Unlocking the Potential: Targeting RIPK1 for ALS Treatment

Amyotrophic Lateral Sclerosis (ALS) is a neuromuscular disease, affecting 12 individuals per 100,000 in the U. S.¹ ALS is incurable, thus, the discovery of novel targets is paramount for improving treatment options. Using Causaly, we identified and assessed the potential of RIPK1 as a target for ALS.

ALS, commonly known as Lou Gehrig’s disease, is a rare neuromuscular disorder that progressively affects motor neurons in the brain and spinal cord, leading to the loss of muscle control.² While ALS can occur at any age, symptoms typically emerge between 55 and 75 years old.³

The exact cause of ALS remains elusive, and effective treatments are still lacking. While current therapies can manage symptoms and slow disease progression, there is a critical need for accelerated target discovery to identify new therapeutic approaches for ALS. In addition, advancements in understanding ALS complexities and potential toxicities related to gene or protein targeting are crucial for developing safe and effective interventions

With advancements in data-driven approaches, researchers can harness the power of technology to accelerate the search for potential therapeutic targets. Using Causaly, more than 1,500 targets associated with ALS were identified, over 300 of which have been found to induce the risk or progression of ALS.

Due to their role in regulating critical cellular processes such as signal transduction, cell survival, inflammation and apoptosis, kinases may be promising therapeutic targets for ALS. Using Causaly advanced filtering capabilities, targets were refined by enzyme subclass, revealing 13 kinases linked to ALS. Among these, Receptor-Interacting Protein Kinase 1 (RIPK1) had the most evidence.

In ALS, where dysregulated cell death pathways and inflammation contribute to neurodegeneration, RIPK1 has emerged as an important therapeutic target. ⁴ The activation of RIPK1 and necroptosis have been genetically and mechanistically associated with ALS and other neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease.⁵

A study showed that the development of ALS in Tbk1^+/−/ TAK1^+/−  double heterozygous mice was alleviated by RIPK1 deficiency, implicating RIPK1 and its regulators as a target for ALS.⁶ Aging facilitated RIPK1 activation by reducing TAK1 expression, contributing to the genetic risk factors associated with ALS onset.⁶

Building on this, research demonstrated that RIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis.⁷ Inhibition of RIPK1 activity could therefore mitigate neurodegenerative processes affected by ALS, and therefore, show promise as a therapeutic target.

Understanding whether a target is safe and effective to approach from an inhibition standpoint is paramount to any prioritization strategy. Using Causaly, we can understand what the associated toxicities are from targeting a protein or gene of interest.

Using Causaly, almost 20 pathways were identified to be affected by RIPK1 in ALS patients, almost half of which have been linked to in vivo studies. In mouse models it was identified that RIPK1 promotes necroptosis and neuron death in ALS. RIPK1 was found to be involved in mediating axonal degeneration via the promotion of inflammation and necroptosis, highlighting the therapeutic potential of inhibiting RIPK1 in reversing axonal pathology.⁸

The need for rapid target identification in ALS research is critical in overcoming the limitations of available treatments. Moreover, understanding the toxicities associated with targeting specific genes or proteins is equally crucial. By managing the data overload, Causaly allows drug discovery scientists to identify, prioritize and assess targets, accelerating the development of safe and effective therapies.