NNZ-2566, a Novel Analog of (1–3) IGF-1, as a Potential Therapeutic Agent for Fragile X Syndrome

Abstract

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, and many agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. In the present work, a novel pharmacological approach for FXS is investigated. NNZ-2566, a synthetic analog of a naturally occurring neurotrophic peptide derived from insulin-like growth factor-1 (IGF-1), was administered to fmr1 knockout mice correcting learning and memory deficits, abnormal hyperactivity and social interaction, normalizing aberrant dendritic spine density, overactive ERK and Akt signaling, and macroorchidism. Altogether, our results indicate a unique disease-modifying potential for NNZ-2566 in FXS. Most importantly, the present data implicate the IGF-1 molecular pathway in the pathogenesis of FXS. A clinical trial is under way to ascertain whether these findings translate into clinical effects in FXS patients.

The therapeutic potential of insulin-like growth factor-1 in central nervous system disorders

“…Electrophysiological studies of hippocampal neurons in Fmr1 knockout mice not only confirmed aberrant activation of PI3K/mTOR and MAPK/ERK pathways (Deacon et al, 2015), but also revealed reduced response to excitatory synaptic currents and enhanced glutamate receptor dependent LTD, suggesting the importance of FMRP, PI3K/mTOR and MAPK/ERK pathways, and glutamate receptor functioning underlying deficits in FXS (Braun & Segal, 2000; Huber, Gallagher, Warren, & Bear, 2002). The disruption of neuronal circuitry in Fmr1 knockout mice leads to similar clinical phenotypes of FXS, including anxiety/hyperactivity, impaired short-term and long-term memory, and impaired social interactions (Deacon et al, 2015; Yan, Rammal, Tranfaglia, & Bauchwitz, 2005). …”

“…Treatment of Fmr1 knockout mice with NNZ-2566 resulted in normalization of phosphor-ERK and phosphor-Akt levels and reduction of dendritic spine neurons, indicating a reversal of MAPK/ERK and PI3K/mTOR signaling abnormalities and correction of dendritic spine morphology. The Fmr1 knockout mice also displayed lower anxiety levels, reduced hyperactivity, improved short-term and long-term memory, improvement in learning and LTP, and normalized social recognition and behaviors (Deacon et al, 2015). The lack of adverse events and positive therapeutic profile in preclinical trials with Fmr1 mice provides evidence for IGF-1 as a potential therapeutic agent in FXS and there is an ongoing clinical trial in phase II with the IGF-1 analogue, NNZ-2566.…”

Initial analysis of peripheral lymphocytic extracellular signal related kinase activation in autism

“…While our methodology utilizes a readily available biological sample that can be accessed across a wide functioning range of persons with autism, we cannot be sure that enhanced ERK activation in peripheral lymphocytes equates with ERK dysregulation in brain where we would expect molecular perturbation to result in an autism phenotype. Despite this, in recent study in the knockout mouse model of FXS, excessive ERK activation was noted in both brain and blood cell samples showing that some correlation may exist (Deacon et al, 2015). …”

Neurobiologically-based treatments in Rett syndrome: opportunities and challenges

“…In 2001, there was one published open-label trial of cerebrolysin, a neuropeptide preparation that includes nerve growth factors [94]. Recently, there have been several trials of full-length recombinant IGF-1 and an active tripeptide component of IGF-1 (trofinetide) that may have a greater effect on glial processes [104]. There are also ongoing trials of two BDNF-boosters, glatiramer acetate and fingolimod (ClinicalTrials.gov identifiers NCT02153723, NCT02061137).…”