Developmental Delay
Fragile X Syndrome – NNI-351
Fragile X syndrome (FXS) is the most prevalent inherited neurodevelopmental disorder, occurring in males at twice the frequency as in females. This rare X-linked hereditary disorder observed in 1:4000 males leads to characteristic autism, intellectual disability, social anxiety and epilepsy (reviewed by Hagerman et al., 2017). The syndrome occurs due to a mutation in the fragile X mental retardation gene (FMR1) causing greater CGG repeats, to ultimately reduce expression of the FMR protein (FMRP). FMRP is critical for regulation of neuron activities, including mRNA translation. Numerous therapeutics are in clinical testing to diminish selective symptoms of the syndrome, but there are no disease modifying therapies for either young or adult patients.
Neuronascent’s oral brain permeable therapeutic, NNI-351, promotes proliferation of neuronal progenitors in the hippocampus (i.e. Neurogenesis), which is directly associated with reduced anxiety, improved learning, and reduced hyperactivity in young animals. The mechanism-of-action for neurogenesis by NNI-351 suggests allosteric modulation of a pathway promoting the mRNA translation, a key pathway in FXS. NNI-351 is being assessed by Neuronascent for potential disease-modifying effects eventually on young and adult FXS patients.
Down Syndrome
Down syndrome (DS) is a genetic disease occurring in approximately one in every 800 live births and leads to heart, skeletal and cognitive impairments. One region of chromosome 21 in humans, the Down syndrome critical region (DSCR), is thought to be responsible for the inhibition of neurogenesis (new neurons) leading to neurodevelopmental impairment. This trisomy disorder with over-expressed genes, specifically, the over-expression of Dyrk1a gene, may be partially responsible for the reduced neuron differentiation and reduced memory and learning. The majority of individuals with Down syndrome have only mild to moderate symptoms, such that a 10% to 20% cognitive improvement might provide an individual with the ability to live more independently (as suggested by the Down Syndrome Research and Treatment Foundation). Presently, no therapies exist to counter the cognitive deficits observed in this disease, representing a vast unmet medical need.
Neuronascent’s oral therapy, NNI-351 promotes new neuron growth in the hippocampus and reverses cognitive deficits in young Down syndrome-modeled mice. It appears the combination of Dyrkla protein inhibition and p70S6kinase activation allosterically by NNI-351 could account for the promotion of neurogenesis and improved cognitive benefit. NNI-351 could therefore result in a significant improvement in quality of life for the DS individual and their family.