Antipsychotic drug may help treat SMA symptoms, research shows
The antipsychotic medication haloperidol may help treat spinal muscular atrophy (SMA) by increasing SMN protein levels and enhancing protective effects in nerve cells, a study found.
Haloperidol boosted nerve cell survival, reduced neuroinflammation, and improved motor function in mice and in patient-derived cells, supporting its potential as a complementary or stand-alone therapy.
“Given its central nervous system [brain and spinal cord] penetrance and clinical approval, [haloperidol] emerges as a promising SMA therapy candidate, warranting further dose optimization and validation for translational potential,” the researchers wrote.
The study, “Haloperidol induces neuroprotection and enhances neuromuscular function in both murine and human models of spinal muscular atrophy,” was published in Experimental & Molecular Medicine.
In SMA, SMN1 gene mutations lead to a deficiency of the SMN protein, disrupting the function of motor neurons (the specialized nerve cells that control movement) and leading to SMA symptoms such as muscle weakness and wasting.
Boosting SMN production
Approved SMA therapies aim to increase SMN protein levels by supplying the SMN1 gene or increasing SMN production from SMN2, a backup gene that typically produces much less protein due to a difference in its DNA sequence that results in alternative splicing – a process by which a gene produces several proteins.
The researchers investigated the therapeutic potential of haloperidol, an antipsychotic (drugs that treat symptoms of schizophrenia and other conditions that involve psychosis), as a potential treatment for SMA, based on a previous screening they performed that showed haloperidol’s ability to increase SMN production from SMN2.
Haloperidol significantly extended mice’s lifespan, by 15.4%. Control mice, who received a placebo, lived 13 days, while treated mice lived 15 days. The treatment also delayed weight loss and improved the animals’ muscle strength and motor function.
“Overall, these results suggest a general improvement in the survival, health (weight gain), strength, and motor coordination (behavioral tests) of mice with SMA upon [haloperidol] administration,” the researchers wrote.
Haloperidol also improved the survival of motor neurons in mice and the survival and communication of motor neurons derived from people with SMA, produced from induced pluripotent stem cells. These cells result from reprogramming adult cells to exhibit stem cell-like properties, which can develop into several cell types.
Further analysis in mice revealed that haloperidol treatment significantly increased SMN protein levels in the brain and spinal cord and activated neuroprotective processes, delaying motor neuron loss. Haloperidol also led to splicing changes in mice, which the researchers suggested “may counteract a core molecular defect in SMA, supporting proper transcript processing for neuronal survival.”
Additional benefits include attenuation of astrogliosis, which occurs when cells called astrocytes respond to damage in the central nervous system, and of microglial activation. These are key processes in neuroinflammation, a well-known feature of SMA.
Additional experiments showed that haloperidol improved SMN levels in skeletal muscles and increased nerve supply at the neuromuscular junction, the site where nerves and muscles communicate to control muscle movements.
“Collectively, these findings support [haloperidol]’s progression toward early-phase clinical evaluation, prioritizing dose refinement, pharmacokinetics in larger preclinical models, and regulatory engagement for potential fast-track approval in rare diseases,” the researchers wrote. Pharmacokinetics refers to how the drug moves into, inside, and out of the body.
While haloperidol showed no major side effects in these models, “its interaction with existing SMA therapies … requires further evaluation,” the scientists wrote. “Clinical trials will ultimately be necessary to determine [haloperidol]’s long-term safety and efficacy in patients with SMA.”
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