Why treating common disease is so hard. Essential Tremor Case study

Essential tremor (ET) stands as the predominant human movement disorder, marked by rhythmic kinetic tremors. Despite extensive research and therapeutic advancements, nearly half of all patients remain unresponsive to standard medications, prompting many patients to turn toward invasive surgical interventions and implants for symptom management. The underlying reasons for this resistance remain elusive, and there is no concrete consensus as to why? However, an emerging thread is that ET may be a common symptom of many different pathologies.

Harmaline-induced tremor has been the gold standard animal model for studying and developing drugs against essential tremor (ET). Harmaline, a drug that causes mice to display rhythmic intention tremors similar to ET, has established the practice of administering Harmaline to mice and subsequently identifying drugs to treat resulting ET. This approach has led to the development of drugs such as propranolol and Primidone, as well as more modern T-type calcium antagonists awaiting FDA approval. These drugs work well, at least in 50% of patients; however, high rates of drug inefficacy persist.

The consensus is growing that drug inefficacy in treating essential tremor (ET) stems from its multifaceted underlying mechanisms. Harmaline is believed to operate by upregulating T-type calcium channels and HCN channels in the inferior olive, inducing rhythmic synchronized firing in the cerebellum and muscles. Another suspected cause includes excessive overgrowth of climbing fibers from the inferior olive into the cerebellum, promoting synchronization. Another potential pathology is leaky ryanodine receptors in cerebellar Purkinje cells.

Currently, it remains unclear whether these alternative mechanisms respond to existing drugs or require a different class of medications. However, the evolving challenges to the Harmaline model offer promising prospects for patients. Should these mechanisms prove unresponsive to current treatments but amenable to a distinct drug class, pharmaceutical developers could redirect efforts accordingly. Notably, the leaky ryanodine receptor model has shown promising responses to a drug known as Rycal, suggesting potential avenues for targeted therapies in ET.

Author: Alexander White

reference:

1. Louis, E. D., Rios, E., & Henchcliffe, C. (2010). How are we doing with the treatment of essential tremor (ET)? Persistence of patients with ET on medication: data from 528 patients in three settings. European journal of neurology, 17(6), 882-884.

2. Pan, M. K., & Kuo, S. H. (2022). Essential tremor: clinical perspectives and pathophysiology. Journal of the neurological sciences, 435, 120198.

3. Cheng, M. M., Tang, G., & Kuo, S. H. (2013). Harmaline-induced tremor in mice: videotape documentation and open questions about the model. Tremor and Other Hyperkinetic Movements, 3.

4. Pan, M. K., Li, Y. S., Wong, S. B., Ni, C. L., Wang, Y. M., Liu, W. C., ... & Kuo, S. H. (2020). Cerebellar oscillations driven by synaptic pruning deficits of cerebellar climbing fibers contribute to tremor pathophysiology. Science translational medicine, 12(526), eaay1769.