Dr. Anil Mehta

Clinical Reader

I am a Doctor who is making new pills for cystic fibrosis

Address:

Division of Molecular & Clinical Medicine
Level 5, Mailbox 12
School of Medicine, University of Dundee
Ninewells Hospital and Medical School
Dundee
DD1 9SY

Phone Number:

+(44) 01382 383110

Email Address:

a.mehta@dundee.ac.uk

Biography

Dr Mehta is a clinical academic undertaking international research into the children’s disease cystic fibrosis whilst working 50% of his time as a consultant paediatrician with a neonatal medicine/paediatric cardiology interest. His focus is on EU-wide patient care, health outcomes, rare disease policy and better informed policy making.

He has tried to improve the welfare of Europeans who suffer because their diseases are very rare in a given hospital setting. This area is a priority for the EU through their forthcoming Rare Disease Directive that will require the NHS to plan care for all rare disease patients (UK to launch end 2013).

Past work: Dr Mehta implemented the first comprehensive UK-wide CF patient registry of ~ 7000 patients across 60 NHS CF clinics between 1995 and 2006 and recently developed the first 30,000 patient, 35-country pan-European demographic CF registry, with EU FP6 funding (2006-2009). My translational science focuses on two areas: (1) discovery of a new pathway in CF disease through collaborations in eight  He is an editor of Royal Society of Medicine’s CF Clinical Update Journal (2011-) He developed the European Demographic CF Registry (2006-2009) and now acts as Scientific Lead on European Registry Executive of the European CF Society (2010-).

IMPACT:

UK CF Database protocols are used by others to improve NHS efficiency:  For example, Registry data from UK CF Centres are used by the CF Trust for (i) NHS resource allocation (patients banded by disease severity – banded between £5K & £40K p.a.) (ii) CF-Centre audit by NHS-commissioner-led peer review and (iii) EMA approved phase-IV studies are followed by the registry for new CF drugs.

Citations: Lancet cover (2007)/editorials/podcasts(2007/10); commentaries in leading specialist journals such as Pediatrics and in annual Scottish and UK audit reports for Government to calculate costs/centre re-imbursement (1995-2006); 23 peer-reviewed research publications impacted beyond academia by describing, inter alia, remote monitoring of toxic drug doses specified by the Committee on Safety of Medicines,  reduced therapies following neonatal screening, cited by CDC Atlanta in Newborn Screening Recommendations Reports: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5313a1.htm and therapeutic windows to address the worse outcomes for CF females with diabetes (guidelines of the American Diabetes Association, doi: 10.2337/dc10-1768, 2010).

European CF Registry impacts: The published research findings created part of the evidence base that, after recent comment on disparities of care from the European Commission, are helping facilitate the lobby to drive the implementation of a recent decision by the European Council of Ministers to ratify the European Rare Disease Directive This has led to unsolicited invitations to influence European policy debate as follows:

Policy Appointments to Advisory Board of the EPIRARE Consortium of meta-registries funded by EU DG Sanco, http://www.epirare.eu/partner0.html Further impact on policy is on-going through membership of in two key ECFS committees and EURORDIS/EPIRARE (2012) to intensify lobbying at the European Commission, the European Council of Ministers and with MEPs to implement the policy changes needed to improve outcomes.

Political Presentations of the findings at the European Parliament (2009, 2010, 2013 on file Peter Liese MEP Bonn and in CF Europe office files and MEP Bart Staes Office ) and;

Keynote Address Invitations from CF Europe to influence CF care policy in Italy/Slovakia/Serbia (2013); Chaired an Irish Governmental Panel for rare disease research funding (Health Research Board, Dublin 2013).

In the period since 2008, these impacts can be classified into the following groups:

Impacting public policy and services. Through the European Commission, European Parliament and committee work in DG Sanco, EURORDIS, the European Cystic Fibrosis Society (ECFS) and CF-Europe; and http://cfkonferencia.sk/en/temy/.

Impacting health and welfare. The beneficiaries are health service / regulatory authorities across rare diseases by demonstrating the poor quality of CF health in low-income EU member states drawing the attention of their respective governments through the Commissionv and at the European Parliament in November on CF days (2009, 2010; 2013;CF-Europe web site). Quantifying disparities in care between member states creates a benchmark for disease survival (current political addresses in the Balkans (2013) and Slovakia (2013). These invitations follow transactions with 20 MEPs after presentations in 2009 to alert their national governments about their relative performances. Translations of the Lancet work into native languages (e.g. Polish, Slovakian) facilitated lobby activity (evidence available in the CF-Europe and Polish and Slovakian CF Association files).

Impacting rare disease practitioners and services outside CF. Other rare diseases share the same implementation challenges; countries such as Argentina, Brazil, Mexico, India etc. who are at the start of their rare disease implementation strategy. The European Rare Disease Organisation (EURORDIS) highlighted the utility of the Dundee rare disease protocols through the award of a EURORDIS prize (Krakow meeting, 2010) and the appointment as EURORDIS Registry Tutor (2011-12) where AM led a symposium for 16 country representatives to advise on the implementation of a registry applicable to any rare disease (Annual Eurordis meeting, Brussels 2012: where AM delivered templates for consent with confidentiality, procedures for quantitative data handling). AM’s RD blogs led to his invitation to join the scientific board of a new Findacure Foundation for Fundamental Diseases (see Guardian news, august 2013), who wish to conjoin rare disease researchers with altruistic funders in order to improve research and care across the rare disease spectrum.

Impacts on society. The evidence has been presented in a user-friendly manner (most recently at the Italian National CF delegate meeting in Rome, September 7th 2013). This impact includes patient-friendly European registry audit reports (2012; www.ecfs.eu) and AM-initiated patient poster campaigns across Europe explaining the origins of current CF medicines to patients to improve recruitment into clinical trials (from 2010; available from I Fajac and the ECFS office in Leuven: https://www.ecfs.eu/ctn/my-current-medication).

Research

Background: CMO-Donaldson’s report (2009, ‘rare is common’) commented that millions suffering from rare diseases (RD) remain inadequately treated because healthcare is hospital-centred where RD-patients are too few for large-scale evidence generation. Registries underpinning research are an important part of the solution, and in cystic fibrosis (CF), no comprehensive UK- or Europe-wide clinical registry existed prior to my team’s work (a post-doctoral scientist Dr E. Sims and MD student J McCormick. Throughout, project manager G. Mehta supervised/trained UK-European hospital administrative staff including the EU CF Society registry group).  

Screening for Cystic Fibrosis: The prior research demonstrating benefit vs. cost of new born CF screening (Lancet 2007) was incorporated into international screening guidelines of European Governments (e.g. Sweden 2010, Netherlands (2009-10), Germany), CDC Atlanta (US) and those of the European CF Society (ECFS, 2009). My parallel research demonstrating poorer outcomes for female patients with CF diabetes was cited in the clinical care guidelines if the American Diabetes Association (doi: 10.2337/dc10-1768, 2010) and recently, in the Lancet (2010), we reported better CF patient survival in established vs. new EU member states. 

UK CF Database (1995-2007; UKCF-Trust Registry thereafter): ~2 million UK-carriers of the CF genetic defect randomly generate thousands of geographically-dispersed CF patients. My team designed and implemented the UK-CF-Database (UKCFD), engineering robust data protection & management protocols ensuring anonymity that drove the research described herein. 7000 CF patients (>40 CF-clinics) were registered at handover to the UK CFTrust. The underpinning research publications facilitated the case to Government for neonatal CF screening by calculating cost-benefit ratios demonstrating less intense drug therapy for a given FEV1 in screened cohortsi. The UKCFD was also applied by others to remotely measure CF-drug toxicities (gut/kidney). In 2007, the UKCFD-data and structure/protocols were embedded into a new registry (www.cftrust.org.uk); now used in NHS commissioning. This registry matches patient disease severity against CF-centre reimbursement for ~10,000 UK patients in 2013 and, its design tracks new, expensive therapies (>£100K p.a. per-patient).

CF Pathogenesis: In CF science, a key unanswered question is the pathway by which the CF gene, through defective encoding of the normal version of its protein (called CFTR), causes disease in the human cell membrane. My work proposes a new pathway that lies at the interface of phospho-histidine and phospho-serine, that has implications for cell growth, cell specialisation and nutrient uptake in cells (see Annesley S et al. 2011).  My collaborators and I  hypothesised that the missing amino acid Phe508, deleted from the normal CFTR protein, did not just destroy the misfolded Phe508delCFTR (as is well established), but additionally, pressed a new ‘switch’. This proposed switch is being researched through collaborations in Italy, Portugal and Hungary in 2014 where new grants have been funded for postdoctoral staff scientists to unravel this complex scenario.

Key Grants:

UKCF Database: Rolling grants (value over £1M) to University of Dundee (1993-2007) from both the Scottish Government through top-slicing of the NHS budget via the National Services Division (~30K per annum, recurrent) and from interleaved project grants (£100k per annum; 1993-2007) from the UK Cystic Fibrosis Trust that underpinned the development of the UK CF Database European CF Registry: European Commission FP6 EuroCareCF (€1.75M, Coordinator DN Sheppard, Bristol) with University of Dundee leading on project management (2006-7) and European Registry workpackage (2006-2010; €423,128);  European Coordination Action for Research in Cystic Fibrosis (EuroCareCF).

Current EU-wide Network Activities/Grants:

See also recent grants awarded with Dr S Land on epithelial polarity.

New grants have been awarded to visiting staff from Lisbon and Milan in 2014 for postdoctoral science links between kinases NDPK CK2 and autophagy and also on the fate of CFTR.

Implementing new EU-wide software for data collection.

Publications

See also list on ResearchGate web site.

Epidemiology of CF:

Sims EJ, Mugford M, Clark A, Aitken D, McCormick J, Mehta G, Mehta A (2007) Economic implications of newborn screening for cystic fibrosis: a cost of illness retrospective cohort study.  Lancet 369:1187-1195; Lancet cover feature.

Mehta A (2001) UK surveillance of drug dosage showing toxic levels of enzyme replacement administration. Further Comments on Fibrosing Colonopathy Study. Lancet 358:1546-7.

Smyth, A., Lewis, S., Bertenshaw, C., Choonara, I., McGaw, J. and Watson, A. (2008) Case-control study of acute renal failure in patients with cystic fibrosis in the UK. Thorax 63, 532–535 (doi: 10.1136/thx.2007.088757)

McCormick J, Mehta G, Olesen HV, Viviani L,  Macek M,  Mehta A (2010) Demographics of the European Cystic Fibrosis Population. Lancet  375:1007-13, and Podcast featured article by Lancet Editors at lancet.com (audio, archive March 20, 2010).

Mehta G, Macek M, Mehta A (2010) Demographics of CF across Europe. European Coordination Action for Research in Cystic Fibrosis (EuroCareCF) Registry Special Issue J Cyst Fibros. Suppl 2:S5-S21.  (free download at www.ecfs.eu; publications list with two associated commentaries, one from the EU Commission Secretariat).

(www.ecfs.eu; registry&research: see registry reports)



Early work on CFTR, as a kinase-kinase hub: Non-specialist Review see Febs J Kunzelmann and Mehta (2013) which summarises:

FATE OF CFTR:

Pagano MA, Arrigoni G, Marin O,  Sarno S, Meggio F, Treharne KJ, Mehta A, Pinna LA (2008) Modulation of Protein Kinase CK2 Activity by Fragments of CFTR Encompassing F508 May Reflect Functional Links with Cystic Fibrosis Pathogenesis. Biochemistry 47:7925-36.

LINKS TO OTHER CHANNELS:

Bachhuber T, Almaca J, Aldehini F, Mehta A, Amaral MD, Schreiber R, Kunzelmann K (2008) Regulation of the epithelial Na+ channel by protein kinase CK2. J Biol Chem 283:13225-32

LINKS TO OTHER KINASES:

Kongsuphol P, Cassidy D, Hieke B, Treharne KJ, Schreiber R, Mehta A, Kunzelmann K (2009) Mechanistic insight into compartmentalized control of CFTR by AMPK. J Biol Chem 284:5645-53.

LINKS TO SMALLPOX:

Treharne KJ, Cassidy D, Goddard C, Colledge WH, Cassidy A, Mehta A. (2009) Epithelial IgG and its relationship to the loss of F508 in the common mutant form of the cystic fibrosis transmembrane conductance regulator. FEBS Lett 583(15):2493-9. Highlighted by the American Physiological Society in October 2009 (Physiology 24:276-280, 2009).

LINKS TO CK2:

Treharne KJ, Xu Z, Chen J-H, Best OG, Cassidy DM, Gruenert DC, Hegyi P, Gray MA, Sheppard DN,  Kunzelmann K, and Mehta A. (2009) Inhibition of protein kinase CK2 closes the CFTR Cl channel, but has no effect on the cystic fibrosis mutant DF508-CFTR. Cell Physiol Biochem. 24:347-60.

Pagano MA, Marin O,  Cozza G, Sarno S, Meggio F, Treharne KJ, Mehta A, Pinna LA. (2010) CFTR fragments with the F508 deletion exert a dual allosteric control over the master kinase CK2. Biochem J. 426(1):19-29.

LINKS TO CELL MODELS AND AMOEBAE:

Annesley SJ, Bago R, Mehta A, Fisher PR. (2011) A genetic interaction between NDPK and AMPK in Dictyostelium discoideum that affects motility, growth and morphologydevelopment. Archives of Pharmacology.



RECENT SPECIALIST PAPERS:

  • Corvol H, Beucher J, Boëlle P-Y, Muselet-Charlier C, Clement A, Ratjen F, Grasemann H, Laki J, Palmer CNA, Elborn JS, Mehta A. (2011) European analysis of ancestral haplotype 8.1 and lung disease severity in cystic fibrosis. J Cyst Fibros E pub.
  • Venerando A, Pagano MA, Tosoni K, Meggio F, Cassidy D, Stobbart M, Pinna LA, Mehta A. (2011) Understanding protein kinase CK2 mis-regulation upon Phe508delCFTR expression. Arch Pharmacol epub May 2011.
  • Luz S, Kongsuphol P, Mendes AI, Romeiras F, Sousa M, Schreiber R, Matos P, Jordan P, Mehta A, Amaral MD, Kunzelmann K, Farinha CM. (2011) The contribution of CK2 and spleen tyrosine kinase (SYK) to CFTR trafficking and PKA-induced activity. Mol Cell Biol Epub 31, 4392-4404.
  • Boëlle PY, Viviani L, Busson PF, Olesen HV, Ravilly S, Stern M, et al, Mehta A, Corvol H; Reference percentiles for FEV1 and BMI in European children and adults with cystic fibrosis on behalf of the French CF Modifier Gene Study Investigators and the European CF Registry Working Group. Orphanet J Rare Dis. 2012 Sep 7;7(1):64
  • King JD Jr, Lee J, Riemen CE, Neumann D, Xiong S, Foskett JK, Mehta A, Muimo R, Hallows KR. Role of binding and nucleoside diphosphate kinase A in the regulation of the cystic fibrosis transmembrane conductance regulator by AMP-activated protein kinase. J Biol. Chem. 33389-400
  • Kendra Tosoni*,1, Michelle Stobbart*,1, Diane M. Cassidy*, Andrea Venerando, Mario A. Pagano, Simão Luz§, Margarida D Amaral§,‖, Karl Kunzelmann, Lorenzo A. Pinna, Carlos Farinha§,, Anil Mehta* CFTR mutations altering CFTR fragmentation (2013). Biochem J 449: 295-305

NEW LINKS TO WORM BIOLOGY OF RAS AND NDPK:

  • Masoudi et al in press (Development, 2013) localises NDPK actions

NEW LINKS TO CONTROL OF CK2 BY CFTR:

  • Venerando et al in press PloSOne (2013) confirms CK2 malfunction in CF

Teaching

I organise and teach a 4-week Student Selected Component (SSC) on the path from cystic fibrosis (CF) science to clinical disease. I teach small groups in year 4 on paediatric cardiology twice a month. I lecture years 1 and 3 on perinatal adaptation, paediatric cardiology and hypoglycaemia / metabolism. I am also an examiner in clinical medicine for years 3, 4 and 5 where my focus is on marking case scenario scripts and project work from year 4 students. I lecture annually to GP trainees on the Child Health Surveillance Course (excellent ratings, every year). I teach postgraduate trainees in neonatal medicine.

PhD Supervision

In addition to the members in group alumni, Dr Mehta now focuses on supervision/examination of external students across the EU: For example:

  1. LISBON (2013); MANCHESTER (2014). BUDAPEST (2014).

Conferences

Since 2005 Dr Mehta has been invited to give >50 lectures/seminars (>40 international invitations) with ~20 invitations in epidemiology (>15 international) and 31 invitations in basic science (23 international

Examples:

  • EU Parliament, three speeches of disparities of CF care over 5 years (latest in 2013)
  • Disparities in CF Care Keynote Lectures (Serbia/Slovakia) 2013
  • Symposium Convenor/Moderator/Co-chair & Speaker CK2 & CFTR, at European CF Society
  • Frontiers in CF Science each year between 2006 and 2012.
  • Speaker/Chair/Co-chair on NDPK, CK2 and CFTR, 8th & 9th International NDPK Conferences
  • Seminars on CK2 and CFTR,  Universities of Pittsburgh and North Carolina, 2010
  • Invited opponent 2 hour lecture on CF screening, Karolinska Institute, Sweden, 2010
  • Invitation to lecture at International Neonatal Update Conference, London 2010
  • Magistral lecture European Registry, Croatian Cystic Fibrosis Association, Zagreb, 2007
  • Protein kinases and ion channel function in CF. EMBL Heidelberg, 2007

Group Alumni

  • My previous Ph.D. student, Dr LJ Marshall, and post-doctoral scientists, Dr R Muimo and Dr M Kerbiriou, have been appointed to University lectureships in Aston, Sheffield and Brest respectively.
  • My last International Wellcome MD student, Dr G Sijumbila, returned as a lecturer to Zambia.
  • My former postdoctoral researcher, Dr E Sims, is CEO of a healthcare consultancy in Norwich.
  • My former Ph.D. student, Dr C Riemen, is a healthcare manager in Hamburg.
  • Three of my previous students are now NHS Consultants (Drs J McCormick, R Shellard and R Smith).

Impact

Peak Flow Meter

BBC Radio Four: Explanation of the Peak Flow Meter