Newborn Screening for Spinal Muscular Atrophy (SMA) - a Proof of Principle Study Using Anonymised Blood Spots.
Condition: Spinal Muscular Atrophy
MeSH terms: Muscular Atrophy; Muscular Atrophy, Spinal; Atrophy
Study type: Observational

Summary: 
      Spinal muscular atrophy (SMA) is a motor neuron disorder caused by the absence of a
      functional survival of motor neuron 1, telomeric (SMN1) gene. Type I SMA, a lethal disease of
      infancy, accounts for the majority of cases. Newborn blood spot screening (NBS)to detect SMA
      has been implemented in public health laboratories in some countries already. In the UK dried
      blood spots are collected within a few days of birth on all babies and subsequent newborn
      screening is currently carried out for other diseases but not for SMA. The investigators
      would like to carry out a proof of principal testing to show that an assay for SMA can be
      carried out on these routinely collected dried blood spots (completely anonymised). The
      investigators would also run some known anonymised SMA positive dried blood spots. The aim is
      to demonstrate that a simple robust test can be used in a routine diagnostic laboratory to
      accurately screen for SMA. The investigators will not have access to identifiable data or
      samples for this project.
    

Detailed description: 
      Spinal muscular atrophy (SMA) is a motor neuron disorder caused by the absence of a
      functional survival of motor neuron 1, telomeric (SMN1) gene. Type I SMA, a lethal disease of
      infancy, accounts for the majority of cases. The majority of babies born with SMA become
      symptomatic as babies (type I) or as toddlers (type II). Type I children will never sit
      unsupported, require ventilated support in the first year of life and usually die before 2
      years of age. Type II children can survive to early adulthood but will never walk. They
      almost invariably develop severe curvature of the spine, feeding and respiratory
      insufficiency that require appropriate intervention. Cognitive abilities are not impaired and
      children are generally bright and sociable.

      Several new therapies have recently been developed for children with SMA and have shown
      remarkable success in clinical trials. One of these therapies, spinraza, has received both
      FDA and EMA approval and is commercially available in most EU countries and in the US, and is
      being currently evaluated by NICE. Because of the early onset and rapid progression of
      infantile SMA, prompt detection of the disease is essential to enable successful treatment.
      It is now recommended that infants be screened for SMA, enabling early drug treatment thus
      preventing further neuron damage2. The recently published work on the development of spinraza
      indeed supports the view that children with shorter disease duration had much better outcome
      [the 2 NEJM papers] a concept that is also emphasised by the interim analysis of infants who
      received spinraza presymptomatically as part of an ongoing study sponsored by Biogen (Nurture
      study). The majority of these children had met the age appropriate milestones by the age of 1
      year, a clearly remarkable outcome. Similar very promising results were obtained in a
      recently published AAV gene therapy study in which a number of the severe infants affected by
      type 1 SMA achieved even the ability to walk unsupported (Mendell SMA gene therapy NEJM
      2017). Also in this manuscript, the children who had a shorter disease duration and those
      treated shortly after the diagnosis had a much better outcome compared to children treated
      later. While the findings from this early gene therapy study are currently being extended in
      a larger global phase 3 study, these dramatic results from emerging therapies have led many
      countries to include SMA in their respective newborn screening programmes.

      A previous study (Adams et al. 2014, J. Clin. Imm) was carried out in an almost identical way
      to the study planned here. The previous study utilised 5000 anonymised leftover blood spots
      from a routine NBS lab to test the robustness and practicality of running a NBS assay for
      SCID. This study was scientifically critiqued leading to publication in a respected relevant
      scientific journal. The study planned here is identical in the approach (5000 normal leftover
      blood spots) to test the robustness and practicality of using a commercial assay for NBS for
      SMA in a routine clinical lab environment. As in the previous SCID study we plan to use a
      number of retrospective known positive samples as well as all the necessary positive/negative
      controls contained in the commercial kit. The sole aim of the study is to assess the
      performance of the commercial kit to provide evidence that NBS screening for SMA could
      feasibly be carried out in routine NBS screening labs.

      The investigators therefore believe this is the correct route to take with SMA Newborn
      Screening as well. Assays for detection of SMA using the dried blood spots collected for
      Newborn Screening (NBS) have now been developed. This utilises the amplification of the SMN1
      gene and subsequent detection of the deleted section that causes SMA. Newborn blood spot
      screening to detect SMA has been implemented in public health laboratories in some countries
      already. In the UK, dried blood spots are collected within a few days of birth on all babies
      and subsequent newborn screening is currently carried out for other diseases but not for SMA.

      The investigators would like to carry out a proof of principal testing to show that an assay
      for SMA can be carried out on these anonymised routinely collected dried blood spots. We
      would also run some known anonymised SMA positive dried blood spots. The aim is to
      demonstrate that a simple robust test can be used in a routine diagnostic laboratory to
      accurately screen for SMA.
    

Observational model: Other
Time perspective: Other
Sampling method: Non-Probability Sample
Study population: 
        All samples used will be leftover dried blood spot material from the Newborn Screening Lab
        at Great Ormond Street Hospital. No extra material will be collected and all blood spots
        will be completely anonymised.

        The anonymous known SMA positive blood spots will be provided by an external company
        (Biogen), in order to determine the accuracy of the assay in detecting SMA positives.
      
Biospecimen description: 
      All samples used will be leftover dried blood spot material from the Newborn Screening Lab at
      Great Ormond Street Hospital. . The anonymous known SMA positive blood spots will be provided
      by an external company (Biogen), in order to determine the accuracy of the assay in detecting
      SMA positives.