PMS

Phelan-McDermid Syndrome
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DISEASE OVERVIEW

PMS is a severe neurodevelopmental disease caused by insufficient expression of the SHANK3 gene in neurons (nerve cells) in the brain.

Patients can experience a wide range of medical, intellectual and behavioural challenges, including life-long intellectual and physical disability. There are no available treatments for patients with PMS.

PYC has developed PYC-002, the first potentially disease-modifying therapeutic for PMS that addresses the root cause of the condition. PYC-002 is currently in pre-clinical studies.

PMS at a glance

An overview of key disease information.
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An urgent need to create treatments

PMS affects 1 in every 8,000–15,000 children.1

An icon of two strands of RNA next to each other. The strand on the left is navy blue and the strand on the right is orange. Both strand are otherwise identical. They are both gently curved vertical lines with short horizontal lines staggered downwards like the rungs of a ladder.

PMS is a monogenic disease

This is a mutation in one copy of the SHANK3 gene.

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Patients with PMS experience severe intellectual and physical delays

These patients usually have a shortened life expectancy.

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PYC’s therapy, PYC-002, represents the first potentially disease-modifying treatment for patients with PMS

PMS patients have a mutation in one copy of the SHANK3 gene – this leads to their neurons producing half as much SHANK3 protein as is required for normal function. PYC-002 seeks to restore the production of SHANK3 protein in patients, therefore rescuing function of neurons and thus stopping disease progression.

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Pre-clinical studies

PYC-002 is currently in pre-clinical trials.

PMS at the genetic level

Understand how a single genetic mutation causes lifelong disease.
An icon of four DNA spirals organised into two sets of pairs. The DNA pairs on the left are both blue and white, and are titled 'Unaffected DNA'. One DNA pair on the right is orange and white while the other is blue and white. This set of DNA is titled 'PMS patient DNA'.

Genetic mutation

PMS patients have a mutation in one of their two copies of the SHANK3 gene – this mutation is present in all the cells in their body but it causes disease in the neurons of the brain.

An icon of two sets of RNA pairs side-by-side. The set on the left is blue and is titled 'Unaffected person'. There is a white arrow below this pair pointing down towards two strands of SHANK3 protein chains. On the right, one strand is orange and one is blue within the pair. It is titled 'PMS patient'. There is a white arrow below this pair pointing down towards one strand of SHANK3 protein chain and a white bubble containing the text '-50%'.

Decreased protein production

The SHANK3 gene mutation creates an unstable RNA message – this leads to approximately half as much SHANK3 protein production as is required for cells to function normally. PYC’s therapeutic, PYC-002, seeks to increase protein expression in the remaining healthy copy of the SHANK3 gene to restore SHANK3 protein production to levels that are sufficient for the cells to function normally.

An infographic of the synapse (space between) two neurons. The neuron on the left contains three white sacks which have three blue balls each within them. These balls are being released by the neuron and across the synapse to the neuron on the right. There is a white arrow communicating the direction of the blue balls from left to right and a title that reads 'Reduce neuron signal'.

Cellular changes

Underproduction of the SHANK3 protein causes alterations in brain development, with reduced neuron communication and function.

 

PYC-002 has disease-modifying potential to halt cellular changes and arrest disease progression – it’s a potentially life-changing therapeutic.

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Patient symptoms

With a reduced production of the SHANK3 protein, PMS patients can experience low or weak muscle tone (hypotonia), developmental delays and absent or delayed speech.

 

At PYC, we aim to halt the progression of symptoms in PMS patients with our first-in-class drug candidate PYC-002 providing a significantly greater quality of life for patients.

The human impact of PMS

PMS is a severe neurodevelopmental disease that causes life-long disability, beginning in childhood.
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Early childhood signs

Common signs of PMS include low or weak muscle tone (hypotonia), poor head control and a weak cry.

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Altered brain development

Patients often experience developmental and speech delays, and intellectual disability.

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Atypical physical features

Patients can experience motor regression and body abnormalities or deformities.

PYC-002 is a potentially life-changing treatment

PYC-002 is a precision RNA therapeutic that targets the underlying SHANK3 gene mutation to correct disease in PMS patients. There are currently no known disease-modifying treatments for PMS in clinical development.

In pre-clinical testing, PYC-002 effectively reaches target neurons (nerve cells) affected by PMS across various brain regions.

A bar graph titled 'Effective PYC-002 delivery across brain regions'. The y axis is titled 'Exon 7 skipping (%)'. There are three sections on the x-axis, from left to right they are titled 'Untreated PMS cells', 'PYC-002 (PPMO) 2.5nmol' and 'RNA therapeutic alone (naked PMO) 10nmol'. Only the centre section for PYC-002 contains bars and there are six bars in this section to correlate with the different sections of the brain. PYC-002 (PPMO) 2.5nmol achieved approximately 25% exon 7 skipping in the motor cortex, 24% in the midbrain, 32% in the striatum, 28% in the thoracic cord, 25% in the lumbar cord and 20% in the olfactory bulb.
Smn exon-7 skipping in mouse brains 5 days post ICV injection (a local injection into the right ventricle of mouse brain). N for each group: PPMO (2.5nmol)=2; PMO=2. Statistical significance calculated as two-way unpaired t-test. #p≤0.1, *:p≤0.05, **p≤0.01.
A table that contains three columns titled 'Unaffected individual', 'PMS patient' and 'PMS patient + PYC-002' from left to right. In the 'Unaffected individual' column there is light and dark blue DNA, two strands of dark blue RNA and two strands of SHANK3 protein, these are labelled '100%'. In the 'PMS patient' column there is dark blue and orange DNA, one strand of dark blue and one strand of orange RNA and one strand of SHANK3 protein, labelled '~50%'. In the 'PMS patient + PYC-002' column there is dark blue and orange DNA, one strand of dark blue and one strand of orange RNA and two strands of SHANK3 protein, these are labelled 'up to 100%'.

In-vitro studies demonstrate that PYC-002 has the ability to restore SHANK3 protein production back to normal (physiological) levels in a manner that is consistent with disease correction.

A bar graph titled 'PYC-002 increases SHANK3 protein production in PMS-affected neurons'. The y axis is titled 'Fold change of SHANK3 protein expression over untreated'. There are two bars in the graph, the left bar is titled 'untreated PMS cells' and reaches a value on the y-axis of approximately 1.0. The right bar is titled 'PMS cells + PYC-002' and reaches a value on the y-axis of approximately 1.4. Above the two bars there is a subtitle that reads '1.4-fold increase'.
SHANK3 protein expression in iPSC-GlutNs derived from unaffected individuals (n=2) with and without treatment with PYC's RNA drug candidate for PMS. Treatment with PYC's RNA drug candidate demonstrates a 1.4-fold increase in SHANK3 protein expression quantified by ELISA assay. Statistical significance calculated using one-way analysis of variance (ANOVA). *p<0.0001.

Patients are our priority

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Our commitment to patients

We believe it is essential to understand the people living with the genetic diseases that we are aiming to treat. At PYC, we make it a priority to collaborate with patients and caregivers across our development process – to ensure that our RNA therapeutics best meet their needs.

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Our patient trials

At PYC, we conduct responsible patient trials to ensure that our treatments are safe and effective. These trials rely on patient volunteers and are crucial to the development of disease-modifying therapies for genetic diseases.

References

  1. Phelan-McDermid syndrome foundation. What is Phelan-McDermid syndrome? Causes, symptoms & treatment [internet]. Florida, USA: Phelan-McDermid syndrome foundation; 2022. Available from: https://pmsf.org/about-pms/ ↩︎
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An image of the PMSF foundation logo. The letters 'PMSF' are printed in white and there is a white circle icon to the left. The circle appears to be swirling with six seperate lines curving together to create the shape of a circle and there are six small dots within the centre of the circle. Below the letters and icon the text 'Phelan-McDermid Syndrome FOUNDATION' is printed in white text.
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