Smart Cholesterol-Mopping Polymer Nanoparticles in Niemann-Pick Disease Type C

Niemann-Pick Disease Type C (NPC), is a recessive, autosomal, and usually fatal, rare genetic disorder caused by the accumulation of unesterified cholesterol in the brain, liver and spleen. In the European Union (EU) NPC has an incidence of 1 per 100,000 people. Most cases are detected during childhood and progress to cause life-threatening complications by the second or third decade of life. In NPC the functional role of the protein regulating cholesterol trafficking in the cell is compromised, and an excessive amount of unesterified cholesterol accumulates in endolysosomes. The build-up of cholesterol causes brain damage, subsequent cognitive and mobility decline. Currently, there is no effective treatment for NPC.
Cyclodextrins (CDs) have recently gained considerable attention as a potential therapeutic intervention in the treatment of NPC disease.
Moving from the current understanding of the role that CDs play in the treatment of NPC, in this project was investigated the activity of a novel class of polymer nanoparticles (‘NanoMops’) with cholesterol-mopping activity.
Such a system is a potential therapeutic approach for brain delivery of CDs in the treatment of the rare genetic disease as well as in the treatment of other neurodegenerative disorders exhibiting impaired cholesterol metabolism such as Alzheimer’s, Parkinson’s and Huntington’s diseases.

The work performed during the project has achieved most of its objectives and milestones for the period, with relatively minor deviations.

Scientific objectives
• Design of a pH-cleavable chemistry strategy to obtain polymers that while assembling under physiological pH could degrade and disassemble at the slightly acidic pH of the lysosome
• Synthesis of cyclodextrin derivatives (CDs) to be incorporated onto the polymers through such pH-cleavable linkage
• Synthesis of bis-functional poly-ε-caprolactone polymers (PCL) of different lengths through a novel microwave-assisted procedure developed during the project
• Conjugation of the CD onto the PCL in order to obtain CD-appended polymers (CD-PCL)
The results of this first block, as per WP1, have already been published in a scientific paper A. Puglisi, et al, Biomacromolecules 2019, 20, 4001−4007
• Study of the self-assembling properties of the different CD-PCL polymers and selection of the best candidate in terms of stability of the CD-based polymersome microparticles (CD-PMs).
• Study of the hydrolysis behavior of the CD-PMs at different pHs
The results of this first block, as per WP2, have already been published in a scientific paper A. Puglisi, et al, Biomacromolecules 2019, 20, 4001−4007
• Cytotoxicity investigation of the CD-PMs
• Cellular uptake of CD-PMs
• BBB-crossing on models for CD-PMs
• Cholesterol-mopping activity for CD-PMs
Some of the results of this first block, as per WP3, have already been published in a scientific paper A. Puglisi, et al, Biomacromolecules 2019, 20, 4001−4007

Besides, a perspective article to set the project in the context of the current state-of-the-art about the importance of cyclodextrin-cased macromolecular systems as cholesterol-mopping therapeutic agents in Niemann-Pick Disease Type C was published:
o A. Puglisi, et al, Macromolecular Rapid Communications 2019, 40, 1800557

The results of this project address a need in the niche area of rare genetic disorders. Strong ties were developed with both charity organizations (INPDA and UK-NPC) as well as with a key industrial partner in CD technology (CycloLab) in order to take further the results of this project and maximize its innovative capacity and its potential societal benefits.
As yet the results of this project do not translate into a new drug but they have been looked with great interest by the scientific community as an innovative approach for cholesterol-associated diseases. This will probably lead to innovation in the field.

Periodic Reporting for period 1 - NanoMop (Smart Cholesterol-Mopping Polymer Nanoparticles in Niemann-Pick Disease Type C)

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