SMN Replacement Therapy for Spinal Muscular Atrophy: Clinical Development

Lead Research Organisation: University of Sheffield
Department Name: Neurosciences

Abstract

SMA is due to premature death of motor neurons which are connected to muscle, and provide the stimulus to initiate muscle contraction. The disease is caused by depletion in the SMN protein levels. We recently showed that genetically modified viruses, making them safe to use in human, can be successfully used to restore the level of SMN both in cells and in a mouse model. The latest experiments showed for the first time that we can replace the SMN gene, reverse the symptoms leading to a dramatic effect on survival in the SMA mouse model. However, further in vivo studies are needed to characterise our strategy before entering clinical application in human. Our major goals are: 1) Optimise a method to produce large quantity of clinical grade vector; 2) select the appropriate dose for further safety studies in rodents; 3) Evaluate the safety and toxicity of our system. These studies represent an important and necessary step towards translation into human treatment.

Technical Summary

Spinal muscular atrophy is caused by mutations of the survival motor neuron (SMN) gene. Gene therapy aimed at restoring the SMN protein expression represents therefore a rationale therapeutic approach to ameliorate the disease phenotype. We recently showed that a gene transfer of self complementary adeno-associated virus serotype 9 expressing a codon optimised version of SMN in SMNdelta7 mice leads to complete correction of the motor deficits in these animals resulting in a substantial extension in their life span. These data provide evidence for the most efficacious therapy observed in this field to date. Our ultimate goal is to progress the SMN replacement approach to a phase I clinical trial in SMA patients. However, progress is limited by the requirement for further pivotal pre-clinical studies and vector production scaling up. The proposed pre-clinical studies will provide essential information about safety and suitability of our vector system for clinical application.
 
Description IMI workshops: Mechanisms to promote and progress advanced therapies to clinic and commercialisations
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
 
Description Impact of prenatal screening for therapy development in SMA
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description CRISPR-Cas9 gene therapy for C9ORF72 linked ALS
Amount € 149,000 (EUR)
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start 04/2017 
End 12/2018
 
Description ERC Advanced Investigator Award
Amount € 2,500,000 (EUR)
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start 03/2012 
End 02/2017
 
Description Gene therapeutics for SPG47
Amount £314,000 (GBP)
Organisation Cure SPG47, Inc 
Start 08/2017 
End 01/2020
 
Description Gene therapy for frontotemporal dementia
Amount £244,000 (GBP)
Funding ID ARUK-PG2018B-005 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2019 
End 01/2022
 
Description Gene therapy strategies for SPG15
Amount £224,000 (GBP)
Organisation The Maddi Foundation 
Start 06/2017 
End 05/2019
 
Description IMmunotolerant Programmed Autologous stem Cell Therapy for Multiple Sclerosis.
Amount £67,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 11/2019 
End 10/2020
 
Description Investigating Mechanisms and Models Predictive of Accessibility of Therapeutics (IM2PACT) Into The Brain
Amount € 9,000,000 (EUR)
Funding ID 807015 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2019 
End 12/2024
 
Description MRC DiMeN DTP PhD studentship
Amount £79,905 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2017 
End 04/2021
 
Description AAV9 vector manufacturing 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Generated proof-of-concept leading to the Award G1001492. Working towards preparing the program for clinical trials in SMA patients
Collaborator Contribution Optimisation and set up of a protocol for AAV9 vector production that can be used for GMP clinical vector production
Impact - Neuroscience - Gene therapy - Clinical development
Start Year 2012
 
Description GLP regulatory Tox studies 
Organisation Center Research Biological
PI Contribution Initiated, designed and coordinated the outsourcing of GLP regulatory tox and biodistribution studies in rodents.
Collaborator Contribution CERB: a CRO in France carried out in vivo Tox study using our gene therapeutic vector in rats. Genosafe: the second CRO (France) completed the biodistribution study. The CROs completed these regulatory studies, got the report audited and signed off under GLP status.
Impact As stated above, the Safety studies were completed and the GLP status of report was signed off. Completion of this GLP Tox studies formed the achievement of the 3rd and final milestone under my MRC DPFS award.
Start Year 2015
 
Description GLP regulatory Tox studies 
Organisation GenoSafe
PI Contribution Initiated, designed and coordinated the outsourcing of GLP regulatory tox and biodistribution studies in rodents.
Collaborator Contribution CERB: a CRO in France carried out in vivo Tox study using our gene therapeutic vector in rats. Genosafe: the second CRO (France) completed the biodistribution study. The CROs completed these regulatory studies, got the report audited and signed off under GLP status.
Impact As stated above, the Safety studies were completed and the GLP status of report was signed off. Completion of this GLP Tox studies formed the achievement of the 3rd and final milestone under my MRC DPFS award.
Start Year 2015
 
Description MICA with AveXis to develop gene therapy for SMA 
Organisation AveXis, Inc
Country United States 
Sector Private 
PI Contribution Prof Azzouz has extensive pre-clinical development expertise and has been developing gene therapy for SMN replacement for over 10 years, demonstrating proof of concept of the therapy in a SMA mouse model. Our goal is to develop gene therapy approach for SMN gene replacement in Spinal Muscular Atrophy. The aim is to develop GMP like vector for GLP toxicology and biodistribution studies in preparation for clinical trials in UK/EU
Collaborator Contribution AveXis holds the exclusive worldwide licence for the AAV9 vector (ChariSMA), the essential carrier to deliver genes to motor neurons. This collaboration will benefit both partners: 1) AveXis has formal clearance from the FDA to begin a trial and has already begun the clinical program. Experience with US regulators will advance the rapid filing for CTA in the EU. AveXis will provide a non-exclusive research licence for access to and use all of their data generated in the USA; 2) Sheffield will make all steps to enable this project to move forward with an appropriate GLP TOX study in UK/EU. 3) Sheffield and AveXis will work together to secure funds required for future clinical studies in UK/EU.
Impact This collaboration just started and we expect that our partnership with AveXis will facilitate and help achieving our final milestone of this project
Start Year 2014
 
Title Orphan Drug Designation 
Description Secured Orphan Drug Designation from European Medicine Agency for SMN gene therapy replacement in SMA 
IP Reference  
Protection Protection not required
Year Protection Granted 2011
Licensed No
Impact N/A
 
Description CureSPG47 foundation, Boston, USA. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Invited by CureSPG47 to present a gene therapy plan to develop therapy for SPG47 in front of Scientific Advisory Group and families of patients.
Year(s) Of Engagement Activity 2017
 
Description Institute of Rare Diseases, Mauro Baschirotto 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Workshop and presentations about gene therapy for rare diseases in particular SPG47. Discussed approaches challenges etc... with patients and families.
Year(s) Of Engagement Activity 2017
 
Description Interview with BBC radio 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Interviewed about our role of UK consortium to tackle the devastating SMA disease.
Year(s) Of Engagement Activity 2015
 
Description Neuroscience School for Advanced Studies 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Students from all over the world attended the course in Tuscany. The lectures were focused on translational neuroscience and in particular gene therapy for monogenic disorders.
Year(s) Of Engagement Activity 2012
 
Description Open day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact over 100 people attended the open days.
Talk followed by questions and discussions. Queries by e-mails and phone calls

patients (both adult and children) asked to visit the labs and talk to researchers
Year(s) Of Engagement Activity 2012,2013,2014,2015
 
Description Presentations by members of the team at the local branch of Motor Neuron Disease Association 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Local branch of Motor Neuron Disease Association requested that we attend one of their meetings and give presentations explaining our research work.
Year(s) Of Engagement Activity 2015