Issue:April 2024
THERAPEUTIC FOCUS - Perspectives on Sigma-2 Modulation as a Therapeutic Modality for Slowing Age-Related Degenerative Disease
INTRODUCTION
The senior population in the US is expected to grow from 46 million today to 95 million by 2060.1 This unprecedented growth is expected to fuel an increase in the number of elderly individuals requiring skilled nursing care for dementia, vision loss, and other conditions that can rob a person of their ability to live independently. Looking forward at the impending impact on the US healthcare system, we feel a distinct sense of urgency to find new treatments for age-related degenerative diseases, which may allow people to live independently longer.
A defining trait of many age-related degenerative diseases is the build-up of toxic proteins, oxidative stress, and inflammation. On a molecular level, these factors impair normal cellular function and ultimately lead to cell death. These cellular changes drive disease progression, translating to functional disability and loss of independence for people with Alzheimer’s disease and other dementias, Parkinson’s diseases, as well as neuro-ophthalmic disorders like dry age-related macular degeneration (dry AMD). Disease-modifying treatments for these and related conditions have eluded researchers – until recently.
Last year, we witnessed very positive news with the FDA approval of the first disease-modifying Alzheimer’s disease treatment, LEQEMBI® (lecanemab-irmb injection for intravenous use) followed by FDA approval of the first complement inhibitor for dry AMD, SYFOVRE® (pegcetacoplan injection). The recent progress against these diseases reinforces our understanding of the factors driving disease progression and helps elucidate potential pharmaceutical targets, one of which is the sigma-2 receptor.
Cognition Therapeutics recently published a comprehensive review examining the sigma-2 receptor complex, which has been shown to have a role in Alzheimer’s disease, dry AMD, and in synucleinopathies, such as dementia with Lewy bodies (DLB).2 There is evidence the sigma-2 receptor acts as a regulator of cellular processes, such as autophagy and protein trafficking, which are impaired in age-related degenerative diseases. We have demonstrated in preclinical models these critical functions can be rescued by administering a sigma-2 receptor modulator, which we believe may protect neurons from the damage inflicted by protein aggregates, oxidative stress, and inflammation.
For these reasons, we and others believe sigma-2 represents a compelling drug target. Currently, Cognition Therapeutics is conducting Phase 2 clinical trials in adults with Alzheimer’s disease, DLB, and geographic atrophy (GA) secondary to dry AMD with CT1812, an investigational, oral, small-molecule sigma-2 receptor modulator. CT1812 represents a distinctly new approach to targeting these degenerative diseases.
SIGMA-2 RECEPTOR MODULATORS IN DISEASE
Interest in sigma-2 receptors as therapeutic targets is growing given the high expression of these receptors in multiple cell types, including neurons in the brain and retina, which are susceptible to damage by pathogenic proteins, oxidative stress, and inflammation. The sigma-2 receptor has been shown to regulate cell functions disrupted by these toxins, such as cholesterol biosynthesis/trafficking, membrane trafficking, breaking down faulty proteins, lipid membrane-bound protein trafficking, and receptor stabilization at the cell surface.2
In vitro studies provide experimental evidence that small molecule sigma-2 modulators can rescue these biological processes. Experimental sigma-2 receptor modulators tested by several independent research groups have been shown to be neuroprotective.
ALZHEIMER’S DISEASE
Synaptic loss is a hallmark of Alzheimer’s disease and is characterized by a progressive reduction of synaptic density in disease-related brain regions.14 The accumulation of Aβ is a hallmark of Alzheimer’s disease progression and is believed to be a primary cause of synaptic dysfunction, dysregulation and eventually neuronal death.15 Aggregated Aβ fibrils and plaque are now readily observable using PET imaging and are the targets of several approved and experimental immunotherapies.
However, while fibrils and plaques may be prevalent, Aβ oligomers are widely recognized as the most toxic. To date, their low molecular weight and relative scarcity has made them difficult to target with monoclonal antibodies. However, results from preclinical Alzheimer’s models and from a small clinical study in adults with mild-to-moderate Alzheimer’s disease show that oligomers can be displaced from synapses by targeting the sigma-2 receptor. In cultured neurons, this displacement facilitates synaptic recovery, which we expect will have a beneficial effect on cognitive decline.6,16
The clinical benefit of recently approved LEQEMBI, which targets soluble Aβ protofibrils, encourages the pursuit of therapies that target similar species of Aβ. There is potential for synergy between the sigma-2 receptor modulator, CT1812, which acts by displacing Aβ oligomers from synapses, and anti-Aβ antibody treatments that increase the clearance of these displaced Aβ oligomers. (Figure 2) Additionally, sigma-2 receptor modulators have been independently shown to rescue memory and cognitive deficits in an Alzheimer’s mouse model, suggesting one of the major debilitating symptoms of Alzheimer’s disease—the loss of ability to form new long-term memories—may be restored at a fundamental level by therapeutics targeting sigma-2 receptors.
ALPHA-SYNUCLEINOPATHIES: PARKINSON’S DISEASE & DEMENTIA WITH LEWY BODIES
Two primary alpha-synucleinopathies are Parkinson’s disease and DLB, both of which are associated with motor function and cognitive decline due to synaptic dysfunction and loss.17,18 There are currently no disease-modifying treatments for either condition. While the cell types and brain structures affected in Parkinson’s disease and DLB differ, a common feature is the accumulation of alpha-synuclein aggregates, a major constituent of the Lewy bodies found in brain neurons. Increasing evidence suggests that alpha-synuclein also forms soluble oligomers, which are more toxic than fibrils.19-21
Based on our understanding of the role of sigma-2 receptors, we conducted preclinical research to determine the impact of alpha-synuclein oligomers on neurons with and without the addition of CT1812. As expected, we observed that alpha-synuclein oligomers are rapidly internalized into neurons, where they impair key cellular functions, such as protein trafficking and autophagy. The addition of the of sigma-2 modulator, CT1812, blocks the internalization of alpha-synuclein, which reverses the trafficking disruption.12
DRY AGE-RELATED MACULAR DEGENERATION
Dry AMD, which affects approximately 2 million Americans, also involves a dysregulation of cellular processes including autophagy. When impaired, the retinal pigment epithelial (RPE) cells are unable to process debris generated by photoreceptors. As debris accumulates into deposits of lipid and protein, known as drusen, the architecture of the RPE is disrupted. Over time, damaged RPE cells die and are unable to support the photoreceptors, which leads to visual impairment.
Several lines of evidence suggest modulation of sigma-2 receptors may provide significant therapeutic utility for the treatment of dry AMD. First, several large-scale, independent genome-wide association studies identify a mutation in the gene encoding sigma-2 (TMEM-97) that confers decreased risk for dry AMD.22,23 Second, proteomic analysis of cerebral spinal fluid (CSF) and plasma from the first cohort of a Phase 2 clinical trial of CT1812 in mild-to-moderate Alzheimer’s disease (SHINE-A), showed the expression of many proteins known to be disrupted in dry AMD were altered by treatment with CT1812 versus placebo.24 Lastly, in vitro studies showed the sigma-2 modulator, CT1812, rescued autophagy in cultured RPE cells that were put under disease-like conditions.25
Taken together, these data indicate CT1812 may slow disease progression and ultimately protect vision in people with dry AMD. The Phase 2 MAGNIFY study is currently testing CT1812 as treatment for people with dry AMD who have measurable geographic atrophy.
DEMANDING A RESPONSE
Alzheimer’s disease, alpha-synucleinopathies, and dry AMD are important age-related degenerative diseases for which current therapeutics are unavailable, offer limited benefit, or require burdensome regimens. Yet the clinical and societal needs to address such diseases are profound. Alzheimer’s disease prevalence is expected to more than double with related costs rising to an estimated $1 trillion by 2050 in the US.26 According to the Parkinson’s Foundation and the Lewy Body Dementia Association, direct healthcare costs for individuals with Parkinson’s disease and DLB are estimated to be more than $55 billion combined. AMD is the leading cause of blindness in people over 50 years of age in the US and afflicts approximately 11 million people.
As we’ve previously discussed, the potential of sigma-2 receptor modulators to protect neurons in the CNS and retina and by doing so preserve their function is compelling. The rigorous preclinical and clinical testing we have conducted, much of which is summarized in our published review, has given us the support we and regulators needed to advance CT1812 into Phase 2 clinical studies in adults with early as well as mild-to-moderate Alzheimer’s disease, DLB, and dry AMD. While the specialty pharmacology trials we have completed have given us valuable insights into the potential of CT1812, the top-line results from the first of our Phase 2 studies, which we anticipate in 2024, will offer us the most concrete evidence yet of its therapeutic potential. If its activity is confirmed, CT1812 and other sigma-2 receptor modulators could represent a significant benefit for people with these devastating diseases and their families.
REFERENCES
- Mather M, Jacobsen LA, Pollard KM. “Aging in the United States,” Population Bulletin 70, no. 2 (2015). https://www.prb.org/wp-content/uploads/2016/01/aging-us-population-bulletin-1.pdf
- Lizama BN, Kahle J, Catalano SM, Caggiano AO, Grundman M, Hamby ME. Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases. International Journal of Molecular Sciences. 2023; 24(7):6251. https://doi.org/10.3390/ijms24076251
- Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE. The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther. 1976;197(3):517-532.
- Hanner M, Moebius FF, Flandorfer A, et al. Purification, molecular cloning, and expression of the mammalian sigma1-binding site. Proc Natl Acad Sci U S A. 1996;93(15):8072-8077. doi:10.1073/pnas.93.15.8072
- Xu J, Zeng C, Chu W, et al. Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site. Nat Commun. 2011;2:380. Published 2011 Jul 5. doi:10.1038/ncomms1386
- Izzo NJ, Staniszewski A, To L, et al. Alzheimer’s therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PLoS One. 2014;9(11):e111898. Published 2014 Nov 12. doi:10.1371/journal.pone.0111898
- Sanchez-Pulido L, Ponting CP. TM6SF2 and MAC30, new enzyme homologs in sterol metabolism and common metabolic disease. Front Genet. 2014;5:439. Published 2014 Dec 11. doi:10.3389/fgene.2014.00439
- Alon A, Schmidt HR, Wood MD, Sahn JJ, Martin SF, Kruse AC. Identification of the gene that codes for the σ2 receptor. Proc Natl Acad Sci U S A. 2017;114(27):7160-7165. doi:10.1073/pnas.1705154114
- Riad A, Lengyel-Zhand Z, Zeng C, et al. The Sigma-2 Receptor/TMEM97, PGRMC1, and LDL Receptor Complex Are Responsible for the Cellular Uptake of Aβ42 and Its Protein Aggregates. Mol Neurobiol. 2020;57(9):3803-3813. doi:10.1007/s12035-020-01988-1
- Alon A, Lyu J, Braz JM, et al. Structures of the σ2 receptor enable docking for bioactive ligand discovery. Nature. 2021;600(7890):759-764. doi:10.1038/s41586-021-04175-x
- Izzo NJ, Yuede CM, LaBarbera KM, et al. Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer’s disease modification. Alzheimers Dement. 2021;17(8):1365-1382. doi:10.1002/alz.12302.
- Limegrover CS, Yurko R, Izzo NJ, et al. Sigma-2 receptor antagonists rescue neuronal dysfunction induced by Parkinson’s patient brain-derived α-synuclein. J Neurosci Res. 2021;99(4):1161-1176. doi:10.1002/jnr.24782
- Colom-Cadena, M., Toombs, J., Simzer, E. et al. Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease. Acta Neuropathol 147, 32 (2024). https://doi.org/10.1007/s00401-023-02679-6
- Tzioras M, McGeachan RI, Durrant CS, Spires-Jones TL. Synaptic degeneration in Alzheimer disease. Nat Rev Neurol. 2023;19(1):19-38. doi:10.1038/s41582-022-00749-z
- Ono K, Yamada M. Low-n oligomers as therapeutic targets of Alzheimer’s disease. J Neurochem. 2011;117(1):19-28. doi:10.1111/j.1471-4159.2011.07187.x
- Izzo NJ, Xu J, Zeng C, et al. Alzheimer’s therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity. PLoS One. 2014;9(11):e111899. Published 2014 Nov 12. doi:10.1371/journal.pone.0111899
- Ingelsson M. Alpha-Synuclein Oligomers-Neurotoxic Molecules in Parkinson’s Disease and Other Lewy Body Disorders. Front Neurosci. 2016;10:408. Published 2016 Sep 5. doi:10.3389/fnins.2016.00408
- Du XY, Xie XX, Liu RT. The Role of α-Synuclein Oligomers in Parkinson’s Disease. Int J Mol Sci. 2020;21(22):8645. Published 2020 Nov 17. doi:10.3390/ijms21228645
- Karpinar DP, Balija MB, Kügler S, et al. Pre-fibrillar alpha-synuclein variants with impaired beta-structure increase neurotoxicity in Parkinson’s disease models. EMBO J. 2009;28(20):3256-3268. doi:10.1038/emboj.2009.257
- Outeiro TF, Putcha P, Tetzlaff JE, et al. Formation of toxic oligomeric alpha-synuclein species in living cells [published correction appears in PLoS One. 2008;3(5). doi: 10.1371/annotation/9282f173-df82-4b70-9120-b4e62b3dacb1]. PLoS One. 2008;3(4):e1867. Published 2008 Apr 2. doi:10.1371/journal.pone.0001867
- Cremades N, Cohen SI, Deas E, et al. Direct observation of the interconversion of normal and toxic forms of α-synuclein. Cell. 2012;149(5):1048-1059. doi:10.1016/j.cell.2012.03.037
- Fritsche LG, Igl W, Bailey JN, et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016;48(2):134-143. doi:10.1038/ng.3448
- Yan Q, Ding Y, Liu Y, et al. Genome-wide analysis of disease progression in age-related macular degeneration. Hum Mol Genet. 2018;27(5):929-940. doi:10.1093/hmg/ddy002
- Hamby, M.E. Targeting the Sigma-2 Receptor for Dry Age-Related Macular Degeneration (AMD). Available online. https://ir.cogrx.com/news-releases/news-release-details/cognition-therapeutics-presents-scientific-rationale-clinical. Accessed 4 December 2022.
- Malagise E, Keeling E, Knezovich N, et al (2022 May). Sigma-2 receptor modulators rescue POS trafficking deficits in RPE cell-based models of dry AMD. Poster presented at: 2022 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO); Denver, CO.
- Alzheimer’s Association. 2021 Alzheimer’s Disease Facts and Figures. Alzheimer’s Dement. 2021, 17, 327–406.
Dr. Anthony O. Caggiano is the Chief Medical Officer and Head of R&D at Cognition Therapeutics. He has broad experience in the development of new medicines for neurological conditions having worked 17 years of at Acorda Therapeutics; he also served as CMO and head of R&D at Neurotrauma Sciences and earlier as acting President and CMO at Constant Pharmaceuticals and Aeromics, Inc. He earned his BA from the University of Virginia in interdisciplinary studies, focusing on biology, chemistry and psychology. He earned his PhD from the University of Chicago, and his MD from the University of Chicago, Pritzker School of Medicine.
Total Page Views: 2680