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Dr Hans Michael Haitchi

MD, MMed(INT), PhD, PD, MRCP(London), FHEA, PGcert

Associate Professor in Respiratory Medicine; Clinician Scientist & NHS Honorary Consultant Physician; Lead of NIHR SBRC Respiratory Clinical Studies Forum (CSF)

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Dr Hans Michael Haitchi’s research group investigates the pathogenesis of asthma, a major burden on our national healthcare service. His particular interest is in the role of the asthma susceptibility gene ADAM33 and influence of the maternal environment on the early origin of lung disease using murine and human asthma research models. 

In collaboration with Dr Jonathan Watts (USA) his group is developing a novel anti-ADAM33 drug as novel disease modifying treatment for asthma. Dr Haitchi is the PI on the observational Maternal Environment in Pregnancy (MEP) and a Co-I on the Wessex AsThma CoHort of difficult asthma (WATCH) studies.

Landmark publications:

1. Fong WCG, Rafiq I, Harvey M, Stanescu S,   Ainsworth B, Varkonyi-Sepp J, Mistry H, Kyyaly MA, Barber C, Freeman A,   Wilkinson T, Djukanovic R, Dennison P, Haitchi HM, Kurukulaaratchy RJ. The Detrimental   Clinical Associations of Anxiety and Depression with Difficult Asthma   Outcomes. J Pers Med. 2022 Apr 26;12(5):686.doi: 10.3390/jpm12050686.

2. *Eger K, Paroczai D, Bacon A, Schleich F,   Sergejeva S, Bourdin A, Vachier I, Zervas E, Katsoulis K, Papapetrou D,   Kostikas K, Csoma Z, Heffler E, Canonica GW, Grisle I, Bieksiene K,   Palacionyte J, Ten Brinke A, Hashimoto S, Smeenk FWJM, Braunstahl GJ, van der   Sar S, Mihălţan F, Nenasheva N, Peredelskaya M, Zvezdin B, Čekerevac I,   Hromiš S, Ćupurdija V, Lazic Z, Milenkovic B, Dimic-Janjic S, Yasinska V,   Dahlén B, Bossios A, Lazarinis N, Aronsson D, Egesten A, Munir AKM, Ahlbeck   L, Janson C, Škrgat S, Edelbaher N, Leuppi J, Jaun F, Rüdiger J, Pavlov N,   Gianella P, Fischer R, Charbonnier F, Chaudhuri R, Smith SJ, Doe S, Fawdon M,   Masoli M, Heaney L, Haitchi HM, Kurukulaaratchy R, Fulton O, Frankemölle B,   Gibson T, Needham K, Howarth P, Djukanovic R, Bel E, Hyland M. The effect of   the COVID-19 pandemic on severe asthma care in Europe: will care change for   good? ERJ Open Res. 2022 May 16;8(2):00065-2022. doi:   10.1183/23120541.00065-2022.

3. Fong WCG, Borca F, Phan H, Moyses HE,   Dennison P, Kurukulaaratchy RJ, Haitchi HM. Asthma did not increase in-hospital COVID-19-related mortality in a   tertiary UK hospital. Clin Exp Allergy. 2021   Feb 24:10.1111/cea.13855. doi: 10.1111/cea.13855.

4. Davies, ER; Perotin,   JM; Kelly, JFK; Djukanovic, R; Davies, DE; Haitchi, HM. Involvement of the Epidermal Growth Factor Receptor   in IL-13 Mediated, Corticosteroid-Resistant Airway Inflammation. Clin Exp   Allergy. 2020 Feb 24. doi: 10.1111/cea.13591.

5. Azim A, Freeman A, Lavenu   A, Mistry H, Haitchi HM, Newell C, Cheng Y, Thirlwall Y, Harvey   M, Barber C, Pontoppidan K, Dennison P, Arshad SH, Djukanovic R, Howarth P,   Kurukulaaratchy RJ. New Perspectives on Difficult Asthma; Sex   and Age of Asthma-Onset Based Phenotypes. J Allergy Clin Immunol Pract. 2020   Jun 13:S2213-2198(20)30594-8.

6. *Davies ER, Denney   L, Wandel M, Lloyd CM, Davies DE, Haitchi HM. Regulation of Ectodomain Shedding of ADAM33 in Vitro and in Vivo. J   Allergy Clin Immunol. 2019 Feb 2. pii: S0091-6749(19)30183-6.

7. *Hannah M.   Pendergraff, Pranathi Meda, Alexandre J. Debacker, Michael   Moazami, Vivek Sharma, Liisa Niitsoo, Yong Yu, Yen Nee Tan, *HM Haitchi,   *Jonathan K. Watts. Locked Nucleic Acid   (LNA) gapmers and conjugates induce potent silencing of ADAM33, an   asthma-associated metalloprotease with nuclear-localized mRNA. Mol Ther Nucleic   Acids. 2017 Sep 15;8:158-168. doi: 10.1016/j.omtn.2017.06.012. Epub 2017 Jun   21. *Shared senior authorship.

8. *E.R. Davies, J.F.C. Kelly, P.H. Howarth, D.I   Wilson, S.T. Holgate, D.E. Davies, J.A. Whitsett, H.M. Haitchi. Soluble   ADAM33 initiates airway remodeling to promote susceptibility for allergic   asthma in early life. JCI Insight. 2016 Jul 21;1(11).   pii: e87632.

9. *Y Yang, J Wicks, HM Haitchi, G   Murphy, RM Powell, PH Howarth, ST Holgate, DE Davies. TGFbeta down regulates   ADAM33 expression during myofibroblast differentiation via histone   modification. Am J Respir Cell Mol Biol. 2012 May;46(5):633-40.

10. *I Puxeddu, YY Pang, A Harvey, HM Haitchi, B Nicholas, H Yoshisue, D   Ribatti, G Clough, RM Powell, G Murphy, N Hanley, DI Wilson, PH Howarth, ST   Holgate & DE Davies. The soluble form of ADAM33 promotes angiogenesis:   implications for airway remodelling in asthma. J Allergy Clin Immunol. 2008   Jun;121(6):1400-6.

11. *HM Haitchi, DJP Bassett, F Bucchieri, Xiufeng Gao, RM   Powell, NA Hanley, DI Wilson, ST Holgate, DE Davies, Induction of ADAM33   during embryonic lung development and the influence by interleukin-13 or   maternal allergy. JACI 2009, Sep;124(3):590-7,   597.e1-11.

12. *Y Yang, HM Haitchi, J Cakebread, D Sammut, JW Holloway, P Howarth, ST   Holgate, DE Davies. Epigenetic mechanisms silence ADAM33 expression in   bronchial epithelial cells. J Allergy Clin Immunol. 2008 Jun;121(6):1393-9.

13. *HM Haitchi, RM Powell, TJ Shaw, PH   Howarth, S Wilson, DI Wilson, ST Holgate, DE Davies. ADAM33 expression in asthmatic airways and human embryonic lungs.  Am J Respir Crit Care Med. 2005 May 1;171(9):958-65.

Major grants:

  • The impact of maternal asthma and being overweight during pregnancy on mediators in offspring that may predispose to the development of asthma in early life. BMA Foundation for Medical Research: The James Trust for research into asthma, UK: £64,996, 2022-2025

  • Multiomic approach to study the impact of maternal allergic asthma during pregnancy on   asthma related mediators including ADAM33 in biologic samples collected   during caesarean sections. BMA Foundation for Medical Research: The James   Trust for research into asthma, UK: £64,954, 2019-2023

  • Prevention and treatment of allergic asthma in vivo using ADAM33 silencing oligonucleotides. MRC Confidence in Concept & EPSRC-Impact Acceleration Accounts grants, Southampton, UK: £52,378, 2019-2021

  • Optimizing ADAM33-targeted ASOs for clinical   development for asthma and COPD. UMass Bridge funding with collaborator Jonathan Watts from RNA Therapeutics Institute, University of Massachusetts, USA: $ 188,000, 2019-2021

  • The impact of the asthma gene, ADAM33, on innate immunity and susceptibility to allergic airways inflammation. BMA Foundation for Medical Research: Jon Moulton Asthma Research grant, UK: £64,300, 2018-2021

  • Medical Research Foundation (MRF)/Asthma UK Research Grant: The impact of pre- and perinatal ADAM33 induced airway remodeling on sensitivity to environmental challenges and the early life development of asthma. £ 291,756, 2016-2019.

  • Stephen T Holgate PhD studentship, Allergy & Inflammation Research (AAIR) Charity, UK; The role of ADAM33 in early life asthma. £106,200, 2014-2018.

  • MRC Clinician Scientist Fellowship; ADAM33 Gene Environment Interactions in Developing Lungs in the Early Origin of Asthma. £1,035,126, 2010-2014

Impact example:

A Disintegrin and Metalloprotease (ADAM)33 was discovered as asthma and bronchial hyperresponsiveness (BHR) susceptibility gene by our group in Southampton in 2002 (Nature 2002).

This has been replicated in different populations not only in asthma but also COPD.

Since the discovery of ADAM33 our group has shown that it is mainly expressed in mesenchymal airway cells such as smooth muscle cells and (myo)fibroblasts (AJRCM 2005, JACI 2008) suggesting that it is an airway remodelling gene.

While the protein should be membrane-anchored, an enzymatically active soluble form (sADAM33) is upregulated in the airways by gain of function in patients with asthma (JCI-I 2016). We have shown the first function of sADAM33 to be pro-angiogenic (JACI 2008) and to be increased in new-born lungs from mothers with allergic airway inflammation during pregnancy (JACI 2009). We recently showed that transforming growth factor (TGF)-β enhances release/shedding of sADAM33 through an autocatalytic mechanism (JACI 2020).

Using robust genetic models, we showed that sADAM33 in allergen-naive mouse lungs initiates airway remodelling (without inflammation), which is reversible when sADAM33 expression is arrested. In mice challenged with low-dose allergen, sADAM33 promotes enhanced BHR and Type-2 airway inflammation. Moreover, in Adam33knockout mice HDM challenge resulted in reduced BHR, airway remodelling and eosinophilic airway inflammation, compared to wild-type mice (JCI-I 2016).

Since airway remodelling is reversible on arrest of sADAM33, and since Adam33 knock-out suppresses BHR, inflammation and airway remodelling, it is a validated target for a disease modifying asthma therapy.

In collaboration with the laboratory of Dr Jonathan Watts at the RNA Therapeutics Institute at University of Massachusetts Medical School we have developed potent mouse and human ADAM33 antisense oligonucleotides (ASOs) (MTNA 2017) and filed an international patent. Based on our first proof of concept studies in mice (JCI-I 2016) and further preliminary data we currently seek funding from government, pharmaceutical/biotech industry partners and investors for further safety studies with our ultimate aim of first in human trials as novel treatment for asthma.

An important press release was sent out by the University of Southampton in connection with Dr Haitchi’s group publication in The Journal of Clinical Investigation - Insight with the title: Soluble ADAM33 initiates airway remodelling to promote susceptibility for allergic asthma in early life in 2016 (JCI-I 2016). This publication has made a significant contribution to the understanding how soluble ADAM33 initiates airway remodelling, which promotes susceptibility for allergic asthma in early life and the press release has attracted wide attention by national and international media and the scientific community (Australia, Austria, Belgium, India, Ireland, USA, UK, ...). The Article was covered over 100 times in the media: in local newspapers (southern Daily Echo) and all national newspapers (The Independent, The Daily Telegraph, The Daily Mirror, The Sun, ...) in the UK and even in international newspapers (Business Standard India, ...). Additionally, it was covered by engagement focused websites, blogs and social media channels, local radio and TV stations and national radio stations.

Dr Haitchi talks about his group’s asthma and ADAM33 research on social media filmed by Asthma UK, BMA or Solent TV.

Dr Haitchi is member of the Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP), a European Respiratory Society (ERS) Clinical Research Consortium and the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) Alliance since 2020. This has resulted in different international collaborative projects and publications.

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