Children's Medical Center Corporation

Massachusetts Institute of Technology

Leland Stanford Junior University

Harvard College

Duke University

Zhigang He

Vuk Koprivica

Kevin C Wang

Jieun A Kim

Kevin Park

Fang Sun

Yang Hu

Kai Liu

Duo Jin

Jing Wang

Liqun Luo

Qiwei Zhai

Ryan Watts

Eric Hoopfer

Rajeev Sivasankaran

Fan Wang

Guoping Feng

Joshua Sanes

Thomas L Schwarz

Xin Duan

Cartoni Romain

Mu Qiao

Fengfeng Bei

Yuanyuan Liu

Boaz Barak

The present disclosure relates to compositions and methods for treating Williams syndrome (WS), herein identified as a neurodevelopmental oligodendrocyte hypomyelination-associated disease, and to compositions and methods for treatment of other neurodevelopmental myelination abnormality diseases or disorders.

Compositions and methods for Williams Syndrome (WS) therapy

Disclosed herein are methods for promoting neuronal outgrowth in a subject with a neuronal lesion in their CNS by administering effective amounts of a pro-regenerative OPN fragment, optionally with IGF1 and/or BDNF. A voltage gated potassium channel blocker can also be administered. Pharmaceutical compositions, devices for administration, and kits are also disclosed.

Methods of promoting corticospinal neuronal outgrowth in neuronal lesions using a pro-regenerative human osteopontin fragment

Disclosed are compositions and methods for promoting survival of or axon regeneration in neurons by increasing mitochondrial motility in the neuron. Also disclosed are methods to treat neuronal injury and disease and disorders characterized by neuronal injury. Agents that increase Armcx1 activity, such as Armcx1 polypeptide or vectors comprising nucleic acid encoding Armcx1 polypeptide, are proposed for use in the methods. Pharmaceutical composition comprising the agents, and methods for identifying additional agents are also disclosed.

Neuronal survival and axonal regeneration through increasing mitochondrial motility

Disclosed herein is a method of promoting sustained survival, sustained regeneration, in a lesioned mature neuron, sustained compensatory outgrowth in a neuron, or combinations thereof. The method comprises contacting the lesioned mature neuron with an effective amount of an inhibitor of PTEN and an effective amount of an inhibitor of SOCS3 to thereby promote survival and/or regeneration and/or compensatory outgrowth of the neuron. Therapeutic methods of treatment of a subject with a neuronal lesion by administration of a therapeutically effective amount of an inhibitor of PTEN and a therapeutically effective amount of an inhibitor of SOCS3, are also disclosed, as are pharmaceutical compositions and devices for use in the methods.

Co-activation of mTOR and STAT3 pathways to promote neuronal survival and regeneration

Survival of, or axon regeneration in a lesioned mature central nervous system (CNS) neuron is promoted by (a) contacting the neuron with a therapeutically effective amount of an exogenous activator of protein translation; and (b) detecting the resultant promotion of the survival of, or axon regeneration in the neuron.

Promoting axon regeneration in the adult CNS through control of protein translation

Compositions and methods for promoting neural regeneration in a patient determined to have a lesion in a mature CNS neuron are disclosed. The method comprises the step of contacting the neuron with an EGFR inhibitor sufficient to promote regeneration of the neuron.

EGFR inhibitors promote axon regeneration

Inhibitors of Nogo Receptor (NgR)-p75 binding are used to reduce NgR-p75 binding mediated axon growth inhibition. Mixtures of NgR and p75 are used in pharmaceutical screens to characterize agents as inhibiting binding of NgR to p75 and promoting axon regeneration.

Methods of determining binding between Nogo receptor and p75 neurotrophin receptor

Oligodendrocyte-myelin glycoprotein (OMgp)-specific binding agents are used to reduce OMgp-mediated axon growth inhibition. Mixtures of axons and OMgp and mixtures of Nogo receptor (NgR) and OMgp are used in pharmaceutical screens to characterize agents as inhibiting binding of NgR to OMgp and promoting axon regeneration.

Reducing myelin-mediated inhibition of axon regeneration

Reducing NgR-p75 mediated inhibition of axon regeneration

Regeneration of a lesioned CNS axon of a mature neuron, determined to be subject to regeneration inhibition by Smad2/3 signaling, is promoted by contacting the neuron with an inhibitor of Smad2/3 signaling sufficient to promote regeneration of the axon.

Inhibiting Smad2/3 signaling promotes neurite outgrowth in dorsal root ganglia

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Wellesley, MA, United States of America

Zhigang He