Investigation of 2-Hydroxypropyl-β-Cyclodextrin Treatment in a Neuronal-Like Cell Model of Niemann–Pick Type C Using Quantitative Proteomics

There are multiple challenges in developing carbohydrate/cyclodextrin-based drugs that we also face at CarboHyde every day. One is to develop proper analytical techniques, which are especially difficult for biological samples and if the drug is not a single compound but a mixture of components (just like HP-b-CD used in Niemann-Pick C). While HP-b-CD has been promising in vitro and in vivo, a clear understanding of the mechanism(s) of action is lacking.
That being said, we particularly welcome the study disclosing method for a large-scale mass-spectrometry-based proteomic study to evaluate proteome changes upon treatment with these small molecules. Investigation of HP-b-CD treatment was performed where we observe that, although HP-b-CD reduces cholesterol storage, levels of NPC1 and NPC2 are not normalized to control levels. The following changes in the proteome suggest that HP-b-CD promotes exocytosis in this neuron-like model. Utilizing state-of-the-art mass spectrometry analysis, these data demonstrate newly reported changes with pharmacological perturbations related to NPC disease and provide insight into the mechanisms of HP-b-CD as a potential therapeutic.
Antony Cougnoux, (Karolinska Institutet), Melissa Pergande, Fidel Serna-Perez, and Stephanie Cologna (University of Illinois Chicago)

See the full article here: Investigation of 2-Hydroxypropyl-β-Cyclodextrin Treatment in a Neuronal-Like Cell Model of Niemann–Pick Type C Using Quantitative Proteomics

Grafting of Cyclodextrin to Theranostic Nanoparticles Improves Blood-Brain Barrier Model Crossing

today’s cyclodextrin:
Core–shell superparamagnetic iron oxide nanoparticles hold great promise as a theranostic platform in biological systems. Antonino Puglisi and coworkers report the biological effect of multifunctional cyclodextrin-appended SPIONs (CySPION) in mutant Npc1-deficient CHO cells compared to their wild-type counterparts. CySPIONs show negligible cytotoxicity while they are strongly endocytosed and localized in the lysosomal compartment. Through their bespoke pH-sensitive chemistry, these nanoparticles release appended monomeric cyclodextrins to mobilize over-accumulated cholesterol and eject it outside the cells. CySPIONs show a high rate of transport across blood–brain barrier models, indicating their promise as a therapeutic approach for cholesterol-impaired diseases affecting the brain.

University of Natural Resources and Life Sciences, Vienna (BOKU)Peter van OostrumErik Reimhult
Università degli Studi di CataniaNoemi BognanniGraziella Vecchio
Ege University: Ece Bayir
University of Oxford: Dawn Shepherd, Frances Platt

See the full article here: Grafting of Cyclodextrin to Theranostic Nanoparticles Improves Blood-Brain Barrier Model Crossing

Confocal micrographs of Npc1-deficient CHO after incubation with 0.1 mg/mL FITC-CySPION for 72 h showing co-localization, with Pearson’s coefficient of 0.37, between FITC-CySPION (green) and LysoTracker Deep Red within the lysosomal compartments (red) within the ROI preproduced on the right. The used excitation wavelengths and fluorescence maxima are indicated in the figures. The field of view is 290 × 290 µm2.

We the Scientists: How a Daring Team of Parents and Doctors Forged a New Path for Medicine

Behind some science, there are stories to learn as the human side is more important than the professional one. The tale that tells us how hydroxypropyl-beta-cyclodextrin became a drug candidate from an excipient to treat desperate patients suffering in Niemann-Pick type C disease is certainly a story worth telling and reading. A new science book by The Wall Street Journal reporter Amy Dockser Marcus took over a decade to write and includes the journey of the Hempel family trying to save Addi & Cassi’s lives with cyclodextrin (they were the first patients treated with the drug).

Order the book on

Cyclo Therapeutics Announces First Patient Dosed in Phase 2b Study of Trappsol® Cyclo™ for the Treatment of Early Alzheimer’s Disease

Cyclo Therapeutics, Inc. announces first patient dosed in Phase 2b study of Trappsol® Cyclo™ for treating early Alzheimer’s disease.

Trappsol® Cyclo™ is the Company’s proprietary formulation of hydroxypropyl beta-cyclodextrin. In multiple clinical studies, it has shown encouraging results in effectively managing the transportation of cholesterol, a known defect in neurodegenerative diseases. Many known risk factors for Alzheimer’s disease are associated with cholesterol metabolism.

Cyclo Therapeutics is currently testing the same investigational Trappsol® Cyclo™ drug in Phase 3 clinical trial (TransportNPC™) and a long-term extension study for the treatment of Niemann-Pick disease Type C1, a rare, fatal, and progressive genetic disorder. Taking the place of the defective NPC1 protein, Trappsol® Cyclo™, with its cyclic structure, facilitates the transport of accumulated cholesterol out of cellular lysosomes so it can be further processed and excreted out of cells. With the biological similarities demonstrated between Niemann-Pick disease Type C1 and Alzheimer’s disease, including cholesterol accumulation in regions of the brain, elevated levels of Tau in cerebrospinal fluid (“CSF”), and amyloid plaques in the brain, the Company believes Trappsol® Cyclo™ has significant potential to be an effective treatment option for Alzheimer’s disease.

Read the full announcement here

ZyVersa Therapeutics Adds Two Esteemed Leaders in Nephrology to Its Renal Scientific Advisory Board to Support Clinical Advancement of Lead Renal Drug Candidate, VAR 200

ZyVersa Therapeutics Inc., developing, among others VAR200, a therapeutic 2-hydroxypropyl-beta-#cyclodextrin for FSGS, Alport syndrome, and diabetic kidney disease, just added two leading nephrologists to their Scientific Advisory Board.
We hope this will help move the program forward to follow this one-of-a-kind application of CDs with great excitement.

See the full article here

Evidence of redox imbalance and mitochondrial dysfunction in Niemann-Pick type C 1 patients: the in vitro effect of combined therapy with antioxidants and β‐cyclodextrin nanoparticles

This research contributes to a better understanding of the mechanism of action of #cyclodextrin in Niemann Pick C, which could lead to further applications. Carmen Vargas – Federal University of Rio Grande do Sul evaluated naked and nanoparticle CDs for restoring mitochondrial functions, as well as the beneficial combined effects of treatment with antioxidant N-Acetylcysteine and Coenzyme Q10
Tatiane HammerschmidtBruna DonidaJéssica Lamberty FaverzaniFernanda PolettoDinara Jaqueline Moura

See the full article here

First Patient Enrolled in Phase 1 Study of MTX-110 (MAGIC-G1 Study) in Patients with Recurrent Glioblastoma

Even though used in many formulations with CDs, new ones entering clinical trials are not often. Midatech Pharma PLC recently announced recruiting the first patient in the Phase 1 Study of MTX-110 for recurrent #glioblastoma (NCT 05324501). Midatech has previously reported encouraging results from a Phase I study of MTX110 in diffuse intrinsic pontine glioma (NCT03566199, NCT04264143), and a Phase I study of MTX110 in medulloblastoma is being undertaken. and recurrent medulloblastoma (NCT04315064).

MTX110 is a water-soluble form of a panobinostat-free base, achieved through complexation with hydroxypropyl-β-cyclodextrin (HPBCD), that enables convection-enhanced delivery (CED) at potentially chemotherapeutic doses directly to the site of the tumor. Panobinostat is a hydroxamic acid and acts as a non-selective histone deacetylase inhibitor (pan-HDAC inhibitor). The currently available oral formulation of panobinostat lactate (Farydak®) is not suitable for the treatment of brain cancers owing to poor blood-brain barrier penetration and inadequate brain drug concentrations.

MTX110 is delivered directly into and around the patient’s tumor via a catheter system (e.g., CED or fourth ventricle infusions) to bypass the blood-brain barrier. This technique exposes the tumor to very high drug concentrations while simultaneously minimizing systemic drug levels and the potential for toxicity and other side effects.

MTX110 has been granted Orphan Drug and Fast Track designations by the FDA and Orphan Medicinal Product designation by EMA.

See the full article here

Beren Awarded Expedited Roadmap for Treatment of Homozygous Familial Hypercholesterolemia

Fascinating news from Beren Therapeutics:
Beren Awarded Expedited Roadmap for Treatment of Homozygous Familial Hypercholesterolemia
Beren’s novel lead asset, BRN-002, was awarded an Innovation Passport under the United Kingdom’s Innovative Licensing and Access Pathway (ILAP), for the reversal of atherosclerosis in patients with Homozygous Familial Hypercholesterolemia. The ILAP aims to accelerate the time to market for innovative medicines that address the needs of patients with life-threatening or seriously debilitating diseases.
“We are excited to begin work under ILAP and look forward to collaborating with other regulators, payors, and governments to expedite the development and identify and remove access barriers.” – commented Jason Camm, CEO. Jules Payne from HEART UK – The Cholesterol Charity added that “Significant unmet needs remain, and with this advancement, we are hopeful for a new treatment option that can truly alter the course of the disease for the children and patients living with HoFH.”
Beren Therapeutics, P.B.C. is currently in stealth.

See the full article here

Cyclodextrins: Only Pharmaceutical Excipients or Full-Fledged Drug Candidates?

What is the future of cyclodextrin: excipient or API?
A very timely review from University of Debrecen (Gyorgy PanyiFlorina Zakany, et al.) discussing #molecular targets, mechanism of action, and ongoing research in several diseases. Which do you think holds the future?

See the full article here

In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe’s Disease

Amazing therapeutic success led by UCSF Pediatrics joined by Duke UniversityOttawa University, and Washington University via in-utero enzyme-replacement therapy for infantile-onset Pompe’s disease: Patients with early-onset lysosomal storage diseases are ideal candidates for prenatal therapy because organ damage starts in utero. After receiving in-utero ERT and standard postnatal therapy, the current patient had normal cardiac and age-appropriate motor function postnatally, was meeting developmental milestones, had normal biomarker levels, and was feeding and growing well at 13 months of age.

See the full article here