Date: 5th January 2021
Traumatic brain injury (TBI) is a leading cause of death and disability in children and young adults, and is a form of acquired brain injury. TBI can lead to long-term neurological dysfunction and has been implicated in the development of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Now, scientists have developed a nanoparticle (NP) platform that enabled brain delivery of siRNA, independent of BBB pathophysiology for the treatment of TBI, allowing them to inhibit the expression of a key neurodegenerative player by up to 50%.
TBI is an injury to the brain caused by a trauma to the head and has in the past been associated with a single incidence of such an event. However, it is becoming increasingly clear that professional athletes who engage in contact sports such as American football, rugby and football/soccer are prone to repetitive head or neck trauma and have a significant increase in the risk of neurodegenerative diseases such as dementia, Alzheimer’s and Parkinson’s disease as well as motor neuron disease. In addition to being implicated in these diseases, TBI is also associated with cognition and sensory processing problems, behaviour or mental health disorders, memory loss and speech irregularities to name but a few.
Treating brain disorders is challenging as most therapeutics cannot cross the blood brain barrier (BBB). Therefore, current approaches for treating TBI have to be administered in a short time window after injury – when the BBB is temporarily breached. Once this window has passed and the barrier has repaired, clinicians lack the therapeutic tools for effective drug delivery to the brain.
Now, scientists from Brigham and Women’s Hospital and Boston Children’s Hospital,US, led by Nitin Joshi, Jeffrey Karp and Rebekah Mannix, have created a nanoparticle platform, which encapsulated therapeutics and facilitated the delivery of its cargo in both a physically breached or intact BBB. The system showed a threefold higher brain accumulation of NPs compared with conventional NPs, and delivery of siRNA (small interfering RNA) achieved 50% gene silencing in TBI mice brains.
The team started by loading NPs with siRNAs, they chose siRNAs as these types of therapies can target specific pathological pathways to mitigate disease progression and offer a precision medicine approach for the treatment of TBI. They used a variety of different surface coating chemistries and coating densities and compared in vitro uptake of the series of NPs in neural cells in addition to assessing their gene silencing efficiencies and ability to cross the intact BBB in healthy mice.
They targeted the tau gene for silencing, as its pathways have been found to be highly associated with chronic neuroinflammation, neurodegeneration, and cognitive impairment caused by TBI.
The team found that gene silencing efficiency were dependent on the surface coating chemistry of NPs in neural cell lines, and could achieve up 70% knockdown of a reporter expression. This also translated into the ability of two particular NPs to cross an intact BBB when intravenously injected into healthy mice.
The researchers also found that the surface coating density affected cellular uptake of NPs, gene silencing efficiency, and penetration of NPs across intact BBB. Increasing the coat density was concurrent with higher accumulation of NPs.
The researchers then chose the best-in-class NP to test in a more clinical relevant model. They injected the siRNA-loaded NPs into the tail vein of TBI mice, in early or late phase of injury, which corresponded to 2 or 24 hours post injury or after 2 weeks. Injection of tau-targeting siRNAs alone (not loaded into NPs) did not affect tau expression however, tau siRNA-loaded NPs significantly reduced expression by ~50% if administered in the early phase. Even when administered during the late injury period, expression of tau decreased by ~40%. Importantly, the team also showed there was no evidence of systemic toxicity and biochemical parameters remained unchanged in the treated animals suggesting the treatment was safe.
Conclusions and future applications
The team here have reported the first example of BBB pathophysiology–independent delivery of siRNA-loaded NPs in TBI. However, many clinical trials have investigated treatment options for TBI, yet none so far have yielded a successful approved treatment. It is hoped that this platform will give the team significant momentum to accelerate translation into human clinical trials in the near future, providing a suitable treatment for this type of brain trauma.
With this in mind the platform offers several clinical advantages over protein or peptide-based methods of augmenting BBB penetration. The NPs are prepared using a robust one-step method, which facilitates low costs, and are easily scalable for large-scale manufacturing and clinical translation, they have the added advantage that NPs are highly stable and offer low immunogenicity. Together, these combinations serve as good indicators for a promising tool for brain delivery of siRNA for TBI treatment.
From a TBI perspective the team recognise this approach can be used to target many other players involved, and they will be investigating this in more depth in the coming months. It is likely that suppressing the tau pathology alone may not be sufficient to alleviate functional or behavioural dysfunction. Indeed, here these outcomes were not assessed and will have to be addressed before this system progresses to the clinic.
Outside of TBI, it is it likely that other neurological diseases therapies could be explored and developed using the platform, benefitting many patients and disorders.
The BBB was once seen as impenetrable barrier however, technological advances are breaking down this perception and there are now many new methods being developed to overcome this obstacle. Nanoparticles lend themselves well to the task and we have seen a number of NPs being formulated to cross the BBB in recent months. For example NPs have been developed to deliver drugs across the BBB to treat HIV-infected macrophages and engineered ultrasound-controllable drug carriers that are dependent on ultrasound for both targeting and uncaging have allowed focal delivery of drugs, again allowing the crossing of the BBB. We have also reported an enzyme NP delivery system, which could target the brain and was recently used in mice to support the treatment of Krabbe Disease. More recently, scientists engineered a synthetic protein nanoparticle (SPNP) equipped with a cell-penetrating, tumour-targeting peptide, which regressed gliobastoma tumours, resulting in long-term survival and immunological memory against reoccurrence.
The work here represents another step forward in translating NPs into a clinical tool for treating a wide range of diseases, offering hope to those with neurological disorders and diseases. These conditions are often severely debilitating, offer poor prognosis and have limited treatment options and regimes. They are associated with a massive burden to both patients and healthcare, and engineering novel technologies such as described here will be vitally important in improving patient outcomes and alleviating devastating symptoms.
Li, W., J. Qiu, X.-L. Li, S. Aday, J. Zhang, G. Conley, J. Xu, J. Joseph, H. Lan, R. Langer, R. Mannix, J. M. Karp and N. Joshi (2021). “BBB pathophysiology–independent delivery of siRNA in traumatic brain injury.” Science Advances 7(1): eabd6889.