PhD Studentship: Periodic paralysis: Novel therapeutic approaches

Periodic paralysis (PP) is a rare neuromuscular condition that manifests initially as episodic weakness usually with onset in the second decade. However, with increasing age most patients develop permanent, progressive weakness with significant impact on mobility and quality of life. PP is caused by mutations in genes encoding ion channels expressed in skeletal muscle. The mutations typically result in enhanced depolarising currents so that the muscle episodically enters a stable depolarised state where voltage gated sodium channels become inactivated and muscle is unable to fire the action potentials that trigger contraction. Current pharmacological treatments of PP are symptomatic. The episodic weakness is often controlled reasonably but the available therapies do not prevent the development of fixed weakness, demonstrating a significant unmet clinical need.

As a novel therapeutic approach to PP, we propose gene therapy using genes that a) suppress activity of an overactive muscle voltage gated sodium channel or b) increase resting hyperpolarising currents in the muscle. The first gene encodes a peptide that inhibits sodium channel activity by shifting voltage dependence of activation to more depolarised voltages, directly counteracting the mechanism of sodium channel over activity in mouse model of PP. The second gene encodes an inward rectifying potassium channel normally present in muscle. Increased potassium current density is predicted to bring the resting membrane potential closer to the reversal potential of potassium and decrease the depolarising effect of an overactive sodium channel. These approaches are likely generalisable to other PP genes and variants.

The main objectives of the studentship will be:

• To develop muscle velocity recovery cycle (MVRC) as a biomarker for successful transduction
• To design and produce of AAV carrying the NaV1.4 inhibiting peptide or KCNJ2 and confirm expression in mice.
• To assess therapeutic effect of the designed AAV constructs on mouse model of PP.

The successful candidate will be a highly motivated individual who can work both independently and as part of a team. Applicants must hold a degree in biological or medical or related subject as or candidates should have (or expect to achieve) a minimum of a 2.2 Honours BSc degree or MD/medical degree or MBBS or MSc. Experience with mouse experiments (e.g. home office personal licence), AAV or electrophysiology methodologies is desired.    

Duration. Full-time: 4-year MDUK PhD studentship, starting from January 2025.

PIs: Drs R Mannikko, J Ng, K Suetterlin.

Funding

PhD stipend starting £21343 per year, for 4 years.

UK home PhD fees and lab consumables paid. Overseas applicants welcome, but are required to pay the international tuition fee balance.

Location

Year 1: Newcastle University, Department of Clinical Neurophysiology

Years 2-4: UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG.

Closing Date: 25/10/2024.

Shortlisted candidates will be interviewed end of October/ beginning of November.

To apply or queries, please send a CV to  r.mannikko@ucl.ac.uk

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