Sorbitol reduction via AT-007 (govorestat) ameliorates synaptic dysfunction and neurodegeneration in models of sorbitol dehydrogenase deficiency

Yi Zhu; Amanda G. Lobato; Adriana P. Rebelo; Tijana Canic; Natalie Ortiz Vega; Xianzun Tao; Sheyum Syed; Christopher Yanick; Mario Saporta; Michael Shy; Riccardo Perfetti; Shoshana Shendelman; Stephan L. Zuchner; R. Grace Zhai

doi:10.1172/jci.insight.164954

Sorbitol reduction via AT-007 (govorestat) ameliorates synaptic dysfunction and neurodegeneration in models of sorbitol dehydrogenase deficiency

Yi Zhu,¹ Amanda G. Lobato,¹ Adriana P. Rebelo,² Tijana Canic,³ Natalie Ortiz Vega,⁴ Xianzun Tao,¹ Sheyum Syed,³ Christopher Yanick,⁵ Mario Saporta,⁵ Michael Shy,⁶ Riccardo Perfetti,⁷ Shoshana Shendelman,⁷ Stephan L. Zuchner,² and R. Grace Zhai¹

Published April 4, 2023 - More info

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Abstract

Sorbitol dehydrogenase (SORD) deficiency has been identified as the most frequent autosomal recessive form of hereditary neuropathy. Loss of SORD causes high sorbitol levels in tissues due to the inability to convert sorbitol to fructose in the two-step polyol pathway, leading to degenerative neuropathy. The underlying mechanisms of sorbitol-induced degeneration have not been fully elucidated, and no current FDA-approved therapeutic options are available to reduce sorbitol levels in the nervous system. Here, in a Drosophila model of SORD deficiency, we showed synaptic degeneration in the brain, neurotransmission defect, locomotor impairment, and structural abnormalities in the neuromuscular junctions. In addition, we found reduced ATP production in the brain and reactive oxygen species accumulation in the central nervous system (CNS) and muscle, indicating mitochondrial dysfunction. Applied Therapeutics, Inc has developed a CNS-penetrant next-generation aldose reductase inhibitor (ARI), AT-007 (govorestat), which inhibits the conversion of glucose to sorbitol. AT-007 significantly reduced sorbitol levels in patient-derived fibroblasts, iPSC-derived motor neurons, and Drosophila brains. AT-007 feeding in Sord-deficient Drosophila mitigated synaptic degeneration and significantly improved synaptic transduction, locomotor activity, and mitochondrial function. Moreover, AT-007 treatment significantly reduced ROS accumulation in Drosophila CNS, muscle, and patient-derived fibroblasts. These findings uncover the molecular and cellular pathophysiology of SORD neuropathy and provide a potential treatment strategy for patients with SORD deficiency.

Sorbitol reduction via AT-007 (govorestat) ameliorates synaptic dysfunction and neurodegeneration in models of sorbitol dehydrogenase deficiency

Yi Zhu,¹ Amanda G. Lobato,¹ Adriana P. Rebelo,² Tijana Canic,³ Natalie Ortiz Vega,⁴ Xianzun Tao,¹ Sheyum Syed,³ Christopher Yanick,⁵ Mario Saporta,⁵ Michael Shy,⁶ Riccardo Perfetti,⁷ Shoshana Shendelman,⁷ Stephan L. Zuchner,² and R. Grace Zhai¹

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Sorbitol reduction via AT-007 (govorestat) ameliorates synaptic dysfunction and neurodegeneration in models of sorbitol dehydrogenase deficiency

Yi Zhu,1 Amanda G. Lobato,1 Adriana P. Rebelo,2 Tijana Canic,3 Natalie Ortiz Vega,4 Xianzun Tao,1 Sheyum Syed,3 Christopher Yanick,5 Mario Saporta,5 Michael Shy,6 Riccardo Perfetti,7 Shoshana Shendelman,7 Stephan L. Zuchner,2 and R. Grace Zhai1

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Yi Zhu,¹ Amanda G. Lobato,¹ Adriana P. Rebelo,² Tijana Canic,³ Natalie Ortiz Vega,⁴ Xianzun Tao,¹ Sheyum Syed,³ Christopher Yanick,⁵ Mario Saporta,⁵ Michael Shy,⁶ Riccardo Perfetti,⁷ Shoshana Shendelman,⁷ Stephan L. Zuchner,² and R. Grace Zhai¹