Targeting epigenetic proteins to treat Spinal Muscular Atrophy

Lead Research Organisation: University of Oxford
Department Name: Physiology Anatomy and Genetics


Spinal Muscular Atrophy is a neuromuscular disorder and leading genetic cause of infant mortality. It is caused by the loss of Survival Motor Neuron 1 (SMN1) gene encoding SMN1 protein, leading to death of motor neurons. The most prevalent type of SMA, Type I, presents itself before 6 months of age, leads to muscle weakness, and death typically before the age of two. Recent FDA approval of Spinraza for the treatment of SMA has given hope that this natural history will soon become radically different. However Spinraza, an antisense oligonucleotide targeting the splicing of SMN2, has its limitations. It is focused only towards the CNS, highly costly, and its' benefits are mainly seen in the most severe patients. In contrast, small molecule which can be given orally and provide neuroprotective effects in SMA patients would offer a more refined and potentially safer option of treatment. A promising target for small molecules are epigenetic proteins. Epigenetic proteins are involved in neuroprotective responses for Huntington's and Parkinson's diseases and regulation of SMN has been shown to be influenced by epigenetic modifiers. The Structural Genomic Consortium (SGC) is a group in Oxford has developed a series of novel chemical probes which inhibit or antagonize proteins involved in epigenetic signalling. We propose to screen these small molecules for activation of SMN expression as well as their effect on proliferation, differentiation and cell survival in cultured neuroblastoma and SMA iPSC-derived motor neurons. Successful molecules will be further analysed in a mouse model for SMA individually and in combination with antisense oligonucleotide treatment. The primary aim of the project is to identify novel small molecule(s) targeting epigenetic regulator mechanisms to treat SMA through SMN and non-SMN dependent pathways.


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Description MRC DTP Supplementary Funding for Randomised Controlled Trials
Amount £2,375 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 11/2019 
End 11/2019
Description Effect of epigenetic modifiers on SMN2 expression in SMA patient iPSC - derived motor neurons 
Organisation University of Oxford
Department Oxford Hub
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided small molecules that have shown positive effect on SMN2 expression in our cellular model (patient fibroblasts). After the experiment, we collected the samples to perform Western Blot on cells.
Collaborator Contribution The collaborator has developed an cellular model of motor neurons that are primarily affected in the disease we study. He tested the molecules we provided.
Impact The collaboration expanded our data set and looked into cells that are more relevant in the disease progression. We would not be able to do this experiment in house as the cell line is not widely available and has proven to be hard to work with.
Start Year 2019
Description Identifying epigenetic regulators of SMN protein using small molecules 
Organisation University of Oxford
Department Structural Genomics Consortium (SGC)
Country United Kingdom 
Sector Public 
PI Contribution We are studying the epigenetic regulation of SMN - in patient fibroblasts - in vivo. We have performed qPCR, WB analysis, in vivo dosing, tissue collection.
Collaborator Contribution The SGC has provided us with the library of compounds that we are using to study the epigenetic regulation of SMN.
Impact My whole DPhil project is based on this partnership
Start Year 2017
Description Member of DARTER COST group 
Organisation European Cooperation in Science and Technology (COST)
Department COST Action
Country Belgium 
Sector Public 
PI Contribution I have joined The COST Action DARTER
Collaborator Contribution From the cost website Members of the COST action CA17103 "The Delivery of Antisense RNA ThERapeutics (DARTER)" are a highly dedicated group of scientists, whose goal is (through COST networking tools) to allow RNA-targeting nucleic acid drugs to reach their full potential and become a mainstream therapeutic option. Antisense oligonucleotides (ASOs) are a new class of drugs that, through precise targeting, could correct genetic defects for rare inherited diseases, modulate autoimmune or neurodegenerative diseases or target tumours or viruses. Regarding delivery, the ASO field is fragmented, with researchers in academia and industry working in isolation on specific conditions, generally focusing on therapeutic effects in target tissues. The created network of researchers acts together to achieve the objectives and create an impact in the field of ASOs therapeutics.
Impact It is still early days but I can attend meetings and workshops for the partnership memebers
Start Year 2018
Description Volunteering for SMA Poland 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact In November 2019 I started volunteering for SMA Poland, where I am a Scientific Information Coordinator. I focus mainly on science communication and write about the biology of Spinal Muscular Atrophy in a simple way, understandable for the patients and the carers.
Year(s) Of Engagement Activity 2019,2020