PYC-002

Phelan-McDermid Syndrome (PMS)

Phelan-McDermid Syndrome (PMS) is a severe neurodevelopmental disorder affecting children

PMS is a rare and severe neurodevelopment disorder causing life-long disability
PMS is caused by a mutation in, or deletion of, one copy of the SHANK3 gene
Patients experience severe intellectual and physical delays and usually have shortened life expectancy
There is a major unmet patient need with no disease-modifying therapies currently available
Estimated ~28,000¹ addressable patients in the Western World
PYC-002 seeks to address the underlying cause of PMS

Symptoms of PMS patients

PYC is proud to work with the Phelan-McDermid Syndrome Foundation to find a treatment for patients. Please visit the PMSF website for further information on PMS

Unaffected individual	PMS PATIENT
		DNA	PMS patients have a mutation in one copy of the SHANK3 gene
		RNA	The mutation leads to an unstable RNA message that is rapidly degraded
		SHANK3 Protein	This leads to neurons having half as much SHANK3 protein as they require to function normally
100%	~50%

Unaffected individual

DNA
RNA
Protein

Functional SHANK3 expression = 100%

2 ‘healthy’ copies of SHANK3 results in functional SHANK3 protein expression

PMS patient

DNA
RNA
Protein

Functional SHANK3 expression = ~50-70%

Patients with PMS have a mutation in one copy of the SHANK3 gene causing insufficient level of functional 'healthy' SHANK3 protein expression

PMS patient treated with PYC-002

DNA
RNA
Protein

Restoration of SHANK3 expression towards 100%

PYC-002 increases expression of the remaining 'healthy' copy of SHANK3 to compensate for the SHANK3 protein insufficiency

PYC-002 is capable of increasing SHANK3 protein expression >2-fold in a nueronal cell line

PYC-002 hit sequences increase SHANK3 protein levels by >2-fold in a neuronal cell line. These increased protein levels are theoretically sufficient to restore gene expression back to wild-type (physiological) levels and therefore holds the potential for a disease-modifying impact in PMS patients. Further studies are underway to confirm this effect in cellular models derived from patients with PMS as well as testing in animal models of the disease.

PYC’s RNA drug modality effectively reaches the cells affected in PMS (neurons) in vivo (in animal models)

The advantages of PYC’s next generation RNA drug (‘PPMO’) are clearly evident in animal models evaluating the ability of the RNA drug to engage
its target in different regions of the brain relevant in PMS

PPMO

PYC’s RNA modality
Target engagement in all regions of the brain.

NAKED PMO

Same RNA drug without PYC’s delivery technology
No target engagement observed in any brain region

References¹

Cochoy DM, et al. Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID. Mol. Autism. 2015;6(23) doi: 10.1186/s13229-015-0020-5
Zeidan J, et al. Global prevalence of autism: A systematic review update. Autism Research. 2022;1–13. doi: 10.1002/aur.2696
https://pmsf.org/about-pms/

Phelan-McDermid Syndrome (PMS)