Targeting Pathogenic Beta-6/Beta-7 Loop Epitope of Misfolded SOD1 to Treat Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic Lateral Sclerosis (ALS) is the most common type of motor neuron disease. It is a progressive disease, with patients becoming increasingly dependent on caregivers and physicians as time from the onset increases, and ultimately, it is fatal. ALS can be split into two origins: hereditary, which is known as fALS (familial ALS, ~10% of cases), or idiopathic, known as sALS (sporadic ALS, ~90% of cases). Currently, the only treatment options for ALS are U.S. Food and Drug Administration (FDA)-approved Rilutek and Radicava/Radicut, neither of which can stop nor significantly slow the progression of the disease. At best, these drugs may increase a patient's life span by up to 6months. Therefore, there is a pressing need for more effective therapeutics for ALS worldwide.

Our aim is to develop treatment/prophylactic strategy for fALS patients caused by mutations in the gene encoding for SOD1 protein (approximately 20% of familial cases). SOD1 is a major enzyme responsible for the body's defense against oxidative damage. Mutations cause SOD1 protein to undergo noxious structural transformation, so-called misfolding, rendering it toxic to motor neurons. Current approaches to mitigate SOD1 toxicity in ALS relay on blocking the production of SOD1 proteins in nervous cells. These approaches, being indiscriminative between misfolded and healthy SOD1 proteins, may have a significant drawback of depriving nervous cells of their essential antioxidant potential, crucial for the normal functioning of the nervous system. We, for the first time, demonstrated that blocking a unique surface feature (epitope) exposed exclusively on toxic, but not on healthy SOD1 proteins, with a specific anybody, neutralizes toxic SOD1 species, thus rescuing motor neurons, strongly delaying disease onset and extending survival in animal model of ALS. Our approach is expected to overcome the limitations of the current indiscriminative methods, and minimize the potential adverse effects of anti-SOD1 therapy by targeting only misfolded (toxic) forms of SOD1, while sparing intact proteins, thereby leading to more efficient and safe ALS therapeutics.

The aim of the proposed research is to fully explore the therapeutic potential of anti-SOD1 ALS therapy relying on targeting the specific pathogenic epitope on misfolded SOD1. We will improve the pharmacological properties of the original antibody, to make it more efficient in neutralizing the toxic SOD1 species, and test its performance, once applied at different disease stages, in ameliorating disease in an animal model of ALS. These experiments are crucial for assessing the feasibility of using the proposed anti-SOD1 therapy for the treatment of diagnosed ALS patients. In addition, we will explore a new modality of targeted anti-SOD1 therapy, which is designed to prevent spreading of the toxic misfolded SOD1 proteins among healthy nervous cells, and thus attenuate disease progression. For this purpose, we will develop a vaccination approach based on the FDA-approved mRNA technology, in which the body itself would be encouraged to produce an array of neutralizing antibodies against the pathogenic epitope of misfolded SOD1, and thus help fighting disease.

We anticipate that our therapy has a potential to be effective in the careers of a mutated version of SOD1 gene if applied at the very early disease stages, when substantial damage to the nervous tissue has not been made yet. Moreover, because of the possibility that also SOD1 proteins without mutation may undergo misfolding, as a result of poorly characterized environmental stresses, and thus contribute to ALS pathogenesis of a significant portion of sporadic ALS cases, our anti-SOD1 therapy may prove effective in a much broader population of ALS patients than just fALS cases with mutated SOD1 gene. Moreover, in recent years, the paradigm of ALS treatment has begun to shift - as a result of advances in genomic sequencing -- toward disease prophylactics, a strategy particularly useful for the carriers of mutated SOD1 gene. Thus, known asymptomatic carriers of mutated SOD1 gene in affected families might be an appropriate population to apply the proposed anti-SOD1 therapy to prevent disease appearance.

Since all methods of the delivery of the therapeutic agents to the nervous system used in the proposed study are FDA-approved clinal tools, the outcome of this study, if successful, might be directly translated into therapeutic application(s), with proceeding to a clinical trial using a limited number of fALS patients with a mutated version of SOD1 gene at the very early disease stage.