What is a Protein?

Proteins are essential for the life of an organism because they participate in virtually every process within the cell. Therefore, if their function is impaired, the consequences can be devastating. When a mutation happens in the genetic code of a protein, this can lead to protein misfolding, which is often the primary cause of many neurodegenerative disorders. It is estimated that ~90% of NPC patients harbor a variant of the NPC1 gene that results in a misfolded, unstable protein.

The Klinsky and Sherry Initiative

In 2022, the APMRF received a $1 million gift from Steve and Maureen Klinsky to launch a program focused on identifying new therapies to correct the NPC1 misfolded protein and, ultimately, a novel treatment for Niemann Pick Type C patients.

After searching for an individual to assist in overseeing the new Klinsky and Sherry Initiative, we were delighted to announce in April of 2023 that Dr. Ross Fredenburg agreed to partner with APMRF and NPC scientists on this new initiative. Fredenburg has more than 15 years of experience driving preclinical drug development programs in biotechnology and pharmaceutical companies and was recently a founding member and vice president of biology of Amathus Therapeutics.

In just a few months, Fredenburg has quickly launched a DNA Encoded Library Screen and forged partnerships with chemists and biologists to carry out the screen. In December the APMRF started receiving information from the screen that is revealing potential new small molecules that can be developed into therapeutics. Currently, Fredenburg is working with collaborators to further develop these small molecules and he is working on development of a phenotypic screen that will identify compounds to correct the misfolded NPC1 protein.

A special thankyou to Dr. Suzanne Pfeffer, Dr. Ed Holson, and Dr. Dan Ory who have been guiding Ross on this initiative.

A genetic screen to identify components that effect NPC1 folding

In 2023, the APMRF received a generous donation form an anonymous donor to understand what genes regulate the folding of NPC1. Understanding the genetics behind NPC1 protein folding will lead to the discovery of novel targets for therapeutic intervention and compliment the Klinsky and Sherry Initiative.

Specifically, the cellular machinery that controls NPC1 protein folding is unknown, and this has impeded the development of desperately needed treatment strategies. Dr. Mark Schultz and Dr. Andy Lieberman have been collaborating on this problem, and in this screen they will systematically turn off thousands of genes in the genome to see which ones can correct the folding of mutant NPC1.

This work addresses a critical unmet need and will provide the community with an essential body of knowledge that will advance efforts toward a disease modifying therapy.