Eludicating the role of marrow-resident myeloid cells in FOP

Awardee: Shailesh Agarwal

Institution: Brigham and Women's Hospital, Harvard University

Award Amount: $40,208

Attention-deficit and hyperactivity links to the brain connectivity of MPS I subjects: multimodal MRI study

Awardee: Igor Nestrasil

Institution: University of Minnesota

Award Amount: $61,589

DEVELOPMENT OF A CHEMOKINE TARGETED THERAPY FOR INCLUSION BODY MYOSITIS

Awardee: Steven Greenberg

Institution: Brigham and Women's Hospital

Award Amount: $102,430

Defining the cellular site of action of the Glut1 protein in Glucose Transporter 1 deficiency syndrome.

Awardee: Umrao Monani

Institution: Columbia University

Award Amount: $46,858

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Final Report Summary:

Glut1 DS is a debilitating pediatric brain disorder for which there are limited treatment options.  An important aspect of our work is to explore Glut1 repletion as a means to new treatments for Glut1 DS.  We previously showed that repletion is indeed effective in treating a Glut1 DS mouse model.  Translating these findings into a treatment for the human patient requires defining precisely which cells one must target in repletion therapies.  We hypothesized that brain endothelial cells are one such cell-type.  Our results from this MDBR project suggest that this is indeed the case.  Using a mouse model of Glut1 DS we have shown that introducing a Glut1 mutation specifically in brain endothelial cells triggers all of the major disease characteristics of Glut1 DS.  Moreover, our study reveals a specific type of brain endothelial cell – the tip cell – as being especially vulnerable to Glut1 mutations.  Tip cells are important in enabling the cerebral capillaries to proliferate and develop during the early postnatal period of life.  Reduced Glut1 within them prevents them from proliferating and giving rise to new blood vessels. This effect likely explains the inability of the Glut1 DS brain to extract adequate energy (glucose) from the blood circulation to sustain the nutritional needs of brain neurons.  This, in turn, provides one plausible basis for the neurodevelopmental delay and cognitive dysfunction in Glut1 DS. 

Our study has also confirmed a previous notion of the temporal requirements for Glut1.  The transporter is especially critical in the young postnatal brain when blood capillaries proliferate and neuronal circuits are established. Once the full complement of cerebral blood vessels and neuronal circuits are established, the requirements for Glut1 wane.  These results have important implications for future therapies and imply that treatments may not have to be chronic.  Finally, our investigation has revealed an important mediator of low Glut1 in the brain.  The mediator, a neurotrophic factor that is known to be important for neuronal health and survival, is greatly reduced in the Glut1 DS brain.  Restoring this factor may therefore constitute a novel or adjunct means of treating Glut1 DS in the future. 

Targeting mitochondrial oxidative metabolism in LAM using a first-in-class lipoate analog

Awardee: Carmen Priolo

Institution: Brigham and Women's Hospital, Harvard Medical School

Award Amount: $72,704

Engineered microvessels derived from human lymphatic endothelium as an in vitro model for drug repurposing for lymphatic malformations

Awardee: Julie Blatt

Institution: UNC Chapel Hill

Award Amount: $62,861

A Prospective Natural History Study of Mucolipidosis type 4

Awardee: Albert Misko

Institution: Massachusetts General Hospital

Award Amount: $78,538

A comparative and quantitative approach to study lysosomal dysfunction in Mucopolysaccharidoses diseases

Awardee: Andrea Ballabio

Institution: Fondazione Telethon, TIGEM

Awarded Amount: $64,063

Can we improve neurologic and psychiatric outcomes in MSUD? Studies in a new mouse model

Awardee: Rebecca Ahrens-Nicklas

Institution: The Children's Hospital of Philadelphia / The University of Pennsylvania

Award Amount: $44,037

Development of novel human stem cell models of Beta-Propeller Protein- Associated Neurodegeneration (BPAN) for disease modelling and drug screening

Awardee: Paul Lockhart

Institution: Murdoch Children's Research Institute

Award Amount: $61,245

Pre-clinical animal model and cell evaluation of candidate therapies for human NUBPL disease.

Awardee: Marni Falk

Institution: Children's Hospital of Philadelphia and University of Pennsylvania

Award Amount: $61,134

Genetic Mechanisms in Neuroendocrine cell Hyperplasia of Infancy (NEHI)

Awardee: Lisa Young

Institution: The Children's Hospital of Philadelphia

Award Amount: $60,989

Tissue-specific and temporal reinstatement of Tcf4 to treat Pitt-Hopkins Syndrome

Awardee: Andrew Kennedy

Institution: Bates College

Award Amount: $68,709

SETBP1 deficiency syndrome as an AKT modifer in human neurons

Awardee: Carl Ernst

Institution: McGill Uniersity (Douglas Hospital Research Institute)

Award Amount: $67,943

Dimethylspermine (Me2Spm) as a novel treatment approach to restore normal spermidine/spermine ratios in Snyder-Robinson Syndrome (SRS) models

Awardee: Robert A. Casero, Jr

Institution: Johns Hopkins School of Medicine

Grant Amount: $69,318

Phenylbutyrate for STXBP1 Encephalopathy – A Pilot Study

Awardee: Zachary Grinspan

Institution: Weill Cornell Medicine

Grant Amount: $69,588

Towards new therapeutic treatments for the hyperinsulinism/hyperammonemia syndrome (HI/HA)

Awardee: Thomas Smith

Institution: University of Texas Medical Branch

Grant Amount: $72,014

Testing the efficacy of new pharmaceutical candidates for APBD

Awardee: Or Kakhlon

Institution: Research Fund of the Hadassah Medical Organization

Award Amount: $52,509

Gene Therapy for Adult Polyglucosan Body Disease (APBD)

Awardee: Baodong Sun

Institution: Duke University

Award Amount: $51,209

Pericyte contractility in CADASIL

Awardee: Fabrice Dabertrand

Institution: University of Colorado Denver Anschutz Medical Campus

Award Amount: $81,951