Novel Method to Treat PACS1 and PACS2 Syndromes

University of Pittsburgh researchers have identified a potential treatment for PACS1 and PACS2 Syndromes, severe neurodevelopmental diseases caused by mutations in the PACS1 (Arg203Trp) and PACS2 (Glu209Lys) genes. The research reveals altered interactions between the PACS1 and PACS2 disease variants and the histone deacetylase HDAC6. Experiments using patient-derived fibroblasts show that inhibiting HDAC6 with tubacin can reverse cellular defects associated with these syndromes. This discovery highlights the therapeutic potential of HDAC6 inhibitors for treating PACS1 and PACS2 Syndromes, which currently have no available therapies.

 

In vivo data show that siRNA knockdown of HDAC6 (A) or inhibition of HDAC6 by Tubacin (B) restores Golgi positioning in PACS1R203W patient-derived fibroblasts, which provide a strong foundation for the therapeutic potential of HDAC6 inhibitor for treating PACS1 and PACS2 syndromes.

Description

Mutations in the PACS1 and PACS2 genes lead to severe neurodevelopmental disorders characterized by cognitive impairment, speech delay, and motor deficits. The researchers have shown that these mutations alter the binding of PACS1 and PACS2 to HDAC6, resulting in abnormal cellular phenotypes, such as an extended Golgi compartment in patient-derived fibroblasts. By using HDAC6 inhibitors, such as tubacin, the researchers were able to reverse the Golgi defect which is one of the main abnormities for PACS1 and PACS2 syndromes. This discovery opens the door to the development of targeted therapies aimed at correcting the molecular dysfunction caused by PACS1 and PACS2 mutations.

Applications

- Therapeutic Development
- Neurodevelopmental Research
- Personalized Medicine

Advantages

This invention fills a critical gap as no therapies currently exist for PACS1 and PACS2 Syndromes. It offers a novel approach by using HDAC6 inhibitors to target the disease’s molecular mechanisms. Preclinical studies show that HDAC6 inhibition reverses key cellular defects, providing strong potential for developing targeted treatments for these neurodevelopmental disorders.

Invention Readiness

This invention is in the preclinical stage, with in vitro experiments using patient-derived fibroblasts demonstrating that treatment with the HDAC6 inhibitor tubacin can reverse cellular defects associated with PACS1 and PACS2 Syndromes. These findings provide a strong foundation for further drug development and testing, potentially leading to a new treatment option for neurodevelopmental disorders caused by PACS mutations.

IP Status

https://patents.google.com/patent/US20210290612A1