipsman N, Kordower JH, 2019)