Reacción a "Reactions: New technique tested to improve gene therapy for Parkinson's disease"

It is a study that offers some hope for patients with Parkinson's disease (PD), which can be extended to other neurodegenerative disorders such as Alzheimer's disease or neurological disorders such as brain tumours or epilepsy.  

Currently, PD affects approximately 6 million people worldwide, a number that is expected to increase gradually and steadily over the coming decades due to global ageing trends. The aetiology of PD has not yet been identified, and despite enormous research efforts, no effective treatment to halt or slow the progression of the degeneration of dopaminergic neurons has so far been achieved. 

However, in recent years, gene therapy has shown promise as a therapy that can provide long-term expression of therapeutic proteins. Adeno-associated virus (AAV) is the most widely used viral vector to deliver complementary DNA sequences encoding genes involved in PD pathology. The goal of gene therapies in PD is to increase the bioavailability of dopamine in the nigrostriatal pathway by directly enhancing proteins involved in dopamine production or to promote the health of dopaminergic neurons by maintaining and restoring neurotrophic factors.  

To achieve this, gene therapy trials require AAV vectors to be administered intrathecally (delivery of a drug directly into the subarachnoid space) or intracerebrally to bypass the blood-brain barrier, which is a critical limiting factor. Indeed, early clinical trials of gene therapy were unsuccessful, and this was commonly due to conservative volumes, resulting in suboptimal coverage of the putamen (the putamen is the brain region most affected by dopaminergic denervation in PD). 

Therefore, this study represents an important advance in improving the distribution of AAV vectors within the target brain region, as well as using intravenous delivery of AAV vectors after opening the blood-brain barrier by low-intensity focused ultrasound (LIFU). 

Recently, it has been shown that low-intensity focused ultrasound (LIFU) combined with intravenously circulating microbubbles can be safely applied to reversibly and temporarily open the blood-brain barrier. Dr Obeso's team pioneered this methodology in a pilot study involving patients with Parkinson's disease and dementia, demonstrating that the procedure is feasible and well tolerated, with no serious adverse events.  

Here, the research group goes a step further and successfully reports in monkeys and three patients that LIFU can become a safe and less invasive tool to facilitate the delivery of gene therapy and other potential molecules such as immunotherapy. The study shows that systemic administration of AAV vectors after opening of the blood-brain barrier in more than one PD-relevant brain region results in the expression of neuronal proteins and, consequently, possible activation of these brain regions. 

Despite its advantages and treatment possibilities, LIFU has its share of challenges. Although better penetration of the blood-brain barrier is a great help for drug delivery, including gene therapy, it increases the risk of unwanted substances, such as foreign bodies and inflammatory agents, entering the brain. 

In fact, the same authors reported that one of the monkeys showed inflammatory responses in brain tissue one month after LIFU application. Therefore, it is important to take into consideration the tissue responses observed after LIFU, such as localised oedema, haemorrhage, ischaemia and glial activation. A better understanding of the risks associated with intravenous microbubble administration is also needed. As with any new therapeutic approach, extensive research is essential to further improve the therapy, expand its applications and determine its long-term effects.