Development of a Growth Hormone Receptor antagonist for the delay or prevention of ADRD
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ABSTRACT Despite major efforts by the research community, effective therapies for Alzheimer’s disease (AD) and related dementias (ADRDs) remain elusive. This indicates that innovative approaches and therapeutic targets are required. One such approach is to base therapeutic development on discoveries made in populations protected from AD. Notably, centenarians, who are resilient to dementia despite advanced chronological age, are carriers of genetic variants that attenuate signaling via the growth hormone/ insulin-like growth factor-1 (GH/IGF-1) pathway. In fact, lower circulating IGF-1 levels are associated with preserved cognition in people with exceptional longevity. Higher circulating IGF-1 levels, on the other hand, are related to greater hazard of developing AD and ADRD, as demonstrated in a study from the UK Biobank and in patients with acromegaly. Furthermore, attenuation of the GH/IGF-1 pathway results in delayed cognitive decline and enhanced memory in multiple aged and AD rodent models. The pathogenesis of AD is multifactorial, while reduction in GH/IGF-1 signaling exhibits pleiotropic effects; this may explain the effectiveness of reduced GH/IGF-1 in protecting from or delaying AD. Attenuation of GH/IGF-1 signaling in rodent models reduces Aß plaque burden, neuroinflammation, hyperphosphorylated tau, oxidative stress, vascular dysfunction, and metabolic dysfunction, while it upregulates autophagy. Our group (InfinixBio) developed a novel GH receptor antagonist (NGHRA) that binds to peripheral GH receptors (GHR) and prevents expression and secretion of circulating IGF-1. Reduction in circulating IGF-1 results in lower IGF-1 in the central nervous system because IGF-1 from circulation crosses the blood brain barrier. The NGHRA is significantly superior to the existing FDA-approved GHRA, pegvisomant, that has been effectively and safely used world-wide since 2003 for the treatment of acromegaly. Compared to pegvisomant, the NGHRA has 10-30X greater affinity for the human GHR and is expected to have similar beneficial effects on insulin sensitivity, slow clearance rate, and excellent safety profile that will make it amenable to chronic subcutaneous administration in older adults to prevent or delay AD. In an effort to develop the NGHRA for clinical use, we propose the following aims for this Phase I project. In Aim 1, we will optimize the production and formulation of the NGHRA and produce gram quantities of the material to be used for the in vivo studies in Aims 2 and 3. In Aim 2, we will determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties of the NGHRA and select the dose levels to be used for Aim 3. In Aim 3, we will establish the efficacy of the NGHRA to achieve moderate or high in vivo PD responses via targeted, sustained reductions in IGF-1 levels in rodent AD models. Achievement of Phase I milestones will pave the way for Phase II to study the efficacy of the NGHRA in rodent AD models for prevention and/or delay of AD and ADRD. The NGHRA is expected to exhibit pleiotropic effects against AD via a novel therapeutic target. Clinical experience with an existing GHRA has demonstrated its safety. Thus, the development of the NGHRA could lead to its expedient testing in clinical trials.
