Applying Omics technology in the treatment path for Batten disease

Applying Omics technology in the treatment path for Batten disease: disease mechanisms, biomarkers, monitoring efficacy and early diagnosis

The development of new treatments for inherited paediatric diseases requires the identification of therapeutic pathways, and rapid diagnosis and monitoring of the efficacy of the therapy. We are developing gene therapies and small molecule drugs to treat the most common the group of diseases known as the neuronal ceroid lipofuscinoses or Batten disease. Here, previously healthy children develop epilepsy, lose their sight and the ability to talk, interact with others, and to work and eventually die. All available evidence suggests that to be most effective treatment will need to begin pre-symptomatically, requiring diagnosis as early as possible, perhaps soon after birth. 

The aim of this studentship is 2-fold and driven by a clinical need to:

• Find the disease mechanisms involved in Batten disease so we can identify drug targets and develop new treatments.
• Develop a rapid and better test to diagnose the disease earlier, more accurately and monitor the efficacy of new treatments.

The neuronal ceroid lipofuscinoses (NCL) or Batten disease (BD) as a group is the most common cause of neurodegeneration in children1 caused by mutations in at least 13 genes. There are no curative treatments available in the clinic for most types of NCL but enzyme replacement and gene therapies are being developed for some of the subtypes, with a focus on CLN2, CLN3, CLN5, CLN6 and CLN7 subtypes at UCL. Brineuria, an enzyme replacement therapy has recently been approved for CLN2 disease (EMA/CHMP/208415/2017, based on a clinical trial at GOSH. The disease course leads to a long period of complete dependence on others, seizures refractive to anti-epileptic medications, loss of vision and compromised motor function and eventually premature death. Understanding of the genotype-phenotype correlation is important for the design of novel therapies and clinical trials as patients with different mutations may respond differently to treatments. Experiments in animal models of disease showed that treatment in presymptomatic animals offers best long-term outcome2,3,4. Thus easily detectable biomarkers are crucial to improve diagnosis allowing the earliest intervention, and accurate monitoring of the disease progression to assess the efficacy of treatments. Preliminary work targeting patients and  samples from sheep disease models has already confirmed significant and specific metabolic changes.

The project divides into 4 steps:
Step 1: Patient samples. Access patient samples (up to 50-100 samples) of urine, plasma, CSF and blood spots from patients with all types of NCL collected by the GOSH clinical team, and in-house samples from different LSD for positive control groups.
Step 2: Targeted and non-targeted pan-omic screening. Analyse plasma, blood spots (Guthrie cards) and urine in the UCL Biological Mass Spectrometry Centre (BMSC). This is a state-of-the-art mass spectrometry facility containing proteomic, metabolomic and lipidomic technology and works in parallel with a translational arm to create new and more accurate tests for rare diseases.
Step 3: Targeted assay development for biomarker validation and creation of translational NHS tests. Translate all potential biomarkers or biochemical pathways disrupted by disease into triple quadrupole, high-throughput and multiplexed tests for validation. Identify additional protein, metabolite or lipid intermediates in affected pathways and augment them into the assay to study those pathways in more detail. Refine validated biomarkers into high-throughput clinical assays to NHS/industrial standard and translated into the clinical service at GOSH.
Step 4: Data exploitation, patient stratification, pathway discovery and mechanism investigation. Evaluate the tests and stratify patients via UK and international collaborations. Verified novel pathways in mammalian cell systems, and their response to relevant small molecules with therapeutic potential.

References:
1) Mole, S. E., Williams, R. E., Goebel, H. H. (Eds.) (2011). The Neuronal Ceroid Lipofuscinoses (Batten Disease). (2nd ed.). Oxford University Press. ISBN 978-0-19-959001-8. Oxford, UK.
2) M.A. Cabrera-Salazar et al. (2007). Timing of therapeutic intervention determines functional and survival outcomes in a mouse model of late infantile batten disease. Mol Therapy, 15: 1782–1788
3) D. Sondhi et al. (2008). Survival advantage of neonatal CNS gene transfer for late infantile neuronal ceroid lipofuscinosis. Experimental Neurology, 213: 18–27
4) S-M kleine Holthaus et al. (2018). Prevention  of photoreceptor cell loss in a Cln6nclf mouse model of Batten disease requires CLN6 gene transfer to bipolar cells. Mol Therapy 26: 1343-1353.