Sunday, August 28, 2016

Blood–brain barrier shuttle peptides: an emerging paradigm for brain delivery

Benjamí Oller-Salvia, Macarena Sánchez-Navarro, Ernest Giralt and Meritxell Teixidó, (Review Article) Chem. Soc. Rev., 2016, 45, 4690-4707 DOI: 10.1039/C6CS00076B

Open Access Article

Although the BBB remains a formidable obstacle, since the Trojan horse concept was coined in the 1980s, the field of drug delivery to the brain has made remarkable progress. In the last few years, a plethora of new BBB shuttle peptides have emerged and hold great promise to overcome the limitations of the first generation of shuttles dominated by large proteins. Peptides are more affordable, easier to characterize and to link to nanocarriers or proteins. Moreover, they have lower immunogenicity and often have a reduced effect on the activity of the cargo than their larger counterparts. Furthermore, many peptide shuttles do not compete with endogenous substrates in contrast to endogenous proteins, nor stay bound to the receptor unlike some antibodies. BBB shuttle peptides have so far provided promising results in terms of brain delivery in preclinical settings. In addition, a relevant increase in the therapeutic effect has been proven in a wide variety of animal disease models, with a focus on brain tumours but also including neurodegenerative and lysosomal diseases as well as epilepsy among others.

Despite the considerable achievements described, new shuttles with higher transport capacity and selectivity are required. Approaches like phage display and natural sources of peptides that reach the CNS offer an excellent opportunity to explore the multitude of poorly characterized or still unknown routes into the brain. These strategies should be complemented with additional efforts in the characterization of the transport mechanisms and in global proteomic approaches to identify new receptors. Also, further comparative studies between shuttles and a more accurate quantification of the free drug in the brain parenchyma would enable a more efficient identification and optimization of BBB shuttles. The next generation of BBB shuttle peptides should aim for an enhanced metabolic stability, a higher transendothelial transport and an improved selectivity for the brain – even for particular regions of this organ – possibly through yet uncharacterized transctytotic pathways.

Acknowledgements: IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain). We appreciate financial support from MINECO-FEDER (Bio2013-40716-R and CTQ2013-49462-EXP), MINECO (PCIN-2015-051 Cure2DIPG), RecerCaixa-2014-Gate2Brain, Generalitat de Catalunya (XRB and 2014-SGR-521), FARA and GENEFA. B.O.-S. and M.S.-N. are grateful for “La Caixa”/IRB Barcelona and Juan de la Cierva fellowships, respectively.

CONTINUUM: Lifelong Learning in Neurology

Ashizawa, Tetsuo MD, FAAN; Xia, Guangbin MD, PhD; August 2016 - Volume 22 - Issue 4, Movement Disorders - p 1208–1226 doi: 10.1212/CON.0000000000000362

Purpose of Review: This article introduces the background and common etiologies of ataxia and provides a general approach to assessing and managing the patient with ataxia.