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D-NAP Prophylactic Treatment in the SOD Mutant Mouse Model of Amyotrophic Lateral Sclerosis: Review of Discovery and Treatment of Tauopathy

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Abstract

Davunetide (NAP) is a leading drug candidate being tested against tauopathy. Davunetide is an eight-amino-acid peptide fragment derived by structure—activity studies from activity-dependent neuroprotective protein, activity-dependent neuroprotective protein (ADNP). ADNP is essential for brain formation. ADNP haploinsufficiency in mice results in tauopathy and cognitive deficits ameliorated by davunetide treatment. This article summarizes in brief recent reviews about NAP protection against tauopathy including the all D-amino acid analogue—D-NAP (AL-408). D-NAP was discovered to have similar neuroprotective functions to NAP in vitro. Here, D-NAP was tested as prophylactic as well as therapeutic treatment for amytrophic lateral sclerosis (ALS) in the widely used TgN(SOD1-G93A)1Gur transgenic mouse model. Results showed D-NAP-associated prophylactic protection, thus daily treatment starting from day 2 of age resulted in a prolonged life course in the D-NAP-treated mice, which was coupled to a significant decrease in tau hyperphosphorylation. These studies correlate protection against tau hyperphosphorylation and longevity in a severe model of ALS-like motor impairment and early mortality. NAP is a first-in-class drug candidate/investigation compound providing neuroprotection coupled to inhibition of tau pathology. D-NAP (AL-408) is a pipeline product.

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Acknowledgments

This work is in partial fulfillment of the Ph.D. thesis requirements of Y. Jouroukhin and the M.Sc. thesis of Ms. Regina Ostritsky. Support was provided by the Levie-Edersheim-Gitter functional brain imaging scholarship, AMN Foundation, IsrALS, Prize4life, Canadian Friends of Tel Aviv University—Montreal Circle of Friends, Joe and Grace Alter, Barbara and Don Seal, the Oberfeld family and the Adams Family, and Allon Therapeutics Inc. We thank the Allon Therapeutics team, Drs. Michael Gold and Alistair Stewart, for valuable input. Professor Illana Gozes is the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and the Director of the Adams Super Center for Brain Studies, the Levie-Edersheim-Gitter Institute for Functional Brain Imaging and the Dr. Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology at Tel Aviv University.

Conflict of Interest

Professor Gozes serves as Director, Founding Scientist at Allon Therapeutics Inc., the company that develops davunetide (NAP) (www.allontherapeutics.com).

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Authors and Affiliations

  1. Department of Human Molecular Genetics and Biochemistry, Sagol School of Neuroscience, Adams Super Center for Brain Studies, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Yan Jouroukhin, Regina Ostritsky & Illana Gozes

  2. Dr. Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology, The Lily and Avraham Gildor Chair for the Investigation of Growth Factors Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel

    Illana Gozes

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  1. Yan Jouroukhin
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  2. Regina Ostritsky
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  3. Illana Gozes
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Correspondence to Illana Gozes.

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Jouroukhin, Y., Ostritsky, R. & Gozes, I. D-NAP Prophylactic Treatment in the SOD Mutant Mouse Model of Amyotrophic Lateral Sclerosis: Review of Discovery and Treatment of Tauopathy. J Mol Neurosci 48, 597–602 (2012). https://doi.org/10.1007/s12031-012-9882-6

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