ADVANCES FOR AMYOTROPHIC LATERAL SCLEROSIS: DOES IPL344 SLOW THE PROGRESSION?

Letter to the Editor

M.G. Onesta^*

Unipolar Spinal Unit, Physical Medicine and Rehabilitation, Cannizzaro Emergency Hospital of Catania, Italy.

*Correspondence to:
Dr. Maria Giuseppa Onesta,
Unipolar Spinal Unit,
Physical Medicine and Rehabilitation,
Cannizzaro Emergency Hospital of Catania,
Catania, Italy.
e-mail: Mp.onesta@gmail.com

KEYWORDS: Amyotrophic lateral sclerosis, neurodegenerative disease, IPL344, therapy, neuron

INTRODUCTION

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, nerve cells in the brain and spinal cord, resulting in muscle weakness, atrophy, paralysis, and death of the patient (1). ALS is characterized by a progressive loss of upper motor neurons in the brain and lower motor neurons in the spinal cord and brainstem. Epidemiological data suggest that approximately 10% of ALS cases are familial, while 90% are sporadic. ALS is characterized by complex molecular and biological mechanisms and further studies are required to understand the impairment of voluntary muscles, neuronal death, and neurodegeneration (2).

DISCUSSION

The genes involved in ALS are superoxide dismutase 1 (SOD1) which, once mutated, can cause protein folding and aggregation, and oxidative stress (3). The mutation of the C9orf72 gene is responsible for the expansion of the GGGGCC repeat and causes toxic RNA foci and disruption of nucleocytoplasmic transport (4).  Some proteins such as TARDBP and Fused in Sarcoma (FUS) can bind RNA and form pathological cytoplasmic aggregates in neurons. TARDBP, which encodes the protein TDP-43, and FUS are RNA-binding proteins critical for the regulation of gene expression and are implicated in several neurodegenerative diseases (5). All of these proteins mentioned can alter cellular and neuronal pathophysiology leading to ALS. There is currently no cure for this disease, however some recent experimental data give us hope.

Recently, an interesting molecule has shown efficacy for ALS therapy. When administered intravenously daily for up to three years, IPL344 has shown safety and tolerability in a clinical study (6). IPL344 is a biologically active peptide designed to activate the PI3K-Akt signaling pathway and plays a crucial role in promoting cell survival and inhibiting apoptosis.  The study reported a significant slowing of disease progression, compared to controls, with a 64% reduction in the rate of decline of ALS. In addition, patients experienced improved lung function and weight gain (6).

In ALS, the Akt signaling pathway is often downregulated, an effect that contributes to the degeneration of neurons. The PI3K-Akt biochemical pathway is observed in many cellular processes such as metabolism, proliferation, and survival. Activation of IPL344 leads to inhibition of motor neuron apoptosis and reduction of inflammation, which are relevant in ALS. Therefore, stimulating the Akt signaling pathway with IPL344 could have the potential to improve neuronal survival and slow disease progression.

CONCLUSIONS

One of the experimental therapies currently being studied for ALS is the use of IPL344. This drug has shown encouraging results regarding the possibility of slowing disease progression. IPL344 is an experimentally used peptide that activates the Akt (Protein Kinase B) signaling pathway. Akt promotes cell survival by acting against apoptosis, reduces oxidative stress, and improves energy metabolism. In ALS, the PI3K–Aky pathway is often underactive, making motor neurons more vulnerable. Some preliminary data using IPL344 show a slowing of the decline in muscle function.

Conflict of interest

The author declares that they have no conflict of interest.

REFERENCES

1. Feldman EL, Goutman SA, Petri S, et al. Amyotrophic lateral sclerosis. The Lancet. 2022;400(10360):1363-1380. doi:https://doi.org/10.1016/S0140-6736(22)01272-7
2. Taylor JP, Brown RH, Cleveland DW. Decoding ALS: from genes to mechanism. Nature. 2016;539(7628):197-206. doi:https://doi.org/10.1038/nature20413
3. Liu W, Venugopal S, Majid S, et al. Single-cell RNA-seq analysis of the brainstem of mutant SOD1 mice reveals perturbed cell types and pathways of amyotrophic lateral sclerosis. Neurobiology of Disease. 2020;141:104877. doi:https://doi.org/10.1016/j.nbd.2020.104877
4. Brown CA, Lally C, Kupelian V, Flanders WD. Estimated Prevalence and Incidence of Amyotrophic Lateral Sclerosis and SOD1 and C9orf72 Genetic Variants. Neuroepidemiology. 2021;55(5):1-12. doi:https://doi.org/10.1159/000516752
5. Balendra R, Sreedharan J, Hallegger M, et al. Amyotrophic lateral sclerosis caused by TARDBP mutations: from genetics to TDP-43 proteinopathy. The Lancet Neurology. 2025;24(5):456-470. doi:https://doi.org/10.1016/s1474-4422(25)00109-7
6. Gotkine M, Schoenfeld DA, Cohen I, et al. Akt Activation With IPL344 Treatment for Amyotrophic Lateral Sclerosis: First in Human, Open‐Label Study. Muscle & Nerve. 2025;71(6):1032-1042. doi:https://doi.org/10.1002/mus.28393