Characterization of hydroxypropyl-beta-cyclodextrins used in the treatment of Niemann-Pick Disease type C1

Abstract

2-Hydroxypropyl-beta-cyclodextrin (HPβCD) has gained recent attention as a potential therapeutic intervention in the treatment of the rare autosomal-recessive, neurodegenerative lysosomal storage disorder Niemann-Pick Disease Type C1 (NPC1). Notably, HPβCD formulations are not comprised of a single molecular species, but instead are complex mixtures of species with differing degrees of hydroxypropylation of the cyclodextrin ring. The degree of substitution is a critical aspect of the complex mixture as it influences binding to other molecules and thus could potentially modulate biological effects. VTS-270 (Kleptose HPB) and Trappsol® Cyclo™ are HPβCD products under investigation as novel treatments for NPC1. The purpose of the present work is to compare these two different products; analyses were based on ion distribution and abundance profiles using mass spectrometry methodology as a means for assessing key molecular distinctions between products. The method incorporated electrospray ionization and analysis with a linear low-field ion mobility quadrupole time-of-flight instrument. We observed that the number of hydroxypropyl groups (the degrees of substitution) are substantially different between the two products and greater in Trappsol Cyclo than in VTS-270. The principal ions of both samples are ammonium adducts. Isotope clusters for each of the major ions show doubly charged homodimers of the ammonium adducts. In addition, both products show doubly charged homodimers from adduction of both a proton and ammonium. Doubly charged heterodimers are also present, but are more intense in Trappsol Cyclo than in VTS-270. Based on the analytical differences observed between VTS-270 and Trappsol Cyclo with respect to the degree of substitution, the composition and fingerprint of the complex mixture, and the impurity profiles, these products cannot be considered to be the same; the potential biological and clinical implications of these differences are not presently known.

2-Hydroxypropyl-β-cyclodextrins and the Blood-Brain Barrier: Considerations for Niemann-Pick Disease Type C1

“…Use of VTS-270 and Trappsol Cyclo has been described in case reports as noted earlier. A recent mass spectrometry study demonstrated significant compositional differences between VTS-270 and another HPβCD product: although both are HPβCDs, they have unique compositional fingerprints and differences in the amounts and types of various ions, monomers, and dimers, and thus should not be considered to be identical [ 33 ]. They may also have different biological and clinical activities and different impurity profiles.…”

Parkinson’s disease phenotypes in patient specific brain organoids are improved by HP-β-CD treatment

“…We further characterized the composition of the used HP-β-CD mixture and determined that the most frequent isomer is one with six degrees of substitution (DS) ( Fig EV4A-C). Knowledge of the HP-β-CD composition will leverage application in future clinical trials and facilitate comparisons of treatment results between different neurodegenerative diseases (Yergey et al, 2017).…”

“…Ion mobility -MS experiments were performed using an Agilent 6560 Ion Mobility -QTOF MS equipped with an Dual Agilent Jet Stream ESI source (Agilent Technologies). The following method is based on a protocol from (Yergey et al, 2017). test was used to evaluate if the samples were drawn from significantly different distributed populations between control and patient lines.…”

Use of 2-Hydroxypropyl-Beta-Cyclodextrin for Niemann-Pick Type C Disease

“…The data suggest that biological and potential therapeutic equivalence should not be assumed. Further studies are needed to examine potential differences in biological and therapeutic effects of Trappsol ® Cyclo™ and VTS-270 [11].…”