Caraway Therapeutics: Advancing Novel Small Molecule Therapies Targeting Lysosomal Function for Neurodegenerative and Rare Diseases

▎Edited by the WuXi AppTec content team

Today, MSD announced that it will spend up to $610 million to acquire Caraway Therapeutics, expanding its pipeline for new drug development in neurodegenerative diseases. As early as 2021, Caraway Therapeutics caught the attention of AbbVie and reached a $267 million Parkinson's disease research and development cooperation agreement with it.

. What's Different About This Newcomer’s Strategy to Tackle Neurodegenerative Diseases?

Caraway Therapeutics Focuses on Toxic Cellular Components Found in Various Neurodegenerative and Rare Diseases, Including Damaged Organelles, Protein Aggregates, and Accumulated Lipids. Efficient Removal of These Toxic Components Is Essential for Maintaining Cellular Health. Genetic Mutations That Impair the Clearance Process Are Associated with Multiple Neurodegenerative and Rare Diseases, Including Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis (ALS), and Others.

Caraway Therapeutics' strategy is to leverage genetic data and unique biological insights to discover small molecule compounds that activate cellular degradation and recycling mechanisms, accelerating the clearance of toxic products and dysfunctional cellular components.

The company's R&D pipeline includes multiple small-molecule compounds targeting lysosome-related pathways.

▲Caraway Therapeutics' R&D Pipeline (Image Source:

Caraway Therapeutics Official Website）

Among them, TRPML1 is a potassium ion channel mainly expressed in lysosomes, and its normal function is to regulate and maintain the ionic composition of lysosomes. Activation of TRPML1 not only enhances the activity of various lysosomal proteases but also increases the expression and activity of glucocerebrosidase (GBA). Mutations in the gene encoding GBA are one of the most significant genetic risk factors for Parkinson's disease. Currently, Caraway Therapeutics is developing small-molecule modulators targeting TRPML1 for the treatment of GBA-associated Parkinson's disease and other neurodegenerative diseases.

▲TRPML1 Modulator Therapy

Potential Mechanisms of GBA-Related Parkinson's Disease (Image Source:

Caraway Therapeutics Official Website)

Loss-of-function mutations in the gene encoding TMEM175 increase the risk of Parkinson's disease, while gain-of-function variants reduce disease risk. Previous in vitro and animal studies have demonstrated that impaired TMEM175 function leads to lysosomal pH instability, reduced activity of key lysosomal proteases, and increased cellular vulnerability to α-synuclein damage.

Caraway Therapeutics has discovered multiple modulators that can rapidly and reversibly enhance TMEM175 activity, boosting lysosomal function in cellular models.

Degradation of pathogenic proteins in neurodegenerative diseases has become one of the important future research and development directions in the field of targeted protein degradation. Craig M. Crews, a professor at Yale University and co-founder of Arvinas, a leading company in the field of targeted protein degradation, along with his collaborators, have previously...

A deep review published in Nature Reviews Drug Discovery pointed out that one of the key features of targeted protein degradation is the ability to degrade proteins that are not targeted by traditional small-molecule inhibitors due to the absence of an active site. This feature makes proteins that accumulate in various neurodegenerative diseases (such as Tau protein, α-synuclein, and mutant huntingtin) potential targets.

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