LEOPARD Syndrome

LEOPARD syndrome, also known as Noonan syndrome with multiple lentigines (NSML) containing multiple lentigines is a rare disease that has an underlying genetic basis and is inherited with an autosomal dominant pattern. Protheragen is a leading research services company focused on the development of transformational therapeutics for rare heart diseases, including NSML. Rely on us to serve as your partner in pioneering medication research and development.

Overview of LEOPARD Syndrome

LEOPARD syndrome is a rare genetic disorder falling under the umbrella of RAS pathway syndromes. Its prevalence is currently undetermined and only around 200 cases have been documented globally. An important identifying feature of this syndrome is multiple lentiginous hyperpigmentation which occurs across the entire body. Roughly 85% of these individuals have some form of congenital heart disease, including significant hypertrophic cardiomyopathy (usually develops in early childhood and may be progressive) and stenosis of the pulmonary valve.

Cardiac MRI of an NSML individual highlights unique features.

Fig.1 Cardiac MRI of an NSML individual. (Rivero-Garcia, P., et al., 2023)

Pathogenesis of LEOPARD Syndrome

LEOPARD syndrome has an autosomal dominant inheritance pattern. For up to 85% of cases of NSML, lesions of the PTPN11 gene which codes for the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2) are the underlying cause. The NSML PTPN11 pathogenic variants are usually at the PTP domain residue which diminishes catalytic activity and therefore RAS/ERK activation.

Each septal shape is linked to its syndrome and specific genetic mutations.

Fig.2 Each septal shape shows its syndrome and genetic mutations. (Kauffman, H., et al., 2021)

Therapeutics Development for LEOPARD Syndrome

Drug Names	Targets	Mechanism of Action	Research Phase
Rapamycin	mTOR	The suppression of the dysregulated mTOR signaling pathway arising from PTPN11 mutations resolves cardiac hypertrophy.	Approved
Dasatinib	Bcr-Abl, c-Kit	Inhibition of c-Src and PZR tyrosyl phosphorylation and phosphorylation of AKT.	Approved
ARQ 092	AKT	Remarkably limited AKT activity, as well as that of his downstream effectors, PRAS and S6RP in NSML mice.	Preclinical

Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a therapy plan recommendation. For guidance on therapy options, please visit a regular hospital.

Our Services

An integrated team of scientists and researchers in our company works closely to develop strategies that precisely target disease mechanisms and therapy research for our client's needs, ensuring that every project is custom-scoped. We carefully assist in every aspect of drug discovery or development with special emphasis on innovative diagnostic development, targeted therapeutic development, and sophisticated disease model development for LEOPARD syndrome.

Therapeutic Development Services

Diverse Platforms

Animal Model Development for LEOPARD Syndrome

Studying the underlying mechanisms of pathogenesis along with the evaluation of potential therapeutic interventions is possible with the use of animal models. Our company works with several facilities and scientists in connection with developing animal models that suit particular custom research proposals for LEOPARD syndrome as well as other genetic disorders.

Genetically Engineered Animal Model

NSML animal models are typically generated by introducing pathogenic PTPN11 mutations via gene editing techniques, recapitulating hypertrophic cardiomyopathy, lentigines, and developmental defects observed in individuals.

Optional models:

Q510E-SHP2 transgenic model
Other models

Ptpn11^Y279C model

In collaborating with us, Protheragen's clients acquire an integrated set of solutions that accelerate innovations in treating rare cardiovascular conditions. Our advanced pharmacokinetics, comprehensive drug safety assessment, and preclinical development services ensure therapeutic candidates are optimally effective and safe. Contact us if you would like to engage our services.

References

Kauffman, H. et al. "Genotype-phenotype association by echocardiography offers incremental value in patients with Noonan Syndrome with Multiple Lentigines." Pediatric research 90.2 (2021): 444-451.
Rivero-García, Pamela et al. "Hypertrophic cardiomyopathy in an adult patient with Noonan syndrome with multiple lentigines." Clinical case reports 11.6 (2023): e7607.

For research use only, not for clinical use.