Now, I'm not sure if the 2591 molecule replaces the function of the SHANK3 (in that it creates the protein that assists in synaptic function) or whether 2591 provides the stimulus for the gene to switch on.
Either way, success in the SHANK3, opens up the discussion on the wider Autism spectrum as at least 43 SHANK3 mutations have been found in people with ASD.
NNZ-2591 doesn’t directly address the SHANK3 gene (or the genes implicated in the other three rare neurodevelopmental disorders that NEU is targeting).
As the company has explained how NZ-2591 works
In biochemical testing, NNZ-2591 was shown to normalise the abnormal length of dendrite spines between brain cells, the excess activated ERK protein (pERK) and the depressed level of IGF-1 in shank3 knockout mice.
So this is a different therapeutic approach to PMS than that being used by another ASX biotech, PYC, whose RNA therapy for PMS restores SHANK3 protein expression from the remaining healthy allele.
I agree that success in PMS opens up discussion on the wider autism spectrum, but so too does success in the other three NEU NNZ-2591 indications – Angelman syndrome, Pitt Hopkins syndrome and Prader-Willi syndrome.
In Angelman syndrome, the rogue gene is UBE3A.
UBE3A is a gene implicated in neurodevelopmental disorders. The protein product of UBE3A is the E3 ligase E6-associated protein (E6AP), and its expression in the brain is uniquely regulated via genetic imprinting. Loss of E6AP expression leads to the development of Angelman syndrome (AS)….conversely, copy number variations (CNVs) that result in the overexpression of E6AP are strongly associated with the development of autism spectrum disorders (ASDs)
Another gene related to ASD is transcription factor 4, 18q21.2 (TCF4; also known as E2-2, SEF2, or ITF2), a basic helix–loop–helix transcription factor that is frequently associated with cognitive dysfunction.14–16 The autosomal dominant mutation or deletion of TCF4 results in Pitt–Hopkins syndrome, 18q deletion syndrome, and three rare ASDs (autistic disorder, Asperger syndrome, and pervasive developmental disorder).17–19 A previous study indicated that in neurodevelopmental pathways TCF4 target genes cluster mostly to schizophrenia, ASD, and ID risk genes.20 Studies such as this have proven the association of these genes with ASD in some ethnic groups.
…many of these disorders that demonstrate autism-like phenotypes at varying degrees have found involvement of chromosome 15q11–q13 segment. Numerous studies demonstrate occurrence of ASD in the presence of chromosomal abnormalities located mainly in Chr15q11–q13 region…. we strongly emphasize the need to develop future therapeutic strategies as well as screening procedures for ASD that target mechanisms involving genes located on the chromosomal 15q11–q13 segment.
I’ve argued before that this selection of four disorders provides (in my view) a type of “proof of concept” in a much broader range of conditions, including those that come under the umbrella of ASD.
(20min delay)