Science Behind Neuren's Products

Neurodevelopmental disorders and IGF-1

Trofinetide and NNZ-2591 are improved synthetic analogues of peptides that occur naturally in the brain and are related to IGF-1, which is a growth factor stimulated by growth hormone. Trofinetide is being developed to treat Rett and Fragile X syndromes, NNZ-2591 is being developed to treat Angelman, Phelan-McDermid, Pitt Hopkins and Prader-Willi syndromes.

In the central nervous system, IGF-1 is produced by both of the major types of brain cells – neurons and glia. IGF-1 in the brain is critical both for normal development and to maintain or restore the biological balance required for normal functioning. During development, the brain and the cells that comprise it change rapidly and in complex ways. IGF-1 and its metabolism play a significant role in regulating these changes. In the mature brain, it plays an important role in responding to disease, stress and injury.

NNZ-2591 mechanism of action

Many neurological conditions share four common, underlying pathological features. The aim of treatment is to restore the natural balance of brain function by:

– reducing inflammation
– restoring the normal functioning of microglia
– improving the dendritic structure of synapses
– normalising the levels of IGF-1 in the brain


Inflammation in the brain (neuroinflammation) is perhaps the most common pathological feature of neurological disorders. Much of it is the result of excess production of molecules called inflammatory cytokines. These are prominent in brain injuries, neurodevelopmental disorders such as Rett syndrome, neurodegenerative diseases like Alzheimer’s and even so-called “normal” aging.

Neuroinflammation places significant stress on brain cells. Stress can disrupt normal cellular processes such as information signalling, increase energy requirements beyond the ability of the cells to meet their metabolic needs and disturb electrical functions which can lead to seizures and other abnormalities and even result in premature cell death.

Over-activation of microglia

Microglia are the resident immune cells in the brain. Once thought to serve primarily a sentinel function – responding to infection and damaged cells by surrounding and removing them – it is now known that they play a central role in maintaining synapses during development and in mature brains by pruning dendrites, the many small extensions of neurons that form synapses. Microglia are also a key source of IGF-1. Due to this wide-ranging maintenance function, they have appropriately been referred to as the “constant gardeners” of the brain.

Microglia are not only activated in response to infection and injury, they also are activated by inflammation. In this activated state, they lose their ability to effectively perform their normal function in synaptic maintenance and also produce more inflammatory cytokines which can further compound the damage to neurons and other brain cells.

Dysfunction of synapses

Neurons communicate with each other by chemical and electrical signals transmitted via synapses. Normal synaptic function is essential for healthy brain function and underlies memory, cognition, behaviour and other brain activities. Normal synaptic function requires that the dendrites (the branches on the neurons) which form synapses are appropriately formed as well as that excitatory and inhibitory signals are kept in balance.

When dendritic structure and synaptic signalling are abnormal, virtually all brain activities can be negatively impacted. Synaptic dysfunction has been identified as a core feature of many conditions including acute brain injury, neurodevelopmental disorders and neurodegenerative diseases.

Reduced levels of IGF-1

IGF-1 levels in the brain have been reported to be depressed in a number of conditions, which means that the critical role of IGF-1 in maintaining and repairing brain cells and synapses is impaired.

Normalisation of IGF-1 levels in shank3 knockout mice after treatment with NNZ-2591