Phelan-McDermid syndrome (PMS) is caused by a deletion or other change in the 22q13 region of chromosome 22, which includes the SHANK3 gene, or a mutation of the gene. Disruption of the SHANK3 gene is also thought to be associated with a large number of cases of autism spectrum disorder. The gene codes for the shank3 protein, which supports the structure of synapses between brain cells.
Characteristics of PMS are intellectual disability, delayed or absent speech, symptoms of autism, low muscle tone, motor delays, and epilepsy. There is currently no treatment specifically for PMS. It is estimated that 1% of people with autism have PMS, which implies that between 1 in 8,000 and 1 in 15,000 people have PMS.
NNZ-2591 was tested in the shank3 knockout mouse model of PMS, with treatment for 3 weeks. The study compared normal mice (“wild type”) and mice with a disrupted shank3 gene (“knockout”). In the knockout mice, deficits in anxiety, repetitive behaviour, motor performance and social interaction were restored to the wild type. Treated knockout mice also showed a 60% reduction in susceptibility to seizures. In addition, the abnormal length of dendrite spines between brain cells, the excess activated ERK protein (pERK) and the depressed level of IGF-1 in the knockout mice were all normalised.
Neuren has been granted Orphan Drug designation by the US Food and Drug Administration (FDA) for NNZ-2591 to treat PMS. The required manufacturing development and non-clinical toxicity studies are progressing in preparation for clinical trials in 2020.