Japanese researchers have shown in mice that GlaxoSmithKline plc's marketed migraine drug Amerge naratriptan could be repurposed to treat spinal and bulbar muscular atrophy.1 The pharma is not saying if it will pursue the new indication for the serotonin (5-HT1D) receptor agonist, but the academics who did the work are planning an investigator-led Phase II trial.

Spinal and bulbar muscular atrophy (SBMA) involves degeneration of lower motor neurons in the spinal cord and brainstem of males. The degeneration causes progressive weakness and atrophy of facial, limb and bulbar muscles. The disease is caused by CAG glutamine repeats within the androgen receptor (AR) gene, which causes pathogenic AR accumulation in the nucleus of motor neurons.

There are no approved treatments for SBMA. Previous efforts to treat the disease have included strategies to eliminate the pathogenic AR accumulation such as treatment with the luteinizing hormone-releasing hormone (LHRH) analog leuprorelin. In 2010, however, Masahisa Katsuno and colleagues reported that leuprorelin failed to improve swallowing and muscle function in an investigator-led Phase II trial.2

Takeda Pharmaceutical Co. Ltd. markets Leuplin leuprorelin acetate to treat prostate cancer.

"Accumulation of abnormal protein is the primary molecular event as well as a substantial therapeutic target for neurodegenerative diseases. However, drugs that inhibit abnormal protein deposits, such as antibodies to b-amyloid and antiandrogens for SBMA, show limited effects in clinical trials. This may suggest that various molecular events downstream of abnormal protein aggregation overwhelm the neuroprotection by such interventions," said Katsuno, who is an associate professor of neurology at the Nagoya University.

Thus, Katsuno and colleagues wanted to probe the downstream effects of pathogenic AR accumulation on gene expression in motor neurons. The team, which also included researchers from The University of Tokyo, used a transgenic mouse model of SBMA in which the mice expressed human AR with pathogenic CAG repeats. Microarray analysis revealed 124 deregulated genes in the SBMA mice, whereas there were no deregulated genes in animals expressing wild-type human AR or in wild-type mice.

Of the identified genes, the group focused on calcitonin gene-related peptide (CGRP) for two reasons: it was significantly upregulated in the SBMA mice and previous studies suggested its expression was restricted to the lower motor neurons in the spinal cord-the parts of the CNS affected by SBMA.

In human neuroblastoma cells expressing pathogenic AR, knockdown or pharmacological inhibition of CGRP protected against toxicity and cell death compared with no knockdown or inhibition. Mechanistically, upregulated CGRP activated the neurotoxic c-Jun N-terminal kinase (JNK) pathway in motor neurons.

Previous studies have shown that CGRP is overexpressed in other neurological conditions including migraine, and marketed serotonin (5-HT1B) receptor and 5-HT1D agonists suppress CGRP secretion and neurological symptoms in patients with migraine. Therefore, Katsuno's group set out to determine whether the migraine therapeutics also could help treat SBMA.

In human neuroblastoma cells expressing pathogenic AR, naratriptan and other 5-HT1D agonists restored cell viability and decreased damage compared with vehicle control.

In male mice expressing human pathogenic AR, naratriptan increased grip strength, body weight and life span compared with vehicle control. The effects were comparable to those seen with Cgrp knockout.

Results were published in Nature Medicine.

Repurposing serotonin receptor agonists

Katsuno told SciBX that the next step is to perform an investigator-led Phase II trial of naratriptan.

Maria Pennuto, group leader in the Department of Neuroscience and Brain Technologies at the Italian Institute of Technology, said it is worth testing naratriptan in SBMA but noted that "naratriptan's use is associated with side effects such as dizziness, nausea and other symptoms, which calls for caution in the use of this drug for the treatment of a chronic disease."

"This treatment has to be continued for the entire life of an individual. It might be possible that a chronic treatment reveals unsuspected side effects or that the already known side effects may become intolerable by the patients," added Angelo Poletti, professor of applied biology in the Department of Pharmacological and Biomolecular Sciences at the University of Milan.

Katsuno countered that the side effects of naratriptan can be attenuated with symptomatic therapies such as treatments for nausea and hypertension. However, patients experiencing angina would need to discontinue naratriptan.

Andrew Cato, group leader at Karlsruhe Institute of Technology's Institute of Toxicology and Genetics, was less sanguine about the repurposing opportunity. "Compared with leuprorelin, naratriptan only had a marginal effect in protecting against neurodegeneration in the mouse experiments. It is therefore debatable whether it would have a major impact on the treatment of patients," he said.

Nobuyuki Nukina, head of the Structural Neuropathology Lab at the RIKEN Brain Science Institute, suggested that a combination of naratriptan with other candidates could generate the best efficacy.

Pennuto agreed. "It may be worth it to design a study in which combination therapy is also considered, for instance, naratriptan together with leuprorelin or other drugs to decrease androgen levels in the serum," she said.

Katsuno told SciBX that his team is running another trial of leuprorelin for SBMA. "If we can prove that leuprorelin suppresses disease progression of SBMA, we want to test the combination of this hormonal therapy with naratriptan," he said.

He added, "Since the results of the previous trial were not conclusive, we are now conducting an additional Phase II trial of leuprorelin that mainly focuses on the SBMA patients whose disease duration is less than 10 years."

Polyglutamine diseases

Despite his reservations, Cato did say that naratriptan's mechanism could apply to neurodegeneration that occurs in other polyglutamine diseases such as amyotrophic lateral sclerosis (ALS).

Indeed, Pennuto wanted to know whether the pathway is upregulated in Huntington's disease (HD) and spinocerebellar ataxias caused by polyglutamine expansion.

She cautioned that the modification of CGPR transcription in SBMA is specifically caused by the polyglutamine repeats within AR. Because other diseases have different affected genes, it remains to be determined whether the same strategy would be efficacious.

Katsuno said the microarray-based strategy used to identify CGPR as a target is applicable to HD and other polyglutamine disorders.

He told SciBX that Nagoya University has filed a patent application covering the findings in the paper and that the licensing status is undisclosed.

GlaxoSmithKline declined to comment on the findings.

Martz, L. SciBX 5(40); doi:10.1038/scibx.2012.1048
Published online Oct. 11, 2012

REFERENCES

1.   Minamiyama, M. et al. Nat. Med.; published online Sept. 30, 2012; doi:10.1038/nm.2932
Contact: Gen Sobue, Nagoya University, Nagoya, Japan
e-mail: sobueg@med.nagoya-u.ac.jp
Contact: Masahisa Katsuno, same affiliation as above
e-mail: ka2no@med.nagoya-u.ac.jp

2.   Katsuno, M. et al. Lancet Neurol. 9, 875-884 (2010)

COMPANIES AND INSTITUTIONS MENTIONED

      GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.

      Italian Institute of Technology, Genoa, Italy

      Karlsruhe Institute of Technology, Karlsruhe, Germany

      Nagoya University, Nagoya, Japan

      Nagoya University Graduate School of Medicine, Nagoya, Japan

      RIKEN Brain Science Institute, Saitama, Japan

      Takeda Pharmaceutical Co. Ltd. (Tokyo:4502), Osaka, Japan

      University of Milan, Milan, Italy

      The University of Tokyo, Tokyo, Japan