The LDDN SMA team travels to Kansas City MO for the Annual SMA Research Conference and to meet up with our collaborators from Indiana University; Elliot Androphy, Sarah Custer and Anne Rietz. 

Sarah presented 'Binding to SMN is essential for the role of alpha-COP in supporting neuronal development" and Anne gave both a poster and talk on our 'Novel small molecules that increase SMN protein and extend survival of SMA mice'.

There was also a little time to taste some Kansas culture.


Publication of Prof. Glenn Lin's paper: "Restored Glial Glutamate Transporter EAAT2 Function as a Potential Therapeutic Approach for Alzheimer's Disease" in The Journal of Experimental Medicine 2015, 212:319-332.


Kou Takahashi,Qiongman Kong, Yuchen Lin,Nathan Stouffer,Delanie A. Schulte, Liching Lai, Qibing Liu, Ling-Chu Chang, Sky Dominguez, Xuechao Xing, Gregory D. Cuny,  Kevin J. Hodgetts, Marcie A. Glicksman,and Chien-Liang Glenn Lin

Abstract  Glutamatergic systems play a critical role in cognitive functions and are known to be defective in Alzheimer’s Disease (AD) patients. Previous literature has indicated that glial glutamate transporter EAAT2 plays an essential role in cognitive functions, and that loss of EAAT2 protein is a common phenomenon observed in AD patients and animal models. In the current study, we investigated whether restored EAAT2 protein and function could benefit cognitive functions and pathology in APPSw,Ind mice, an animal model of AD. A transgenic mouse approach via crossing EAAT2 transgenic mice with APPSw,Ind. mice (e.g., see Panel C), and a pharmacological approach using a novel EAAT2 translational activator, LDN/OSU-0212320 (e.g., see Panel B), were conducted. Findings from both approaches demonstrated that restored EAAT2 protein function significantly improved cognitive functions, restored synaptic integrity, and reduced amyloid plaques. Importantly, the observed benefits were sustained one month following compound treatment cessation, suggesting that EAAT2 is a potential disease modifier with therapeutic potential for AD.

Carmela Abraham celebrates launching Klogene Therapeutics with a virgin organic margarita. Kevin and Menachem Abraham go more traditional.

Our collaborator, Professor Carmela Abraham launches Klogene Therapeutics. Klogene is a start-up company developing novel treatments for neurodegenerative diseases. Its first target is Alzheimer's disease (AD). The company's drug development platform is based on small molecule compounds that enhance the expression of the Klotho gene. 

The Klotho enhancing compounds were discovered in a collaboration between Carmela Abraham at Boston University School of Medicine (BUSM) and the LDDN at BWH. Klogene's initial drug discovery platform is based on an exclusive license of the BUSM/BWH intellectual property.

see: www.klogene.com


Focused on central nervous system (CNS) drug discovery efforts, this book educates drug researchers about the blood-brain barrier (BBB) so they can affect important improvements in one of the most significant – and most challenging – areas of drug discovery.


  • Written by world experts to provide practical solutions to increase brain penetration or minimize CNS side-effects

  • Reviews state-of-the-art in silico, in vitro, and in vivo tools to assess brain penetration and advanced CNS drug delivery strategies

  • Covers BBB physiology, medicinal chemistry design principles, free drug hypothesis for the BBB, and transport mechanisms including passive diffusion, uptake/efflux transporters, and receptor-mediated processes

  • Highlights the advances in modelling BBB pharmacokinetics and dynamics relationships (PK/PD) and physiologically-based pharmacokinetics (PBPK)

  • Discusses case studies of successful CNS and non-CNS drugs, lessons learned and paths to the market


Blood-Brain Barrier in Drug Discovery: Optimizing Brain Exposure of CNS Drugs and Minimizing Brain Side Effects. Edited by Kerns and Li ​Published by Wiley and includes our contribution:


Chapter 19  Case studies of CNS Drug Optimization - Medicinal Chemistry and CNS Biology Perspectives. ​By Kevin J. Hodgetts

2015 Heighlights

Focused on central nervous system (CNS) drug discovery efforts, this book educates drug researchers about the blood-brain barrier (BBB) so they can affect important improvements in one of the most significant – and most challenging – areas of drug discovery.


• Written by world experts to provide practical solutions to increase brain penetration or minimize CNS side-effects


• Reviews state-of-the-art in silico, in vitro, and in vivo tools to assess brain penetration and advanced CNS drug delivery strategies


• Covers BBB physiology, medicinal chemistry design principles, free drug hypothesis for the BBB, and transport mechanisms including passive diffusion, uptake/efflux transporters, and receptor-mediated processes


• Highlights the advances in modelling BBB pharmacokinetics and dynamics relationships (PK/PD) and physiologically-based pharmacokinetics (PBPK)


• Discusses case studies of successful CNS and non-CNS drugs, lessons learned and paths to the market

- February 2015


Blood-Brain Barrier in Drug Discovery: Optimizing Brain Exposure of CNS Drugs and Minimizing Brain Side Effects. Edited by Kerns and Li ​Published by Wiley and includes our contribution:


Chapter 19  Case studies of CNS Drug Optimization - Medicinal Chemistry and CNS Biology Perspectives. By Kevin J. Hodgetts

March 2015 Publication of Prof. Glenn Lin's paper:

The Journal of Experimental Medicine 2015, 212:319-332


"Restored Glial Glutamate Transporter EAAT2 Function as a Potential Therapeutic Approach for Alzheimer's Disease

Kou Takahashi,Qiongman Kong, Yuchen Lin,Nathan Stouffer,Delanie A. Schulte, Liching Lai, Qibing Liu, Ling-Chu Chang, Sky Dominguez, Xuechao Xing, Gregory D. Cuny,  Kevin J. Hodgetts, Marcie A. Glicksman,and Chien-Liang Glenn Lin

Abstract  Glutamatergic systems play a critical role in cognitive functions and are known to be defective in Alzheimer’s Disease (AD) patients. Previous literature has indicated that glial glutamate transporter EAAT2 plays an essential role in cognitive functions, and that loss of EAAT2 protein is a common phenomenon observed in AD patients and animal models. In the current study, we investigated whether restored EAAT2 protein and function could benefit cognitive functions and pathology in APPSw,Ind mice, an animal model of AD. A transgenic mouse approach via crossing EAAT2 transgenic mice with APPSw,Ind. mice, and a pharmacological approach using a novel EAAT2 translational activator, LDN/OSU-0212320, were conducted. Findings from both approaches demonstrated that restored EAAT2 protein function significantly improved cognitive functions, restored synaptic integrity, and reduced amyloid plaques. Importantly, the observed benefits were sustained one month following compound treatment cessation, suggesting that EAAT2 is a potential disease modifier with therapeutic potential for AD.

April 2015 Our R21 grant to discover small molecules to treat Spinal Muscular Atrophy is awarded.

Optimization of a novel series of thiazolopyridines for the treatment of SMA with Professors Elliot Androphy at Indiana University and Christian Lorson at Missouri University. ​

Elliot's group originally characterized the mechanism of alternative splicing of the SMN2 gene, which leads to skipping of exon 7 and failure to protect from motor neuron loss found in spinal muscular atrophy (SMA). We identified compounds that increase levels of the SMN protein that is deficient in SMA and optimization has led to the discovery of compounds with excellent brain penetration following oral dosing.

We believe that compounds that emerge from the stringent in vitro and in vivo evaluation we are proposing will be of suitable quality for final pre-clinical evaluation and advancement into clinical studies to treat SMA.

May 2015

News

2015