muzza111, I think you got dudded by your friendly AI! Like a politician, the AI used a lot of words and went round in circles, but didn’t actually answer your question. Not a single suggestion as to what new “neurodevelopmental synaptopathies” the company might have been looking at!
So here’s a few of my own suggestions. I trimmed the number to six. All six are rare paediatric neurodevelopmental disorders in which there is synaptic dysfunction. All disorders have autistic features or overlap with autism. There are preclinical mouse models available for each of these disorders and each disorder has one or more active patient advocacy groups/research foundations. Finally, it appears that each has a sufficient potential patient population to make development commercially viable.
To be clear, these are simply suggestions and it’s possible that none of these conditions is being actively looked at by the Company. However, at minimum, these conditions provide some evidence of the further potential that NNZ-2591 might have in treating neurodevelopmental disorders.
Tuberous Sclerosis Complex (TSC)
A growing body of evidence indicates that the neurobiological basis of autism in TSC may be abnormal synaptic plasticity and alterations in neural connectivity.
In the U.S., an estimated one in 6,000 children are born each year with this disorder; another estimate suggests 1 in 6,000-10,000. The disorder occurs in both males and females, but females tend to have a milder version of the disorder.
The prevalence of autism in patients with TSC is over 40–50%.
Developmental delay occurs in about 50-79% of people with TSC. Delays range from mild learning disabilities to severe impairment of cognitive abilities.
Behavioural problems include aggressive behaviour, sudden rage, ADHD, OCD and repetitive, destructive, or self-harming behaviour.
Most people with TSC are affected by seizures at some time in their life.
There are drugs approved and in development to treat the epilepsy associated with TSC and drugs in development for the various skin conditions associated with the disorder. However, there are no approved treatments for the cognitive and behavioural symptoms of the disorder.
TSC was specifically named as a neurodevelopmental disorder in Neuren’s granted patent for NNZ-2591 in treating autism.
The condition has a unique ICD 10 code.
Smith-Magenis syndrome (SMS)
SMS is an autosomal dominant condition typically caused by de novo deletions or pathogenic variants in RAI1 at 17p11.2. RAI1 protein plays a role in the homeostasis maintenance of synaptic plasticity.
Smith-Magenis syndrome is estimated to occur in 1 in 15,000 -25, 000 people. It occurs equally in males and females.
Children with Smith-Magenis syndrome are often also diagnosed with ASD, ADHD, OCD and mood disorders.
This disorder affects behaviour, emotions, and learning processes. Symptoms include mild to moderate intellectual disability, delayed speech and language skills, behavioural problems, sleep disturbances and hyperphagia.
There is an approved drug specifically for the severe sleep disorder associated with the disorder and another drug in Phase 2 for associated hyperphagia, but there appears to be no drugs in development for the cognitive and behavioural symptoms.
SYNGAP1 syndrome
SYNGAP1 syndrome is caused by a variant on the SYNGAP1 gene (6p.21.32).
SYNGAP1 controls the maturation of dendrites, synaptic function, and network activity in neurons.
Reported incidence for the disorder is variously 1 per 4/10,000 individuals, 1 per 16,000 individuals or 1 to 2 per 100,000. SYNGAP1 syndrome comprises approximately 1-2% of all Intellectual Disability (ID) cases, making it one of the most common genetic causes of ID, similar to syndromes like Fragile X, Angelman and Rett.
SYNGAP1 is a rare genetic condition that causes learning disabilities. It affects both boys and girls and generally occurs randomly.
Symptoms include cognitive impairment, severely impaired expressive and receptive language, behavioural deficits, sleep disorders, sensory processing disorder, gross and fine motor skill delays, low muscle tone, visual abnormalities and epilepsy. The condition is frequently diagnosed with ASD and ADHD.
Stoke Therapeutics has a drug in development which is still at preclinical stage.
The condition has a unique ICD 10 code.
CDKL5 deficiency disorder
CDKL5 has been shown to play distinct roles in forebrain glutamatergic and **Aergic neurons to regulate cellular morphology, synaptic function, and circuit excitability.
CDKL5 deficiency disorder was previously classified as an atypical form of Rett syndrome.
CDKL5 deficiency disorder has a reported incidence of 1 in 40,000 to 60,000 newborns. Approximately 1,500 patients have been diagnosed with CDKL5 deficiency globally.
About 90% of those diagnosed with CDKL5 deficiency disorder are girls.
Development is impaired in children with CDKL5 deficiency disorder. Most have severe intellectual disability and little or no speech. The development of gross motor skills, such as sitting, standing, and walking, is delayed or not achieved. Only about a third of affected individuals are able to walk independently. Fine motor skills are also impaired; about half lack purposeful use of their hands. Most people with this condition have vision problems.
Other common features of CDKL5 deficiency disorder include repetitive hand movements such as clapping, hand licking, and hand sucking; teeth grinding, disrupted sleep, feeding difficulties and gastrointestinal problems including constipation and reflux.
The condition has a unique ICD 10 code.
Helsmoortel-Van Der Aa syndrome (ADNP syndrome)
The neuroprotective ADNP protein plays a role in regulating synaptic formation. ADNP deficiencies and ADNP gene mutations in transgenic mice have been shown to cause alterations in mRNA/protein expression profiles as well as slower microtubule-dependent axonal transport, aberrant dendritic spine formation and tauopathy.
Studies have placed the ADNP gene as a top single gene cause of ASD and accounts for approximately .2% of all cases of ASD.
Two estimates of prevalence of ADNP Syndrome are 1 in 20,000 and 1-9/100,000. The disorder was only identified 10 years ago.
Slightly more males than females are affected by the disorder.
The most common characteristics found in those with ADNP syndrome are developmental delays (100%), intellectual delays (100%), complex motor planning delays (96%), delayed or absent speech (98%) and autism spectrum disorder including autistic features (93%). Many infants present with low or weak muscle tone and feeding difficulties. Children with ADNP syndrome tend to have a very happy demeanour, similar to Angelman syndrome.
FOXG1 syndrome
FOXG1 Syndrome is a rare neurodevelopmental disorder caused by a mutation of the FOXG1 gene.
Deletion of FOXG1 has been shown to decrease dendritic complexity and spine density, leading to a reduction in synaptic transmission.
The estimated prevalence of FOXG1 Syndrome is 1 in 30,000. There are currently about 1,000 known people in the world diagnosed with the condition.
FOXG1 syndrome was previously described as a congenital variant of Rett syndrome. However, Rett syndrome is diagnosed almost exclusively in females, while FOXG1 syndrome affects both males and females. Rett syndrome also involves a period of apparently normal early development that does not occur in FOXG1 syndrome. Because of these differences, physicians and researchers now usually consider FOXG1 syndrome to be distinct from Rett syndrome.
Symptoms include inability to sit or walk without assistance, near absence of speech and language skills, feeding problems, delayed gross and fine motor skills, limited purposeful use of hands, repetitive behaviours (hand washing, hand wringing, clasping hands), irritability and excessive crying, poor eye contact, teeth grinding, sleep disturbance, sensory processing issues, reflux, constipation, temperature regulation issues, low muscle tone, seizures.
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