Pharmacokinetics and in vivo efficacy of DA1 macrocyclic peptides in a murine model of Alzheimer's disease

Janusq, Llc, Rocky River OH

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT JanusQ, LLC is a startup biotech company, spun out of Case Western Reserve University, that is developing a peptide-based therapy for treatment of mitochondrial dysfunction in Alzheimer’s Disease (AD), which erodes memory and cognitive ability in ~6 million Americans. The role of amyloid-β (Aβ) in AD pathogenesis is poorly understood, and therapies addressing A have had limited success in the clinic. Like many other neurodegenerative diseases, AD is linked to mitochondrial dysfunction that leads to neurotoxicity. The mitochondrial protein ATAD3A, which spans both inner and outer membranes, is critical in cholesterol trafficking and maintaining the mitochondrial nucleoid complex. However, during the stress of AD, ATAD3A oligomerizes and inappropriately binds Drp1 (the mitochondrial-fission GTPase), causing mitochondrial fragmentation and nucleoid instability. We have found that DA1, a linear peptide discovered by a JanusQ cofounder, prevents ATAD3A oligomerization and association with Drp1, reduces mitochondrial fragmentation, improves nucleoid stability, and—when delivered subcutaneously (SQ)—reduces behavioral and neurological deficits in mouse models of AD. This success inspired the search for optimized macrocyclic peptides. In-vitro studies show that one of these peptides—DA45—has 3-fold increased stability in mouse plasma, 30% improved potency, and enhanced efficacy. This SBIR project has two aims, both designed to evaluate DA45 in vivo using the AD mouse model 5XFAD: (1) Assess the pharmacokinetics (PK) of DA45 to test exposure and stability. Based on our success with DA1, we will develop bioanalytical methods to extract DA45 from plasma and brain tissue for quantitation by tandem liquid chromatography mass spectroscopy. Following peptide administration, we will determine the time course of plasma and brain DA45 levels and calculate standard PK parameters. (2) Assess DA45 efficacy. We will determine DA45 efficacy at doses of 0.032, 0.1, or 1 mg/kg/day SQ (aged 3–9 months), and assess ATAD3A oligomerization, mitochondrial bioenergetics, measures of AD pathology (e.g., Aβ accumulation, synaptic integrity), and cognitive function during AD development. Besides generating the necessary bioanalytical methods, the proposed work will determine whether DA45 has the pharmacological properties—PK characteristics and dose-response for DA45 protection—necessary for advancement to preclinical safety testing. An effective treatment would improve quality of life and survival of AD patients, reduce reliance on medical caregivers and thus reduce overall medical costs. In the US, direct AD medical costs alone exceeded $305B in 2020. This SBIR grant is a crucial step for JanusQ to develop an optimized DA1 peptide as a breakthrough treatment for AD and would markedly enhance the ability of JanusQ to attract a commercialization partner.