Jennifer Trust for Spinal Muscular Atrophy Research Strategy 2008/11

Introduction

Spinal muscular atrophy is a genetic condition, inherited as an autosomal recessive trait, which leads to progressive muscle weakness and in the most severe cases premature death from respiratory failure.

Considered within the context of autosomal recessive diseases as a whole, SMA is relatively common. Approximately 1 in 50 people carry the causative genetic mutation and SMA is one of the most frequent genetic causes of infant death and second only to muscular dystrophy as a cause of childhood neuromuscular disability.

Despite being first described and characterised at the pathological level in the late 19^th century, SMA remains a disorder for which there is no effective treatment except supportive nutritional and respiratory care. The Jennifer Trust for SMA is unique in being the only patient group in the UK dedicated solely to supporting patients and families with the disease.

Those most closely affected by SMA have consistently expressed the view that research into the cause of the disease and the search for effective treatments is high in their list of priorities. Furthermore, advances in research into SMA have only been possible through a partnership between motivated SMA families and scientists throughout the world, initially in the collection of DNA that was so vital in identifying the causative gene and more recently in the emerging clinical trials of potential therapies.

It is therefore entirely appropriate that the JTSMA takes a role in fostering research into SMA both by providing grant funding and also by facilitating communication between scientists and affected families.

We are committed to playing our part in finding effective treatments and eventually a cure for SMA.

Our own funding programme will concentrate on:

Research that helps us better understand the mechanisms of SMA
Research that will help us find new and better treatments for SMA
Research that will lead to higher standards of care for people with SMA

We would also like to see people with SMA in this country, should they so wish, to have the opportunity to take part in a clinical trial or other forms of research, or to benefit from that research. We will, therefore work with the international research community to promote, facilitate, and influence SMA research and clinical trials and to emphasise the important role of the patient group in that context.

We will continue to support the annual UK SMA Research Meeting and will look at ways of increasing the effectiveness of this event.

To maximise the impact of our research activities, we will appoint a dedicated in-house Research Coordinator.

Key Funding Priorities

After an intense period of international collaborative research the genetic cause of the majority of cases of typical autosomal recessive SMA was identified by French researchers led by Dr Judith Melki in 1995. A complex genetic mutation leads to marked reduction in levels of the protein product of the 'Survival of Motor Neurons' (SMN) gene on chromosome 5. The severity of the disease correlates with the total residual SMN protein level. SMN is present in every cell in the body and complete absence of the gene product is not compatible with life. However, it appears that reductions in SMN levels to a range of 20-40% of normal can be tolerated by all cells except motor neurons, and above approximately 40% of normal SMN levels there is no detectable neurological phenotype.

In addition to proximal SMA due to mutations in the SMN gene there are a number of related conditions with muscle wasting and weakness in different clinical patterns. In some of these diseases a gene has been identified. The Trust will consider funding projects of high scientific quality relating to non-SMN forms of SMA. Project applications that address the potential overlap between various forms of spinal muscular atrophy would be particularly welcome.

Although we do not rule out any specific SMA related research, it is likely that the key areas of focus for SMA research that we will fund will include:

1) SMN function .

The SMN protein is expressed in all cells and throughout development and adult life. The protein shows very high sequence conservation between mammals and key functional domains are conserved through to simple unicellular organisms such as yeast. This strongly suggests that SMN has a key functional role in all cells and a number of lines of evidence indicate that complete absence of SMN is incompatible with cell viability. SMN is localised to both the cytoplasm of cells and the nucleus where it is found in discrete sub-organelles called gems. In this context SMN exists as part of a macromolecular complex associated with a group of proteins (Gemins 2-8 and unrip).

The principal function of the SMN complex identified to date is in the process of maturation or biogenesis of small nuclear ribonucleprotein (snRNP) complexes which acquire addition of Sm core proteins before importation from the cytoplasm to the nucleus. A reduction in RNP biogenesis would be predicted to have a general effect on splicing function and presumably affect many downstream pathways.

Attempts to determine whether a defect in RNP biogenesis correlates with SMN levels and with disease severity have so far been inconclusive. Therefore at present it remains unclear whether the best characterised and general function of SMN is relevant to the specific loss of motor neurons seen in SMA. An alternative view is that SMN has a distinct function in motor neurons which is not related to RNP biogenesis. Evidence in support of this comes from various sources. SMN is clearly found in axons of motor nerves and in the developing axon at the growth cone, locations which are not associated with RNP biogenesis. In this context SMN associates with a subset of the gemin proteins and not with Sm proteins. Absence of SMN from the axon leads to loss of beta-actin mRNA and loss of axon outgrowth. It is hypothesised that the function of SMN complex in the motor axon is in the delivery of specific subclasses of mRNA to the growing axon for local translation, particularly during the development of the neuromuscular system.

A clear understanding of both general and cell specific functions of SMN is critical to the development of therapies for SMA.

2) The basis of relative motor neuron vulnerability leading to SMA.

The range of motor neuron diseases (SMA, amyotrophic lateral sclerosis, distal motor neuropathy and others) indicates that these cells have a number of points of vulnerability. These include the almost unique architecture of these cells which are 30,000 fold longer than they are wide.

Specific mechanisms for transport of protein, RNA and organelles such as mitochondria are required to maintain cellular homeostasis. Motor neurons also have a specific developmental program which is target (muscle) dependent and involves programmed cell death, with 50% of all embryonic motor neurons dying through apoptosis as part of a normal process of competition for the muscular target.

Motor neurons do not exist as discrete cells but are part of a complex motor system with connections to the descending corticospinal tract, local interneurons and ultimately to muscle. SMN deficiency leads to relatively isolated motor neuron loss, leaving other cells unaffected, except for some minor, sub-clinical, changes in thalamic and sensory neurons. This may arise because of a motor neuron specific function of the protein in the developing motor neuron.

Alternatively motor neurons, for some as yet unidentified reason, may have a specific requirement for snRNP mediated exon splicing which renders them vulnerable at a lower threshold level of SMN than other cells. This is shown in the diagram below where below a certain level of SMN (estimated at 20% of typical normal levels) the organism is not viable because there is a critical requirement for snRNP biogenesis. Between approximately 20% and 40% of SMN there is sufficient SMN for all cells apart from motor neurons which therefore have a specific window of vulnerability.

A complete understanding of the molecular and cellular basis of motor neuron vulnerability in SMA is critical for SMA research and the development of therapies. Approaches to therapy dependent on replacing SMN in motor neurons only (for example by retrograde transport from muscle) may ameliorate motor neuron degeneration but reveal other vulnerable cell populations in previously severely affected children who live for longer than historical cases.

3) The nature of cell death in SMA.

Although often referred to as a 'neurodegenerative disease' SMA differs from classical neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and Parkinson's disease which are age-dependent diseases with insidious onset and relentless progression arising on the background of normal development and adult life.

Pathologically these diseases are characterised by a failure of cell homeostasis manifest by the accumulation of misfolded protein in insoluble aggregates, mitochondrial dysfunction and death through apoptosis. SMA is mostly a disease of childhood in which onset may appear quite abrupt in Types I and II. This may reflect a motor neuron specific role for SMN operating at a specific developmental stage eg; during formation of the neuromuscular junction.

The pattern of cell death in SMA tissue is reminiscent of changes seen after axonal damage with appearances consistent with a disorder that has both developmental (evidence of enhanced developmental apoptosis and smaller pool of post-natal MNs, some immature) and degenerative (central chromatolytic changes in apparently mature motor neurons) components. If SMA is a true neurodegenerative disease it may share some common pathways in pathogenesis with diseases like ALS. If however, the principal component of the pathophysiology is neurodevelopmental this has profound implications for the prospects of identifying therapies to prevent disease progression or restore function.

Most critically there is a need to establish whether replacing SMN after the period of neuromuscular development will lead to a restoration of function or a slowing of the disease process, or whether any beneficial effect will only operate during a specific period of development.

4) The primary site of dysfunction: motor neuron soma, axon, neuromuscular junction or muscle?

Motor neurons have distinct subcellular compartments (cell body, axon and pre-synaptic terminal) and are connected to muscle through the neuromuscular junction. In principal the trigger to cell death could arise at any of these points.

Generalised cellular failure (for example because of a reduction in a basic cellular function such as transcription) would be likely to manifest as synchronous degeneration of the cell soma and axon. Primary dysfunction of the neuromuscular synapse would lead to retraction and dying back of the axon. While most researchers favour a primary neuronal process, the involvement of muscle has not been formally excluded.

SMN replacement therapies depend on a clear understanding of the relative contribution of nerve and muscle to the pathogenesis of SMA.

5) The restoration of SMN levels as a therapy.

Since the molecular basis for SMA is deficiency of SMN it follows that the most logical therapy is to increase SMN levels. There are several potential approaches to this.

i) Direct delivery of SMN packaged into viral vectors and injected into muscle where it can be retrogradely transported along axons. While this has been demonstrated to be possible in principle in rodent models, its applicability to humans is uncertain

ii) General transcriptional upregulation of the SMN2 gene to produce more full length SMN protein. This has been demonstrated in vitro using tailed oligonucleotides which lead to alteration in the splicing behaviour of SMN2 so that more of the transcript includes exon 7 and is therefore fully functional

iii) increasing transcription of the SMN2 gene by using drugs which act on targets known to regulate gene expression, specifically histone deacetylase inhibitors such as sodium valproate or phenylbutyrate.

6) Care Research

Statutory providers face ever increasing demands on finite resources. As a result, 'evidence-based medicine' has become the foundation of decision making on healthcare provision, replacing ad hoc rationing or decision-making informed by fashion and vested interest. This is the environment in which the Trust must operate in order to successfully influence allocation of resources. Ensuring that SMA is treated as a priority requires us to champion changes in care provision at all levels, but we need a strong evidence base to be successful.

The Trust's health and social care research activities will support our principal aim - to achieve the best standards of care for people affected by SMA.

Priorities for funding will be based on consultation with clinicians and healthcare researchers but will focus on areas where research could make a significant impact on disease management.

Funding Criteria

It is anticipated that the Trust will only be able to fund a limited number of 2 or 3-year project grants at any one time. Priority will be accorded to collaborative studies between UK research groups that carry added value either in bringing new researchers into the field or by cementing existing collaborations. International applications will be accepted, but priority will be accorded to consortia that include a UK collaborator.

Funding Schemes

Funding will be provided through the following schemes:

Project grants

Awards of up to £200K over three years will be available to researchers. Funding will be based on broad criteria of relevance to SMA, scientific merit and novelty. However, successful applicants will also have clearly demonstrated a potential therapeutic route from lab to clinic and/or the clinical relevance of their proposed research.

Studies will generally be anticipated to relate to human SMA, but research linked to phenotype in animal models will also be considered if the research is likely to significantly advance understanding or treatment of the human condition.

PhD Studentships

Project funding will remain reactive and based upon the key criteria of relevance to SMA, scientific merit, novelty and the quality of the research environment and training. Grant funding for PhD studentships will include the student stipend and bench fees, plus funding for consumables and conference attendance. Awards of up to £80K for three-year projects will be made available.

Small Grant Scheme

A small grant scheme is also planned from 2009 which will award grants of up to £5,000 to anyone with a professional interest in SMA to assist financially in innovations which will improve the management and quality of life for children and adults with SMA.

Decisions on the Small Grant Scheme will be made by the JTSMA Research Sub-Committee on the basis of criteria that are set out in a separate document that is available from the Trust's office.

Eligibility for funding

Successful applicants will be able to demonstrate an established track record in a relevant area of laboratory research and that appropriate facilities are available to carry out the research. It is not necessary to have a record of publications in SMA research but applications should demonstrate that there is a long term commitment to the disease in the host laboratory. The lead applicant will be a tenured University employee with experience of successfully running program grants for research.

Successful applications for clinical based research (qualitative studies, drug trials, biomarkers) are likely to come from clinical neurologists with a significant clinical patient base in SMA, with access to sufficient patients to adequately power their proposed studies. Allied health professionals will be funded through this mechanism. Applications from clinical consortia are likely to be especially suitable. The lead applicant will be a senior clinician, probably with an academic clinical appointment, but we also encourage applications from independent scientists or clinicians who wish to apply for a grant themselves as the primary applicant of a jointly held grant.

Availability of funding and timescale

The Trust uses the Motor Neurone Disease Association's Research Advisory Panel (RAP) to advise it on the suitability of research applications for funding. Research grant applications will be accepted once per year and will be assessed by the MND Association's panel of experts who will have access to external peer review of each application. Representatives of the Jennifer Trust sit on the MND Association's RAP while applications to the trust are being considered.

Potential applicants should read the Trust's separate note on how to apply for funding in conjunction with this strategy.

January 2008