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New perspectives in SPAX5 research: Sephin-1 as a possible therapy

04 March 2024
Research

Researchers from IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University have identified, in patient cells and preclinical models, the activation of a new response pathway to mitochondrial stress in a rare neurodegenerative disease, autosomal recessive spastic ataxia type 5

The research, just published in the journal Brain, also demonstrates how the Sephin-1 drug is able to improve the phenotype of the SPAX5 mouse model, recovering the functionality and morphology of the mitochondria, seriously affected in this pathology.

The SPAX5 disease

Autosomal recessive spastic ataxia type 5 (SPAX5) is a serious neurodegenerative disease with pediatric onset, characterized by problems with motor coordination and balance (ataxia), spasticity, peripheral neuropathy and in some cases epilepsy. It is a very rare pathology, with few patients described in the literature, which is why the disease is probably under-diagnosed. Affected children are already confined to wheelchairs at a few years of age and currently treatment of the disease is only symptomatic and focuses on controlling spasticity through physiotherapy. However, through continuous interaction with patient associations, we are aware of many cases around the world.

SPAX5 is caused by mutations in the AFG3L2 gene, which encodes the mitochondrial protein of the same name, crucial for the quality control of proteins in this organelle. SPAX5 patients, as well as mouse models of the disease, show severe structural and metabolic alterations of the mitochondria, also known as the body's powerhouses, especially at the level of the largest neurons in the central and peripheral nervous system (Purkinje neurons and motor neurons). To date, there is no therapy capable of mitigating the effects caused by SPAX5.

The study

In the study, coordinated by Dr. Francesca Maltecca, group leader of the Mitochondrial Dysfunction in Neurodegeneration Unit at IRCCS Ospedale San Raffaele, through combined in vitro and in vivo approaches, the researchers identified that the drastic reduction of AFG3L2 levels in patient cells and in the mouse model generates severe protein accumulation toxicity in the mitochondrion.

This protein-toxic stress suffered by the mitochondrion is communicated to the whole cell via a specific molecular pathway, called the OMA1-DELE1-HRI axis, which activates a protective response in the cytoplasm helping cells counteract the primary damage at the mitochondrial level. This is the first time that this pathophysiological mechanism has been identified in a human neurodegenerative disease, and the research team has also shown how the enhancement of this response turns out to be beneficial.

Based on these findings, the researchers in fact administered the drug Sephin-1, a neuroprotective molecule capable of prolonging the adaptive OMA1-DELE1-HRI response, to mouse models of SPAX5.

Dr. Maltecca states:

The treatment proved effective, we observed significant improvements in the clinical phenotype in the mouse models. Furthermore, we have shown that the treatment improves the morphology of the neurons most affected in the disease, the Purkinje neurons, and, even more importantly, is able to recover severe structural and metabolic alterations of the mitochondria. These results further support the optimization of this drug in preclinical and clinical settings for the treatment of SPAX5 patients, but potentially also other ataxias caused by impaired mitochondrial proteostasis.

Dr. Maltecca's group, in collaboration with the National Ataxia Foundation (which funded this study) and the Miracles for Mighty Milo Foundation, is seeking to create a worldwide patient registry to expand the caseload to aid research. The next steps will involve further insights into the new data obtained to identify the mitochondrial targets of this drug and to optimize treatment with Sephin-1 in preclinical trials.

The drug Sephin-1 (IFB088) has already been tested in healthy adult subjects for safety and tolerability and it is already being tested in a clinical trial for another neurodegenerative disease, Amyotrophic Lateral Sclerosis - ALS, albeit caused by other mechanisms.

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