A novel oral formulation (CoM pat. pend.) of HP‐alpha‐cyclodextrin as a safe (not ototoxic) and convenient (oral) drug against Alzheimer’s disease

Abstract

AbstractBackgroundThere are few, if any, disease‐modifying treatments (DMTs) for AD. HP‐beta‐cyclodextrin (HPβCD) was effective in AD models and ph1/2 trials of overnight IV HPβCD qow showed reduction of CSF tau protein, but also confirmed its risk of cholesterol‐related ototoxicity. As the hearing loss seen in these short (12 wk) trials was only transient (Fig. 1), the FDA accepted INDs for IV HPβCD as a drug against NPC1 (ph3) and AD (ph2).MethodTo avoid ototoxicity and the need for overnight infusion, we conducted a human PK/PD study of a novel (non‐covalent) clathrate of HPαCD and a milk/coconut oil medium‐chain fatty acid (capric acid, C10). HPαCD alone, co‐administered with, and as a clathrate with C10 (2:1 molar) were administered orally before bedtime. HPαCD and phospholipids (PLs) were measured by FPLC in morning urine. We also conducted animal studies in breast cancer and fast progressing neurodegenerative diseases (ALS/HD), where high levels of endocytosis are also known to “derail” the endocytosis‐lysosome‐autophagy (ELA) axis.ResultIP animal studies had showed HPαCD as more effective than HPβCD in breast cancer (reducing endocytosis and inflammation) While aCDs are reducing obesity in WT animals (and humans), HPaCD increasing bodyweight as a DMT in models of ALS?HD. Clinically, some HPαCD and PLs appeared in morning urine after oral administration as a mixture, but twice as much with the clathrate (Fig. 3).ConclusionIntermittent fasting (IF) and the IF mimetic HPαCD (too small to fit cholesterol) are not only effective against ALS, but were previously shown to be at least as effective as HPβCD in lysosomal storage diseases (LSDs, Fig. 4) and more effective in cancer, where endocytosis is also involved, albeit with different manifestations (Ancidoni 2021) (Fig. 5). With the new results showing that (a) the HPαCD clathrate ASD‐005 is intestinally absorbed , safe, and has systemic effects in other ELA axis diseases and (b) HP‐CDs are active across the blood‐brain barrier (Fig. 1), oral HP‐cyclodextrin clathrates are now emerging as more convenient, safer, and often more effective DMTs for AD or, when formulated with the GRAS aCD, as nutraceuticals to improve neurologic and cardiometabolic health in aging (ASD‐NP6).