Restoration of retromer complex in neurodegenerative diseases via transcriptional regulator

This technology targets CREB3L2 for the treatment of neurodegenerative diseases, including Parkinson’s and Alzheimer’s diseases.

Unmet Need: Effective therapies against neurodegeneration

Alzheimer’s disease (AD) is a neurodegenerative disease that currently has no cure and only palliative treatments. While the transcription factor ATF4 is known to regulate several genes involved with AD progression and may, therefore, be a valuable therapeutic target, it is difficult to safely modulate ATF4 activity directly as this factor is also required for homeostasis and cell survival. Additionally, the protein complex “retromer”, which is involved in endosomal trafficking, is known to be dysregulated in AD although the underlying cause and mechanism are unclear.

The Technology: Therapeutic targeting CREB3L2, a modulator of ATF4 in neurodegenerative disease

This technology targets the transcription factor CREB3L2 through its formation of a transcription factor complex with ATF4 for the treatment of neurodegenerative diseases. In neurodegeneration, this factor binds with ATF4 to form a complex that regulates retromer dysfunction, a major contributor to pathogenesis in Alzheimer’s and Parkinson’s diseases. The technology permits determining the level of CREB3L2-ATF4 transcription factor complex in samples and subsequently modulating the association between CREB3L2 and ATF4. Targeting CREB3L2 to normalize CREB3L2 transcription and restore retromer function can be used to slow or reverse disease progression of AD and other neurodegenerative diseases.

This technology has been tested in vivo to show that activation of the ATF4-CREB3L2 complex induces functional consequences involving disease progression.

Applications:

• Therapeutic target for neurodegenerative diseases
• Treatment for Alzheimer’s disease and Parkinson’s disease
• Diagnostic and prognostic tool for assessing neurodegeneration
• Research tool for studying the interaction between CREB3L2-AFT4
• Research tool for studying DNA-binding profiles of transcription factors and gene expression regulation in neurodegenerative diseases
• Screening tool for small molecules disrupting CREB3L2-AFT4 complex

Advantages:

• Provides a potential therapeutic target for drug development
• May halt or reverse disease progression, as opposed to relieving symptoms
• Provides rationale for how retromer dysfunction occurs in neurodegenerative disease
• Identifies a previously unknown transcription factor interaction
• May serve as an additional or combination therapeutic target or therapy
• May apply to various neurodegenerative diseases in addition to AD or PD

Lead Inventor:

Ulrich Hengst, Ph.D.

Patent Information:

Patent Pending (WO/2023/201219)

Related Publications:

• Roque CG, Chung KM, McCurdy EP, Jagannathan R, Randolph LK, Herline-Killian K, Baleriola J, Hengst U. “CREB3L2–ATF4 heterodimerization defines a transcriptional hub of Alzheimer’s disease gene expression linked to neuropathology” Sci Adv. 2023 Mar 3; 9(9):eadd2671.

• Walker CA, Randolph LK, Matute C, Alberdi E, Baleriola J, Hengst U. Aβ1-42 triggers the generation of a retrograde signaling complex from sentinel mRNAs in axons” EMBO Rep. 2018 Jul; 19(7): e45435.

• Baleriola J, Hengst U. “Targeting axonal protein synthesis in neuroregeneration and degeneration” Neurotherapeutics. 2015 Jan;12(1):57-65.

• Baleriola J, Walker CA, Jean YY, Crary JF, Troy CM, Nagy PL, Hengst U. “Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions” Cell. 2014 Aug 28;158(5):1159-1172.

Tech Ventures Reference:

• IR CU18398, CU21318, CU22191

• Licensing Contact: Jerry Kokoshka