REV-0100 for Stargardt disease (a rare pediatric retinal disease)

drug development,

Paul Fehlner, co-founder and CEO of reVision Therapeutics, Inc., provided an overview of our their program, REV-0100, for Stargardt disease, a rare pediatric retinal disease. REV-0100 has the potential to expand to dry age-related macular degeneration (AMD). During the session, he discussed various aspects of REV-0100, including its mechanism of action, in vivo efficacy in Stargardt mouse models, systemic safety, competitive advantage, and development timeline.
REV-0100 is sulfobutyl-ether-beta-cyclodextrin, a commonly used pharmaceutical excipient now evaluated in this orphan indication. 

Long-term administration of intravenous Trappsol® Cyclo™ (HP-β-CD) results in clinical benefits and stabilization or slowing of disease progression in patients with Niemann-Pick disease type C1: Results of an international 48-week Phase I/II trial

carbohydrates, drug development, ,

Long-term administration of intravenous Trappsol® Cyclo™ (HP-β-CD) results in clinical benefits and stabilization or slowing of disease progression in patients with Niemann-Pick disease type C1: Results of an international 48-week Phase I/II trial.
Niemann-Pick disease type C (NPC) is a rare, fatal, pan-ethnic, autosomal recessive lysosomal storage disease characterized by progressive major organ failure and neurodegeneration. Preclinical studies confirmed the critical role of systemically administered hydroxypropyl-β-cyclodextrin (HP-β-CD; Trappsol® Cyclo™) in cholesterol metabolism and homeostasis in peripheral tissues of the body, including the liver, and in the central nervous system (CNS). Herein, the pharmacokinetics (PK), safety, and efficacy of HP-β-CD and biomarkers of NPC were assessed in pediatric and adult patients with NPC1.
Cyclo Therapeutics, Inc. –  Caroline Hastings, Sharon Hrynkow et al

Long-term administration of intravenous Trappsol® Cyclo™ (HP-β-CD) results in clinical benefits and stabilization or slowing of disease progression in patients with Niemann-Pick disease type C1: Results of an international 48-week Phase I/II trial – ScienceDirect

ZyVersa Therapeutics Announces Article Published in Metabolism Pointing to Glomerular Cholesterol Accumulation as Key Factor Exacerbating Renal Injury and Dysfunction in Diabetic Kidney Disease

Today's cyclodextrin,

today’s #cyclodextrin:
ZyVersa Therapeutics Inc. published a press release on the mechanism of action of their lead asset, VAR-200, which is hydroxypropyl-beta-cyclodextrin targeting patients with glomerular diseases (#diabetic #kidneydisease, focal segmental glomerulosclerosis, and Alport Syndrome). VAR-200 was able to reduce renal cholesterol and lipid accumulation that damages the kidneys’ filtration system, to mediate transport of excess cholesterol out of kidney cells passively, and by upregulating cholesterol transporter ABCA1.
Deposition of glomerular cholesterol contributes to structural damage and dysfunction of the kidney’s filtration system in models of type 2 diabetes is consistent with data from VAR 200’s preclinical program. By mediating cholesterol transport out of the glomeruli through passive transport and upregulation of ABCA1 transporters, VAR 200 protected against glomerular injury and fibrosis, and significantly reduced protein spillage into the urine in all three kidney diseases

See more about this topic here:
ABCA1 deficiency-mediated glomerular cholesterol accumulation exacerbates glomerular endothelial injury and dysfunction in diabetic kidney disease

ZyVersa Therapeutics Announces Article Published in Metabolism Pointing to Glomerular Cholesterol Accumulation as Key Factor Exacerbating Renal Injury and Dysfunction in Diabetic Kidney Disease

Molecular Mind Games: The Medicinal Action of Cyclodextrins in Neurodegenerative Diseases

carbohydrates, ,

Cyclodextrins are often used as molecular carriers for small active ingredients in the medicine. Recently, the intrinsic medicinal activity of some of these compounds has been under investigation, mainly related to their ability to interfere with cholesterol and, therefore, prevent and treat cholesterol-related diseases such as cardiovascular disease and neuronal diseases arising from altered cholesterol and lipid metabolism. One of the most promising compounds within the cyclodextrin family is 2-hydroxypropyl-β-cyclodextrin (HPβCD), owing to its superior biocompatibility profile. This work presents the most recent advances in the research and clinical use of HPβCD against Niemann–Pick disease, a congenital condition involving cholesterol accumulation inside lysosomes in brain cells, Alzheimer’s and Parkinson’s. HPβCD plays a complex role in each of these ailments, going beyond the mere sequestering of cholesterol molecules and involving an overall regulation of protein expression that helps restore the normal functioning of the organism.
Fantastic review by Susana Santos Braga form Universidade de Aveiro

See the full article here: Molecular Mind Games: The Medicinal Action of Cyclodextrins in Neurodegenerative Diseases

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

carbohydrates, drug development,

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

drug delivery,

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 Oostrum, Erik Reimhult
Università degli Studi di Catania: Noemi Bognanni, Graziella 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

carbohydrates,

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 amazon.com

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

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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

carbohydrates, ,

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