Spinal muscular atrophy (SMA) originates from a lack of Survival of Motor Neuron (SMN) protein, with clinical types ranging from infant mortality to locomotor defects with no lifespan reduction. Even though it mainly affects motoneurons, a primary myopathy has also been described. Three therapies have reached market authorization, but critical medical needs on SMA remain because of their limitations. Available drugs are (1) costly, and patients with milder SMA types are at risk of being excluded from the treatments, and (2) the routes of administration are invasive and lack systemic effects or have a small target population, or (3) their long-term toxicity profile is unknown. We previously identified haloperidol, with extensive toxicology and pharmacovigilance track record, as a repositionable drug and validated its use in SMA motor neurons and a murine model in an international collaborative effort. Haloperidol also increased the SMN protein levels in the most relevant preclinical models, addressing the root cause of the disease. However, optimizing its PK/PD profile for SMA patients is necessary to advance its clinical use.

SMN protein levels were analyzed in motoneurons (MNs), spinal cord, and quadriceps from Delta7 mice following treatment with haloperidol at two different doses, nusinersen, or a combination of both treatments. Dopamine receptor 2 (DRD2) protein levels were also measured in the brain of Delta7 mice and in MNs.