Identification and synthesis method for small molecules that inhibit stress granule formation and pathological tau aggregation as a novel approach for treating neurodegenerative disorders

This technology is a tool to identify compounds that block the activity of TIA1, an RNA-binding protein that regulates stress granule formation and the generation of pathological forms of tau protein, and is implicated in a range of neurodegenerative diseases.

Unmet Need: Intervention for effectively treating and slowing down neurodegenerative disease

There are currently no disease-modifying therapeutics for the treatment of Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other related neurodegenerative diseases. A common clinical feature of these diseases is the presence of tau pathology in the central nervous system (CNS). Most current anti-tau therapies in development are immunotherapies, which have thus far been ineffective, in large part because of poor antibody penetration into the CNS and poor membrane permeability. The development of small molecules with blood-brain barrier permeability and ability to target pathological forms of tau is of paramount importance.

The Technology: Screening tool for identification of stress granule and tau aggregate inhibitors

This technology is a FRET-based drug screening tool that identifies TIA1 inhibitors that can potentially limit neurodegeneration across a range of neurological disorders. TIA1 is an RNA-binding protein that regulates stress granule formation, as well as aggregation and misfolding of the tau protein in the CNS. We have identified and synthesized several drug-like small molecule inhibitors of TIA1 that block stress granule formation in both cell lines and patient-derived motor neurons, and also limit the generation of toxic tau oligomers in vivo in mouse models of neurodegenerative disease.

Applications:

• Therapeutic for Alzheimer’s disease (AD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP) and other tauopathies
• Therapeutic for other neurodegenerative disorders, including Welander distal myopathy (WDM), a rare autosomal dominant disorder caused by a missense mutation in the human TIA1 gene
• Therapeutic for cancers such as those with KRAS mutations, which rely on stress granule formation for chemotherapeutic resistance
• Therapeutic for viral infections, given the dynamic functional relationship between viruses and SG formation
• Research tool for understanding stress granule and tau aggregate formation in the central nervous system
• Positive early cellular data for oncology and virology applications.

Advantages:

• Treats underlying pathology of tauopathies, not just symptoms
• Small molecules penetrate the CNS and pass through cell membranes (unlike main competitors, which are antibody-based)
• Specific to TIA1, avoiding non-specific effects with minimal toxicity in animal studies (unlike other methods for inhibiting signaling events upstream of TIA1 activation)

Lead Inventor:

Donald W. Landry, M.D., Ph.D.

Patent Information:

Patent Pending

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 2;22(1):59-71.

Tech Ventures Reference:

• IR CU22124, CU19237

• Licensing Contact: Jerry Kokoshka