The Sheffield NIHR Biomedical Research Centre

Translational Neuroscience for Chronic Neurological Disorders

Professor Dame Pam Shaw

NIHR Senior InvestigatorProfessor of Neurology, Vice President & Pro-Vice Chancellor

for Medicine, Dentistry and Health, University of Sheffield

Consultant Neurologist, Sheffield Teaching Hospitals NHS Foundation Trust

The University of Sheffield

Sheffield

BRC

Sheffield Teaching Hospitals

“To translate lab-based discoveries into new cutting edge treatments, technologies, diagnostics and other interventions for patients with

neurological conditions”

BRC Mission:

Target Identification Drug screening Optimization Pre Clinical

Studies Phase 1: Safety Phase 2: Efficacy Safety

Phase 3: Efficacy Safety

Collaborating together as one Biomedical Research Centre

Structure of the BRC:

DirectorPam Shaw

Deputy Director Chris McDermott

Neuro & Cross cutting theme

leads

Junior AcademyClinical Fellows &

PhD students

BRC Manager Jodie Keyworth

Comms & PPI/E Lead

Laura Evans

Clinical Trial Manager

Sarah Moll

Data Coordinator Sarah Birchell

AdministratorTBA

BRC Nursing teamAlex Radford, Grace

Cole, TBA

BRC Executive

BRC Operational

Group

Data Manager TBA

Cross cutting theme rolesLorenza Angelini

Mark Dunning & Dennis Wang

Adriana Anton

Info sharing

Reports to

Training LeadOliver Bandmann

Sheffield Translational Neuroscience: Key Research Strengths

Biom

edic

al S

cien

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Rese

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Hea

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Scie

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CEREBRO-VASCULAR

In silico Medicine (INSIGNEO)

Genomics and Bioinformatics

Advanced Medical Imaging

Technologies for health and well being

SCHOOL OF HEALTH AND RELATED RESEARCH (ScHARR)HEALTH SERVICES RESEARCH, CLINICAL TRIALS SUPPORT, HEALTH ECONOMICS, OUTCOME

MEASUREMENT, DECISION SCIENCE, STATISTICS, PUBLIC HEALTH, EPIDEMIOLOGY

NIHR Clinical Research Facility

- Motor neuron disease- Parkinson’s disease- Dementia and brain

ageing

- Multiple sclerosis- Auto-immune CNS

disorders- Ataxia

- Acute therapies- Prevention- Rehabilitation

NEURO-DEGENERATION

NEURO-INFLAMMATION

Relevance of the Sheffield Translational Neuroscience Portfolio

• Cerebrovasular disease –stroke is a leading cause of death and adult disability.

• The top 3 neurodegenerative disorders: Increasing in prevalence with increasing age and changing demographics. 1 in 4 adults who live to > 80 years will develop a neurodegenerative disorder.

Alzheimer’s disease Parkinson’s disease Motor neuron disease

• Neuro-inflammation –multiple sclerosis is the commonest cause of disability in young adults in the UK

Overarching aims for Neurology research

CEREBRO-VASCULAR

- Motor neuron disease- Parkinson’s disease- Dementia and brain

ageing

- Multiple sclerosis- Auto-immune CNS

disorders- Ataxia

- Acute therapies- Prevention- Rehabilitation

NEURO-DEGENERATION

NEURO-INFLAMMATION

• Establish standardised ways of observing patient symptoms and their underlying biology

• Identify biomarkers for progression and response to treatment

• Categorise patients with similar biological characteristics into groups so they can receive tailored treatments and therapies

• Use all this information to develop new drugs and treatments

Cerebrovascular Disease

Arshad Majid

Stroke rehabilitation studies

Remote ischemic conditioning

In post-stroke fatigueBRC PhD project

Effect on cerebral perfusion and MR spectroscopy

Transcutaneous Vagal Nerve stimulation

Developing protocol for testing tVNSfor MS related fatigue and recovery of upper limb function

Target Identification

In vitro assay design and screening

In vivooptimistation/Hit

-to-lead

Pre-clinical screening/LO

Proof of concept in Man

• Preclinical pharmacology• Pharmacodynamic readouts• MND zebrafish models• SOD1G93A and TDP-43 mouse models• Mechanisms of action biomarkers• Hit to lead (collaboration or

outsourced)

• Gene Therapy• Preclinical Pharmacology• SOD1G93A mouse model• TDP-43 mouse model• SMA mouse model• Optimised/Novel readouts• MRI imaging• Behavioural Analysis• Neuropathology

• Clinical Neuroscience• Clinical Trials• DENDRON• Design of new outcome measures• MRI Imaging

• Viral vector production• Known drug libraries• Focussed drug libraries

(eg MRCT ~14,000)• MND patient fibroblasts• iAstrocyte and iNeuron technology• Cellular models SOD1, C9orf72,

TDP43

• Genomics/Candidate Gene Screening• Transcriptomics• RNASeq• Microarray• Protein Biochemistry• RNA Biochemistry• Neuropathology• Cell biology

SITr

aNEx

perti

seEx

ampl

es o

f Pro

ject

sSt

age

SMN replacement gene therapy for SMA

KEAP1 inhibitors for PD/MND

AZD1236 a MMP-9/12 inhibitor for stroke

Small molecule Nrf2 activator for MND

SOD1 silencing gene therapy for MND

UDCA for PD

Kinase inhibitor

SRSF2 gene therapy for MND

iAstrocyte and iNeuron Phenotypic assays (PD/AD/MND)

mGlu5 antagonist for MND

Aclipse One

Therapeutic Pipeline for Translation

MOTOR NEURON DISEASE STUDIES IN THE BRC

• Experimental medicine Phase 1 /Phase 2 clinical trials.

• Biosample collection and biomarker studies.

• Assistive devices and improvements in symptomatic management.

Gene therapy for SMA and MND

1) AAV-Mediated SMN ReplacementSMA Clinical Development

Proof-of-concept in SMN 7 mouse modelJCI | 114 | 1726 | 2004Sci Trans Med | 2 | 2010

ᐃ

Dosing in SMNᐃ7 mouse model

GLP Tox & Biodistribution studies

Dossier submission for regulatory approval

Briefing document to MHRA

ODD secured from EMA

Nature | 429 | 2004Nature Medicine | 11(4) | 429-3 | 2005

Muscle delivery

Vector particle with rabies-G envelope

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100 150 200 250

Age (days)

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2) SOD1 Silencing-Familial ALS

Delivery to cisterna magna

• MHRA Briefing and Scientific meeting 26 May 2017• Collaboration with Avexis: Clinical Development• Early discovery encouraged development of Biogen ASO

approach currently in clinical trials in fALS

3) Pre-clinical Gene Therapeutics• Gene editing strategy to excise

C9ORF72 expansion

• Gene-based strategies to reduce DNA damage in ALS and SMA

• Gene therapeutics for HSP (SPG15, SPG47)

UK Biogen ALS/MND Innovation Hub MND gene therapy studies

• Antisense Oligonucleotide

• Double blind placebo-controlled SOD1 trial completing

• SOD1 open label extension

• C9ORF72 ascending dose

AMBROSIA: Longitudinal biosamplecollection

• First 42 patients recruited in Sheffield

• Five year project with Oxford and UCL

• Robust biomarkers will objectively track response to new treatments

A Multi-centre Biomarker Resource Strategy in ALS

Genetically Subtyped

Blood markers

Urinary Analysis

CSF markers

Clinical Observations

Measured over-time

• First large systematic observational study over-time of MND

• Template for standardised biosample collection for other diseases

NRF2-ARE Pathway as a Therapeutic Target for MND and PD

CoEN Centres of Excellence for Neurodegeneration

Hit compound developmentWith industrial partners

Orphan Drug Designation Gene expression profiling in cellular models

Nrf2 activation improved parameters in ALS mice

Aclipse One 0

50

100

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Relat

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ll sur

vival

(% ba

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Control Nrf2 Activator

Muscle Imaging Biomarkers Patients

Controls

L leg L hand

R arm

Both legs

Bulbar L leg L hand

L hand Both legs

R leg

R leg

Bulbar

L arm

R hand

R arm

L leg

R leg

b1000 maps shown

Site of onset

Neck muscle weakness

Neck Muscle Weakness - a common and uncomfortable problem

16

Tackling Neck Muscle weakness

• Head weighs ~ 5kg

• Existing support devices either immobilise the neck or provide insufficient support

17

Head Up Project• User group sessions identified current problems and

importantly what is actually required by patients:

• Support allows movement• Adaption to patients needs

• Customise to each patient• Customise over time

• Artificial support should replace type of support originally provided by weakened muscles

• Collaboration between Neurologists, MDT team (nurses & physiotherapists) Patients, Carers, Bioengineers, Materials Scientists, Fashion Designers, Commercial companies

18

S Baxter et al ALS & FTD 2016A Pancani et al Clin Biomech 2016 CI Prof Chris

McDermott

New Devices for Improved Symptom Management in MND: Engineering Meets Neuroscience

Industrial Partnerships

Impact of Neurology-Engineering collaboration

New device “Head up” collar commercially available April 2018

SS model

Outcomes

Single muscle properties

Non-invasive quantification of functional loss

Neck Assessment Tool

20

New NOCRI case study

HeadUp Collar

50 sold in first week

Dementia

Matteo De Marco Annalena Venneri

The volume of the ventral tegmental area (VTA) as a pre-symptomatic indicator of Alzheimer’s disease• First study to have

commenced and completed at the Sheffield BRC

• Loss of dopaminergic activity in the VTA could be an early indicator of AD

• And potential therapeutic target

April 2018 Journal of Alzheimer’s Disease

Identification of UDCA as promising mitochondrial rescue drug in Parkinson’s disease

Mitochondrial dysfunction in both PD brains and

fibroblasts of genetically stratified PD

2000 compounds screened for

mitochondrial rescue effect

Ursodeoxycholic acid (UDCA) identified

as potent mitochondrial rescue compound

Rescue effect of UDCA confirmed in i-neurons and

drosophila

Proof of concept clinical trial

Validation

UDCA effect to be assessed using

31PMRS and clinical scores

Fibroblasts established as new model

for PD drug screens

H Mortiboys/O Bandmann

Parkinson’s disease

• Randomized, double-blind, placebo-controlled clinical trial

• Two centres (Sheffield and UCL)

• 30 patients (20 on UDCA, 10 on placebo)

• Patients will be on trial medication for 1 yr

• Primary outcome: Safety and tolerability

• Secondary outcome: Clinical progression/motor rating scales

• Novel study design aspects:• Enrichment for fast progressors• 31P MRS – quantification of ATP in

patients’ brains• Objective quantification of motor activity

Phase II - Proof of concept study for UDCA in PD

ATP quantification using 31P-MRS

Biosensor-based quantification of motor impairment

Drug response Correlated to Genotype

Novel aspects supported by BRC cross-cutting themes

Multiple Sclerosis collaboration

Non-myeloablative autologous haematopoietic stem cell transplant (AHSCT) to “reset” the immune system in

aggressive relapsing-remitting multiple sclerosis (MS)

• JAMA cohort - Over a 4 year follow-up period –80% of patients relapse free and 87% free of disability progression

• Reached an international audience of 180 million

• MIST – The first randomized phase III trial of AHSCT in highly active MS

MIST interim results announced

Basil Sharrack

NIHR Efficacy and Mechanism Evaluation (EME) Programme

Cross-cutting themes

CEREBRO-VASCULAR

In silico Medicine (INSIGNEO)

Genomics and Bioinformatics

Advanced Medical Imaging

NIHR Clinical Research Facility

- Motor neuron disease- Parkinson’s disease- Dementia and brain

ageing

- Multiple sclerosis- Auto-immune CNS

disorders- Ataxia

- Acute therapies- Prevention- Rehabilitation

NEURO-DEGENERATION

NEURO-INFLAMMATION

In Silico medicine as a cross-cutting theme

Develop biomarkers for progression in movement disorders

• Gait Analysis• Muscle Strength Assessment• Remote activity monitoring with wearable sensors

Integrate movement and imaging data

Test predictive patient models for in silico augmentedClinical Tests against experimental medicine results

Aims:Short Term

Medium Term

Longer Term

Gait Analysis

• Optogait 5m system (Microgate Corp., Italy)

Detects footfall withspatiotemporal sensitivity

of 1000Hz and 1cm

Dr Alisdair McNeillEllen Buckley

• OPALS triaxial inertial sensors (APDM Inc. USA)

Measures sway (upper body motion) during walking

INSIGNEO team developed MatLabscripts to analyse data from these

sensors

Developing Gait Biomarkers144±16cm

Healthy Control

12±3cm72 ± 8cm

Ataxia

119±20cm**

60±10cm**

17 ± 5cm**

CEREBELLAR ATAXIA

• Shorter and wider gait

• Truncal instability differentiates pre-symptomatic from clinically manifest

Stratifying patient risk for Parkinson’s disease with clinical, gait and transcriptomic biomarkers in

DiGeorge syndrome

Data 1

SITSIT-

C0

10

20

30

40

50

*

DiGeorge syndrome (Prevalence 1/2500) carries 20 fold increased risk for Parkinson’s disease

Gait Impairment• Reduced speed• Reduced cadence• Increased single limb support

time

Deletion at chromosome 22q11.2 Differential Blood Transcriptomics

Dr Alisdair McNeill

Ellen Buckley

Hyposmia

Biomechanics Clinical Lab

Lorenza Angelini Claudia Mazza

Isokinetic dynamometer to measure joint forces and torques in different neurological conditions

Distinctive Contribution: Advanced Medical Imaging

• £7.5m MRC award for RF hardware design and manufacture

• 1st demonstration of hyperpolarised Xe transfer to human brain

• 1st clinical MRI studies using hyperpolarized gas in the UK• 1st clinical-use 3T Philips MR

in UK (2003)• Neuroimaging – Inegenia 3T

Academic Radiology & NeuroImaging: Hospital-based, Integrated-multidisciplinary team with proven translation & academic output

Multi-modal MR → biomarker paradigm shift

Volmetry

DTI / Tractography

Resting-ShefMRI

Spectroscopy (1H, 31P)

Task-ShefMRI

PerfusionPre-stent

Post-stent

PET-MRI IMAGING FACILITY: The Future of Imaging

7 PET-MRI scanners currently in the UK

~80 worldwide

DPUK

Great potential for :

-Motor Neuron Disease-Alzheimer’s Disease-Parkinson’s Disease-Stroke-Oncology-Diabetes

Participation in advanced clinical trials and the provision of a regional service

Sheffield can lead developments in PET-MRI

PET-MRI IMAGING FACILITY• PET-MR imaging and cyclotron - £10m from UoS and space allocated by STH

Trust.

The Power of PeopleFundraising

Estates

ScientificExpertise

Clinical Departments

Procurement and BusinessServices

Top down support

PET-MRI IMAGING FACILITY: PROGRESS TO DATE

C floor Radiology Site identified for self-contained PET-MR facility:

Access road (former A&E entrance)

Royal Hallamshire Hospital

Prof Karl Herholz

Facility to house both:

• Clinical PET-MRI

• Future-proofed for onsite Cyclotron and GMP-facilities for radiotracer development

www.sheffieldbrc.nihr.ac.uk

@sheffieldBRC