PhD Project in the CDT in Neurotechnology

Development of a Noninvasive and Localised Blood-Brain Barrier Opening System for the Treatment of Alzheimer’s Disease

Deadline: 29 January 2016

External project link: CDT in Neurotechnology

Team:

1st Supervisor: Dr. James J. Choi, Department of Bioengineering, Imperial College London
2nd Supervisor: Dr. Magdalena Sastre, Department of Medicine, Imperial College London
Collaborator: Dr. Simon Schultz, Department of Bioengineering, Imperial College London

Funding:

All CDT studentships are for 4 years and provide a stipend (currently £15,863 for the 2014/15 academic year), payment of Home/EU tuition fees, and a yearly budget for consumables and attending UK and international conferences. Click for more details.

Eligibility:

Places are open to UK and EU applicants only. Click for more details.

Project description:

Novel drugs, such as antibodies, siRNA, gene therapies, and nanoparticles have emerged as potent biological agents that have better targeting, specificity, and therapeutic abilities (e.g., silencing a gene). Yet their ability to treat neurodegenerative diseases (e.g., Alzheimer’s disease (AD)) has been limited due to the blood-brain barrier (BBB) – the interface lining cerebral capillaries. The two major reasons for this is that (1) the BBB prevents nearly all molecules greater than 400 Da from entering the brain, and (2) knowledge of this is used as a criterion in the design of new drugs, which eliminates consideration of most novel drugs. Current AD drugs approved by the EMA and FDA treat symptoms, but do not modify the underlying AD process in patients.

The overarching aim of the proposed neurotechnology project is to develop a non-invasive, localised, and safe BBB opening technology that reduces AD pathological features and improves cognitive function. The PhD student will construct a technology that uses focused ultrasound (US) and systemically administered microbubbles to control mechanical stress within the cerebral capillaries of mice (Fig. 1). Producing the correct magnitude of stress and a homogeneous distribution of stress along the capillary length is critical to producing an effective and safe distribution of BBB opening. The MRes project aims to construct a BBB opening system by assembling state-of-the-art US technologies in the Choi Group to deliver a normally impermeable fluorescently-labelled molecule in transgenic AD (APP23) mice from the Sastre Group. The PhD project aims to develop and design a novel US control system that provides an unparalleled level of control of the microbubble-induced mechanical stress within cerebral capillaries. He/she will then characterise the system by assessing BBB permeability for different US sequences and evaluate the consistency of the delivered dose and distribution for compound of different molecular weight. Based on this characteristic map, we will identify one known (e.g., solanezumab) and one novel drug candidate and deliver it to the hippocampus and frontal cortex of AD mice. Ultimately, we will treat AD by reducing Aβ and improving cognitive function.

Fig. 1. The (AC) left hippocampus was sonicated using short US pulses during systemic microbubble circulation while the (BD) right region was not exposed. (AB) Fluorescently-labelled 3-kDa dextran was delivered to the left region (CD) without detectable damage as assessed using H&E staining [1]. The white bar depicts 1 mm.

Fig. 1. The (AC) left hippocampus was sonicated using short US pulses during systemic microbubble circulation while the (BD) right region was not exposed. (AB) Fluorescently-labelled 3-kDa dextran was delivered to the left region (CD) without detectable damage as assessed using H&E staining [1]. The white bar depicts 1 mm.

Sought Candidate:

We are seeking a passionate, intellectual, and dynamic individual who can work on a multi-disciplinary team to take on this challenging project. The work will involve the understanding of how ultrasound can be used to volumetrically oscillate microbubbles (i.e., acoustic cavitation) within a capillary in order to alter the BBB permeability. The student will develop methods to control and monitor the oscillations using an ultrasound transducer, a programmable ultrasound imaging engine, and advanced signal and image processing algorithms. The student will also be handling animals (i.e., in vivo experiments), identify the best therapeutic agents to deliver, and analyse efficacy by evaluating AD pathology through histology and non-invasive imaging (e.g., MRI). We are seeking the best candidate with a background in physics or engineering who has a strong interest, understanding, or capability in biology.

Key References:

  1. Choi JJ, Selert K, Vlachos F, Wong A, Konofagou EE. Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles. Proc Natl Acad Sci U S A. 108(40) 2011.
  2. Choi JJ, Selert K, Gao Z, Samiotaki G, Baseri B, Konofagou EE. Noninvasive and localized blood-brain barrier disruption using focused ultrasound can be achieved at short pulse lengths and low pulse repetition frequencies. J Cereb Blood Flow Metab. 31(2) 2011.
  3. Pouliopoulos A, Bonaccorsi S, Choi JJ. Exploiting flow to control the in vitro spatiotemporal distribution of microbubble-seeded acoustic cavitation activity in ultrasound therapy. Phys Med Biol. 59(22) 2014.
  4. Sastre M et al. Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. Proc Natl Acad Sci U S A. 103(2) 2006.
  5. Mi W, Pawlik M, Sastre M, et al. Cystatin C inhibits amyloid-beta deposition in Alzheimer's disease mouse models. Nat. Genet. 39(12) 2007.
  6. Parr C, Carzaniga R, Gentleman SM, Walter J, Van Leuven F, Sastre M. Glycogen synthase kinase 3 inhibition promotes lysosomal biogenesis and autophagic degradation of the amyloid-β precursor protein. Mol Cel. Biol. 32(21) 2012.