Neurodevelopmental brain disorders (NDDs) pose an immense burden on both the families of patients and the health and educational systems, without any effective therapies. We propose, based on our novel findings that are supported by recent clinical data, a potential gene therapy strategy that might restore the brain activity of patients to a healthy regime. 

UNMET NEED
NDDs like autism and intellectual disability are characterized by abnormal brain electrical activity. To-date, the only treatment options for these individuals is only partly effective with a small subset of symptoms, leaving the major behavioral in intellectual abnormalities unattended. Insulin-like growth factor-1 (IGF-1) was used in clinical trials for several NDDs with modest degrees of success. 

OUR SOLUTION
In the healthy brain, an intricate homeostatic system of molecular and physiological processes is constantly stabilizing brain electrical activity to avoid disruptions1. We recently discovered a central role for IGF-1 receptors in this homeostatic system by regulating mitochondrial function2. Moreover, we discovered that a sub-population of these receptors reside within neuronal mitochondria, and are responsible for mitochondrial calcium homeostasis and for the stabilization of electrical brain activity2. We propose that targeting this sub-population of receptors could be key in re-stabilizing brain electrical activity of NDD patients, thus alleviating their core behavioral symptoms. 

APPLICATIONS
Increase in the fraction of mitochondrial IGF-1 receptors by central nervous-system targeted gene therapy.

STATUS
We have established a complete in-vitro screening assay for the assessment of both mitochondrial calcium and neuronal activity homeostasis. Our results show that delivery of IGF-1 receptors to mitochondria restore mitochondrial calcium and neuronal activity homeostasis in response to a perturbation in a SHANK3-based NDD mouse model. We are currently designing a similar screening system to work with human induced neurons from NDD patients.

INTELLECTUAL PROPERTY
FRAMO-P012-US 

REFERENCES
1. Ruggiero A, Katsenelson M, & Slutsky I (2021) Mitochondria: new players in homeostatic regulation of firing rate set points. Trends in neurosciences 44(8): 605-618.
2. Katsenelson et al. IGF-1 receptor regulates upward firing rate homeostasis via the mitochondrial calcium uniporter, Proceedings of the National Academy of Sciences 119, e2121040119.