Cyclo Therapeutics is a clinical-stage biotechnology company developing novel small molecule therapeutics targeting BiP (Binding Immunoglobulin Protein, also known as GRP78), the master endoplasmic reticulum (ER) chaperone and central regulator of the Unfolded Protein Response (UPR). The company was founded in 2019 and is headquartered in Cambridge, Massachusetts, a hub for neurodegenerative disease research and drug development[1].
The therapeutic rationale for BiP modulation in Alzheimer's disease (AD) stems from the well-documented ER stress pathway activation in AD brain tissue and the critical role of BiP in maintaining cellular proteostasis. By enhancing BiP function, Cyclo aims to improve ER protein folding capacity, reduce chronic ER stress, and restore neuronal survival pathways that are compromised in Alzheimer's disease[2][3].
| Attribute | Details |
|---|---|
| Headquarters | Cambridge, Massachusetts, USA |
| Founded | 2019 |
| Focus | BiP/GRP78 modulators for neurodegenerative diseases |
| Stage | Clinical-stage, private |
| Technology | Small molecule ER chaperone modulators |
| Attribute | Details |
|---|---|
| Target | BiP/GRP78 (Binding Immunoglobulin Protein) |
| Mechanism | Allosteric modulation of BiP activity to enhance protein folding capacity |
| Indication | Alzheimer's disease |
| Phase | Phase 2 |
| Route | Oral |
| Program | Indication | Stage | Mechanism |
|---|---|---|---|
| CTI-002 | Parkinson's Disease | Preclinical | BiP/GRP78 modulator |
| CTI-003 | ALS | Discovery | BiP/GRP78 modulator |
| CTI-004 | Parkinson's Disease | Discovery | BiP/GRP78 modulator |
BiP (GRP78), also known as HSPA5 or binding immunoglobulin protein, is a 78 kDa ER-resident Hsp70 family chaperone that serves as the central regulator of ER homeostasis:
Multiple studies have documented BiP/GRP78 alterations in AD brain:
The chaperone deficiency in AD creates a vicious cycle: protein misfolding sequesters BiP, reducing folding capacity, causing more misfolding, and triggering chronic ER stress that leads to neuronal dysfunction and death[5][6].
Trap-Lect (CTI-001) modulates BiP activity through an allosteric mechanism:
This approach is distinct from direct UPR pathway inhibitors — by enhancing BiP, Trap-Lect addresses the upstream cause of UPR activation rather than blocking the downstream stress response[7].
Trap-Lect is currently in Phase 2 clinical development for Alzheimer's disease. The Phase 2 program is evaluating:
The rationale for BiP modulation in AD is supported by:
Gorbatyuk & Gorbatyuk (2013): Established GRP78/BiP as a therapeutic target for neurodegenerative disorders, demonstrating that most neurodegenerative diseases feature UPR activation and modified GRP78 expression[2:1].
Kudo (2010): Reviewed therapeutic strategies based on ER stress for AD, identifying BiP-inducing compounds as promising agents[3:1].
Voronin (2023): Provided comprehensive analysis of chaperone-dependent mechanisms as pharmacological targets for neuroprotection, including BiP and Sigma1R pathways[5:1].
Hiramatsu (2015): Discussed ER stress in AD and therapeutic implications of modulating the UPR pathway[7:1].
Uchoa (2020): Reviewed ER stress in AD pathogenesis and emerging therapeutics targeting this pathway[6:1].
Liu (2022): Analyzed targeting ER stress and autophagy as therapeutic strategies for AD[8:1].
Trap-Lect has demonstrated:
Cyclo competes with other companies developing ER stress/UPR modulators for neurodegenerative diseases:
| Company | Program | Mechanism | Indication | Stage |
|---|---|---|---|---|
| Cyclo Therapeutics | Trap-Lect (CTI-001) | BiP/GRP78 modulator | AD | Phase 2 |
| Araim Pharmaceuticals | A-966084 | ATF6 activator | AD | Phase 1 |
| Biogen | BIIB110 | IRE1-XBP1 pathway modulator | AD | Preclinical |
| Biogen | BIIB094 | PERK inhibitor | AD | Preclinical |
| QurAlis | QRL-101 | IRE1 inhibitor | ALS | Preclinical |
| Lab MF | LMF-001 | PERK modulator | AD | Preclinical |
Cyclo is applying its BiP modulation platform to:
The Molecular Chaperone GRP78/BiP as a Therapeutic Target for Neurodegenerative Disorders. J Genet Syndr Gene Ther. 2013. ↩︎ ↩︎
Therapeutic strategies for Alzheimer disease based on endoplasmic reticulum stress. Nihon Shinkei Seishin Yakurigaku Zasshi. 2010. ↩︎ ↩︎
Novel interactions of GRP78: UPR and estrogen responses in the brain. Cell Biol Int. 2013. ↩︎
Chaperone-Dependent Mechanisms as a Pharmacological Target for Neuroprotection. Int J Mol Sci. 2023. ↩︎ ↩︎
Endoplasmic reticulum stress in Alzheimer's disease: from pathogenesis to therapeutics. Front Aging Neurosci. 2020. ↩︎ ↩︎
ER stress in Alzheimer's disease: therapeutic implications. Nihon Shinkei Seishin Yakurigaku Zasshi. 2015. ↩︎ ↩︎
Targeting ER stress and autophagy for Alzheimer's disease therapy. Ageing Res Rev. 2022. ↩︎ ↩︎
ER stress and autophagy in neurodegenerative diseases. J Occup Health. 2018. ↩︎