We target disease
at its core

Key Mechanism of Action for Neurodon’s Therapeutics

Neurodon’s proprietary technology (NRDNs) targets
SERCA, a vital enzyme that transports calcium
within the cell.

How it works:

Neurodon’s proprietary small molecule technology binds to SERCA.

This modulates SERCA’s conformation to accelerate its function, allowing for increased calcium transport from the cytoplasm to the ER (endoplasmic reticulum) selectively in cells having disrupted calcium balance. Cellular stress pathways are effectively turned off, and the cell returns to a healthy state.

The Science Behind
Neurodon

The importance of intracellular calcium has long been recognized by the scientific community as the key to modifying many diseases, including, but not limited to, diabetes,1 Alzheimer’s,2 Parkinson’s,3 and Duchenne muscular dystrophy (DMD).4 Calcium stored in a cell’s endoplasmic reticulum, or “ER,” is needed for proper protein production. A calcium concentration gradient is required for the ER to function properly, demanding a higher concentration of calcium in the ER than in the cytosol of the cell. A transport pump called SERCA is vital to maintaining calcium homeostasis.
Located on the ER membrane, SERCA moves calcium against the concentration gradient from the cell’s cytosol into the ER. When SERCA is impaired, a shortage of calcium in the ER occurs and contributes to ER stress. This happens when excess calcium builds up in the cell’s cytosol, and less calcium is transported into the ER, leading to misfolded proteins. The body tries to eliminate these damaged proteins through a process called the UPR, or unfolded protein response. Excessive calcium in the cytosol also triggers many cell death pathways. Different UPR stress sensors including inositol-requiring protein 1 (IRE1), protein kinase RNA-like ER kinase (PERK) and activating transcription factor 6 (ATF-6) activate both transcriptional and non-transcriptional responses along the secretory pathway: protein folding, ER biogenesis, ER-associated degradation (ERAD), protein entry to the ER, autophagy and secretion, and more.5

When SERCA is impaired, calcium flow into the ER is reduced, leading to misfolded proteins from the calcium imbalance

The UPR is activated to help clear misfolded proteins, but a prolonged UPR can lead to cell dysfunction and even cell death.

However, a prolonged UPR can lead to cell dysfunction and even apoptosis, or programmed cell death. Dysfunction has shown to manifest itself differently across diseases, including beta cell dysfunction in diabetes, amyloid aggregation in Alzheimer’s, and neuronal death in Parkinson’s. Disease progression rapidly accelerates from here. At Neurodon, we found that accelerating the activity of SERCA with our small molecules is the key to correcting the cell’s calcium imbalance. After gaining intimate knowledge of the biophysics of SERCA and the subtle conformational changes that lead to enzyme activation, we developed an NRDN platform of synthetic small molecules that promote SERCA activation and relieve ER stress. During calcium transport, SERCA continuously goes through several conformations to transport calcium into the ER. Binding of NRDNs to SERCA leads to acceleration of the transitions between the conformations to restore the malfunctioning SERCA and subsequently restore calcium equilibrium. In pre-clinical studies thus far, NRDNs were shown to reduce the need for insulin, improve outcomes in memory tests, and enhance skeletal muscle function without any adverse effects observed. These results show strong potential to change the outcome of disease presentation in patients’ lives.

Calcium is the hidden backbone of the body’s homeostasis

Calcium in cells, while inconspicuous, is the backbone of health. Disturbance of normal calcium levels triggers the ER stress pathway that leads to cell dysfunction, encompassing impaired signaling, respiration, and protein processing. This drives the progression of many diseases.

At Neurodon, our research works to increase the transport of cellular calcium to restore calcium homeostasis and relieve compromising cellular stress pathways. By targeting the source of this stress, we aim to provide disease-modifying effects that slow down the progression of diseases.

The benefit of calcium equilibrium can be seen in the following disease states:

Calcium in Diabetes

Decreased levels of SERCA expression and activity have been observed in diabetic humans and animal models. This leads to aberrant Ca2+ handling, and subsequently ER stress as well as pancreatic beta cell dysfunction and death.

Calcium in Parkinson’s

Loss of calcium homeostasis and ER stress via dysfunctional SERCA is a known contributor of damage to dopaminergic neurons in the substantia nigra (SN), the site of Parkinson’s in the brain. Differences in calcium signaling leads to increased susceptibility of SN neurons and cell death.

Calcium in Alzheimer’s

Cellular calcium dyshomeostasis in Alzheimer’s is caused by various factors, including ryanodine receptors (RyR), inositol trisphosphate receptors (Ip3R), calcium channels, impaired SERCA, and presenelin interaction with the ER membrane.

Calcium in DMD

Elevated cytosolic Ca2+ in DMD myofibers contribute to muscular necrosis, a major driver of disease. DMD patients subsequently experience muscle weakness as well as cardiac and respiratory dysfunction. Restoring Ca2+ dynamics can not only halt necrosis but also improve muscle contraction/relaxation.

References

1. Diabetes
Jacobson, D. A., & Shyng, S.-L. (2019, August 30). Ion channels of the islets in type 2 diabetes. Journal of Molecular Biology. Retrieved July 13, 2022, from https://www.sciencedirect.com/science/article/abs/pii/S0022283619305236

Klec, C., Ziomek, G., Pichler, M., Malli, R., & Graier, W. F. (2019, December 4). Calcium signaling in ß-cell physiology and pathology: A revisit. International journal of molecular sciences. Retrieved July 13, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940736/

2. Alzheimer’s
Berridge, M. J. (2013, January 1). Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia. Prion. Retrieved July 13, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609045/

Green, K. N. (2009, September 13). Calcium in the initiation, progression and as an effector of Alzheimer’s disease pathology. Journal of cellular and molecular medicine. Retrieved July 13, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498936/

Hutton, M., & Hardy, J. (1997). The presenilins and Alzheimer’s disease. Human molecular genetics. Retrieved July 13, 2022, from https://pubmed.ncbi.nlm.nih.gov/9300655/

3. Parkinson’s
Michel, P. P., Hirsch, E. C., & Hunot, S. (2016, May 18). Understanding dopaminergic cell death pathways in Parkinson disease. Neuron. Retrieved July 13, 2022, from https://pubmed.ncbi.nlm.nih.gov/27196972/

Sgobio, C., Sun, L., Ding, J., Herms, J., Lovinger, D. M., & Cai, H. (2019, March 19). Unbalanced calcium channel activity underlies selective vulnerability of nigrostriatal dopaminergic terminals in Parkinsonian Mice. Nature News. Retrieved July 13, 2022, from https://www.nature.com/articles/s41598-019-41091-7

4. Duchenne muscular dystrophy
Goonasekera, S. A., Lam, C. K., Millay, D. P., Sargent, M. A., Hajjar, R. J., Kranias, E. G., & Molkentin, J. D. (2011, March). Mitigation of muscular dystrophy in mice by SERCA overexpression in skeletal muscle. The Journal of clinical investigation. Retrieved July 13, 2022, from https://pubmed.ncbi.nlm.nih.gov/21285509/

JM, G. (1996, March). Membrane abnormalities and Ca homeostasis in muscles of the MDX mouse, an animal model of the Duchenne muscular dystrophy: A Review. Acta physiologica Scandinavica. Retrieved July 13, 2022, from https://pubmed.ncbi.nlm.nih.gov/8729700/

Loboda, A., & Dulak, J. (2020, July 20). Muscle and cardiac therapeutic strategies for Duchenne Muscular Dystrophy: Past, present, and future – pharmacological reports. SpringerLink. Retrieved July 13, 2022, from https://link.springer.com/article/10.1007/s43440-020-00134-x

5. UPR
Hetz, C. (2012, January 18). The unfolded protein response: Controlling cell fate decisions under ER stress and beyond. Nature News. Retrieved July 13, 2022, from https://www.nature.com/articles/nrm3270

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