Pharmacological inhibitors of TIA1 multimerization for prevention of neurodegeneration

This technology is a group of lead compounds that effectively prevent TIA1 multimerization and stress granule formation, with potential applications for treating neurodegenerative diseases.

Unmet Need: Effective therapeutic target for stress granules in neurodegenerative diseases

Many current treatments for neurodegenerative diseases such as Alzheimer’s disease help manage symptoms, but do not address the underlying processes that contribute to disease progression. Recently, studies have shown that the RNA-binding protein TIA1 plays an important role in the formation of stress granules and is linked to the accumulation of disease-associated proteins, including tau. As a result, TIA1 has emerged as a potential therapeutic target for neurodegenerative diseases. Compounds that disrupt TIA1 multimerization and stress granule formation may help reduce the formation of harmful protein aggregates. Previous approaches have targeted signaling pathways upstream of TIA1, but these strategies are associated with toxicity and non-specific effects. Directly targeting TIA1 may provide a more focused therapeutic approach.

The Technology: Effective inhibitors of TIA1 as a potential therapy for neurodegenerative disease

This technology identifies TIA1 as a therapeutic target for treating neurodegenerative conditions and describes lead compounds that prevent TIA1 multimerization and decrease TIA1-dependent stress granule formation. TIA1 multimerization and stress granule formation can be triggered by the release of zinc within stressed cells. The compounds described in this technology inhibit this process and may provide a new approach for treating diseases associated with abnormal stress granules and protein aggregation. These compounds represent a class of potential therapeutics with a mechanism of action that is distinct from approaches that target signaling pathways upstream of TIA1. By targeting TIA1 more directly, these compounds may also have the potential for lower toxicity and fewer non-specific effects than other compounds that target neurodegeneration in the TIA1/tau/stress granule pathway. This technology has been validated in human and mouse cell lines.

Applications:

• Treatment for neurodegenerative tauopathies, such as Alzheimer’s disease and frontotemporal dementia (FTD)
• Treatment for ALS
• Potential treatment for other diseases associated with abnormal TIA1 activity or stress granule formation
• Diagnostics for tauopathies
• Treatment for other stress granule-mediated diseases, such as Welander distal myopathy
• Tools for preclinical models and studies of tauopathies, TIA1, and stress granules

Advantages:

• Identifies compounds that target TIA1-dependent stress granule formation
• May reduce disease-associated protein aggregation
• Directly targets TIA1 rather than signaling pathways upstream of TIA1
• Minimal toxicity in animal studies
• Less toxic compared to other compounds that target neurodegeneration in the TIA1/tau/stress granule pathway
• Potential applications across multiple neurodegenerative diseases

Lead Inventor:

Shi-xian Deng, Ph.D.

Patent Information:

Patent Pending(US/2022/0332689)

Related Publications:

• Rayman JB, Karl KA, Kandel ER. “TIA-1 Self-Multimerization, Phase Separation, and Recruitment into Stress Granules Are Dynamically Regulated by Zn2” Cell Rep. 2018 Jan; 22(1): 59–71.

Tech Ventures Reference:

• IR CU19237, CU16219, CU22124

• Licensing Contact: Jerry Kokoshka