Awarded Grants

Awarded Grants

MDBR, CHM Million Dollar Bike Ride MDBR, CHM Million Dollar Bike Ride

Pharmacological induction of autophagy to treat CHM

Ivan Conte

University of Naples Federico II

$64,990

Awardee: Ivan Conte

Institution: University of Naples Federico II

Award Amount: $64,990

Funding Period: February 1, 2021 - January 31, 2022

Final Report Lay Summary:

The main goal of this project was to characterize at fine scale the contribution of molecular network regulating the autophagy pathway in the Retinal Pigment Epithelial ce ls. We demonstrated that impairment of ce l clearance in the RPE may affect visual system in the Choroideremia. Interestingly, we put the basis for developing a new therapeutic strategy to treat CHM, which stil represents a cha lenge, Remarkably, the therapy described herein was safe and wel tolerated showing no adverse effects associated with pharmacological treatment up to 3 months of treatment, the longest time for which the drug was tested on CHM mice. Lately, in vitro studies using hiPSC-derived RPE ce l sheet give us the opportunity to move forward with regulatory studies prerequisite to clinical trials for choroideremia patients.

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MDBR, CHI Million Dollar Bike Ride MDBR, CHI Million Dollar Bike Ride

Maximising the Utilisation of the Hyperinsulinism Global Registry (HIGR) [Max HIGR]

Indraneel Banerjee

University of Manchester, Royal Manchester Children's Hospital

$73,190

Awardee: Indraneel Banerjee

Institution: University of Manchester, Royal Manchester Children's Hospital

Award Amount: $73,190

Funding Period: February 1, 2021 - January 31, 2022

Summary:

The HI Global Registry (HIGR) is a unique rare disease patient registry developed by Congenital Hyperinsulinism International. This international online registry that gathers important information on different types and treatments for low sugars due to hyperinsulinism. The completion of HIGR relies on parents and families uploading their child's required details. Our proposed study "Maximizing the Utility of HIGR" (MaxHIGR) aims to build on the opportunity to add medical grade information to existing parent reported HIGR information, thereby joining up clinical and parent perspectives in the search towards better understanding and improved treatment for HI. MaxHIGR will lay the basis for HIGR to evolve into a registry that will tell us about the natural history of disease, which treatments are better and have less side effects and how we can improve the quality of life of children and families living with HI.

Final Report Summary:

MaxHIGR has brought international co laborators to agree on a common data colection to replicate natural history of Congenital Hyperinsulinism. MaxHIGR required close co laboration across time zones around the world, while adapting to a a common set of rules for data entry. The form is now currently being integrated into an online tool for use in a pilot study. This study has been delayed to accommodate in person patient-clinician consultations that had been set back due to the pandemic.

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MDBR, CADASIL Million Dollar Bike Ride MDBR, CADASIL Million Dollar Bike Ride

HB-EGF/EGFR signaling in capillary dysfunction in CADASIL

Masayo Koide

University of Vermont Larner College of Medicine

$82,795

Awardee: Masayo Koide

Institution: University of Vermont Larner College of Medicine

Award Amount: $82,795

Funding Period: February 1, 2021 - January 31, 2022

Summary:

CADASIL, short for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarct and Leukoencephalopathy, is the most common genetic cause of a pathology known as small vessel disease (SVD) of the brain. During SVDs such as CADASIL, the structure and function of small blood vessels (arteries, arterioles, venules, and capillaries) within the brain become compromised. An early result of this vascular dysfunction is a decrease in blood flow to the brain (cerebral blood flow or CBF), which eventually leads to dementia and/or strokes. This study will elucidate the molecular mechanisms of compromised CBF increases in response to neural activity (“functional hyperemia”) using a clinically relevant CADASIL mouse model. We will specifically focus on examining the impact of CADASIL on capillaries, the smallest and most abundant vessels in the brain, which we have previously shown to be the molecular cornerstone in functional hyperemia responses in healthy animals. Considering that it is known that CADASIL causes an abnormal accumulation of specific proteins around the outside of small vessels in the brain, we propose to examine how two of these proteins, epidermal growth factor receptor (EGFR) and heparin-binding EGF-like growth factor (HB-EGF), contribute to capillary dysfunction in CADASIL. This project, by providing a greater understanding of the cellular pathways contributing to CADASIL pathologies, will create a firm footing for future therapeutic development.

Publications:

PIP2 corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.1 activity

Final Report Lay Summary:

CADASIL, short for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarct and Leukoencephalopathy, is the most common genetic cause of a pathology known as smal vessel disease (SVD) of the brain. During SVDs such as CADASIL, the structure and function of smal blood vessels (arteries, arterioles, venules, and capilaries) within the brain become compromised. An early result of this vascular dysfunction is a decrease in blood flow to the brain (cerebral blood flow or CBF), which eventua ly leads to dementia and/or strokes. This study examined the molecular mechanisms of compromised CBF increases in response to neural activity (“functional hyperemia”) using a clinica ly relevant CADASIL mouse model. We specifica ly focused on examining the impact of CADASIL on capilaries, the sma lest and most abundant vessels in the brain, which we have previously shown to be the molecular cornerstone in functional hyperemia responses in healthy animals. Considering that it is known that CADASIL causes an abnormal accumulation of specific proteins around the outside of sma l vessels in the brain, we examined how two of these proteins, epidermal growth factor receptor (EGFR) and heparin-binding EGF-like growth factor (HBEGF), contribute to capilary dysfunction in CADASIL. State-of-art techniques, including laser Doppler flowmetry, patch-clamp electrophysiology, two-photon microscopy and a newly developed capilary-arteriole continuum preparation were used to examine the role of capilary EGFR signaling in causing cerebral blood flow deficits in CADASIL model mice. Notably, we found that CADASIL-induced functional hyperemia deficits were caused by insufficient phosphatidylinositol 4,5-bisphosphate (PIP2), an endogenous activator of Kir2.1 potassium channels in capilary EC membranes. Furthermore, our data demonstrates that PIP2 content in capilary EC membranes can be modified by HB-EGF/EGFR signaling. In fact, the application of PIP2 or stimulation of EGFR restored capilary Kir2.1 channel activity and functional hyperemia in CADASIL mice. These results support the concept that HB-EGF/EGFR signaling modulates PIP2 content in capilary EC membrane, EC Kir2.1 channel activity, and functional hyperemia. In summary, we demonstrated a novel mechanism underlying functional hyperemia deficits in CADASIL. Our findings suggest that capilary HB-EGF/EGFR signaling and exogenous PIP2 administration may have potential as therapeutic targets as CADASIL treatments. This project, supported by the 2021 Milion Do lar Bike Ride Pilot Grant program, provides a wealth of new information to deepen our understanding of the pathologies involved in CADASIL and other smal vessel diseases of the brain and creates a foundation for future therapeutic studies.

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MDBR, AT Million Dollar Bike Ride MDBR, AT Million Dollar Bike Ride

Development of at-home speech and wearable sensor biomarkers for ataxia-telangiectasia

Annopum Gupta

Massachusetts General Hospital and Harvard Medical School

$129,898

Awardee: Anoopum Gupta

Institution: Massachusetts General Hospital and Harvard Medical School

Award Amount: $129,898

Funding Period: February 1, 2021 - January 31, 2022

Final Report Lay Summary:

Promising disease-modifying therapies are being developed for ataxia-telangiectasia and other pediatric neurological diseases, but current assessment tools are very insensitive at determining efficacy, resulting in large and expensive trials. This project aimed to develop precise motor outcome measures, using inexpensive and widely accessible digital technologies, that can sensitively determine if a therapy is effective in children of a l ages. We co lected continuous wrist accelerometer data from 31 individuals with ataxiatelangiectasia and 27 controls aged 2-20 years old. Longitudinal wrist sensor data were colected in 14 ataxia-telangiectasia participants and 13 controls. A novel algorithm was developed to extract wrist movement patterns the accelerometer data. Wrist sensor features were compared with caregiver-reported motor function and ataxia severity on neurologist-performed ataxia rating scales. We found that these wrist sensor-based features show strong potential as novel disease measures for clinical trials: they demonstrate high reliability, correlate with clinician assessments of motor severity and caregiverreported motor function, and show potential to sensitively quantify disease progression. By passively measuring everyday activity, the information obtained can be more ecologica ly valid and comprehensive than task-specific measurements and is applicable in young children as we l in older, non-ambulatory individuals.

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MDBR, MPS Gene Spotlight, MPS Million Dollar Bike Ride MDBR, MPS Gene Spotlight, MPS Million Dollar Bike Ride

The “molecular tweezer” CLR01 as a new potent drug candidate to slow CNS pathology progression in MPS-I

Alessandro Fraldi

University of Naples "Federico", Dept of Translational Medicine

$65,040

Awardee: Alessandro Fraldi

Institution: University of Naples "Federico", Dept of Translational Medicine

Award Amount: $65,040

Funding Period: February 1, 2021 - January 31, 2022

Summary:

Progressive neurological deterioration characterizes both severe (Hurler) and intermediate (Hurler-Scheie) forms of MPS-I. Unfortunately, to date, there is no treatment for the CNS pathology in MPS-I patients.

Under different stress conditions, certain aggregation-prone proteins misfold and self-assemble into neurotoxic insoluble deposits called amyloids. Aggregation and deposition of amyloid proteins in the brain is a hallmark of many neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. By studying mouse models of Sanfilippo syndrome we have recently shown that deposition of amyloid proteins also occurs in the brain of these mice and is a key event contributing to the neurodegenerative processes. Furthermore, extending previous observations, we have shown that similarly to the Sanfilippo syndrome, amyloid deposition also occurs in the brain of other mouse models of MPS and, in particular, is associated to neurodegenerative processes in the brain of post-mortem patients with MPS-I.
To counteract these amyloid-mediated pathological processes, we made use of a potent and specific inhibitor of amyloid protein aggregation known as CLR01. CLR01 is a lead compound of the “molecular tweezers” class of small molecules that act by a unique mechanism to efficiently inhibit abnormal self-assembly of multiple amyloidogenic proteins. CLR01 has been shown to be effective in protecting against neurodegeneration in mouse models of Alzheimer’s and Parkinson’s diseases. Moreover, previous studies also have shown that CLR01 has a wide safety margin in mice and crosses the blood-brain barrier when administered systemically. We have shown that subcutaneous injection of CLR01 in the mouse model of MPS-IIIA, the most and severe form of Sanfilippo syndrome resulted in a striking reduction of amyloid protein deposition in the brain and correction of neuropathological phenotype, including cognitive function.

Here we want to extend the proof of efficacy of CLR01 beyond MPS-IIIA and test the hypothesis that inhibiting amyloid deposition by CLR01 is an effective therapeutic option to slow CNS manifestations in MPS-I forms with CNS involvement. Overall our results may open the possibility to develop effective CNS therapies for MPS-I based on parenteral administration of CLR01, a drug with a unique mechanism of action and with a high translational potential.

 

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MDBR, GLUT1 Million Dollar Bike Ride MDBR, GLUT1 Million Dollar Bike Ride

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

Umrao Monani

Columbia University

$46,858

Awardee: Umrao Monani

Institution: Columbia University

Award Amount: $46,858

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. 

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