Vascular Stem Cells as a novel potential treatment for Retinopathy of Prematurity Dr. Derek P. Brazil Centre for Vision and Vascular Science Queen s University Belfast
Centre for Vision and Vascular Science (CVVS) Derek Brazil (d.brazil@qub.ac.uk) http://www.qub.ac.uk/research-centres/centreforvisionandvascularscience/ CLINICAL & EXPERIMENTAL OPHTHALMOLOGY Age-related macular degeneration Diabetic Retinopathy, Glaucoma, Retinal occlusive disorders DIABETIC VASCULAR COMPLICATIONS Micro/Macro vasculopathy Retinopathy Nephropathy; Pregnancy; Cardiac Ischaemia 24 Academic groups - (8 appointments in last 6 months) 3.8 Grant Income/year (MRC, BBSRC, EU-FP7, Research Charities) Integrated, collaborative, disease-focused
4.8M... now 32 Million! 300 scientists ~7500 m 2 Centre for Experimental Medicine Diabetic complications Retinal diseases Prof Augusto Azuara-Blanco Prof Tim Lyons Prof Noemi Lois
Brazil Group Research Interests Diabetic kidney disease Retinopathy of Prematurity (ROP)
What is Retinopathy of Prematurity? -a disease of the eye affecting premature babies -primary cause is the sudden increase in oxygen experienced by premature babies -room air -NICU chamber -this fluctuation in O 2 levels causes disorganised growth of blood vessels in the retina -most at risk babies are those born <32 wk and 1500 g
What is Retinopathy of Prematurity? -advances in neonatal care means smaller and more premature infants surviving -17 % of premature infants will develop ROP -70 % of premature infants <26 wk, <750 g will develop ROP -the good news is that 90 % of all ROP cases will not require treatment
What causes Retinopathy of Prematurity? -the baby in the womb experiences 80 % O 2 saturation (low), stimulates normal blood vessel growth in the retina -normal term birth, O 2 increases to 90 %, stop signal for blood vessel growth -premature babies-the stop signal arrives before the blood vessels are properly formed -room air or ventilation chamber causes premature stop of blood vessel growth -formation of the avascular ridge Abnormal blood vessels form here, due to low O 2 levels
Premature babies may need oxygen support therapy in the early weeks of life Dr. Martin Couney-saved over 6500 babies
1922 1926 1930 1934 1938 1942 1946 1950 1954 1958 1962 1966 1970 1974 1978 1982 1986 1990 1994 1998 2002 2006 2010 Number of Births Registered 36,000 Number of Births Registered in Northern Ireland (1922 to 2011) 34,000 32,000 30,000 28,000 26,000 24,000 22,000 20,000 Registration Year
Incidence of severe ROP requiring treatment Year Live births No of infants <32 weeks % of infants <32 weeks requiring ROP Treatment 2000 21,512 282 1.1% 2001 21,962 249 2% 2002 21,385 264 1.5% 2003 21,648 277 1.8% 2004 22,318 267 4.1% 2005 22,328 266 4.9% 2006 23,272 289 5.2% 2007 24,451 275 4.4% 2008 25,631 293 5.1% 2009 24,910 303 5.6% 2010 25,315 299 3.3% 2011 25,273 270 6.3% The incidence is 49/100,000 per live births.
Babies requiring ROP treatment 1 in 25 babies less than 32 weeks 1 in 10 babies less than 27 weeks 1 in 2000 live births
Stages of ROP development Stage I/II ROP: mild/moderate abnormal blood vessel growth, disease usually resolves without treatment Stage III ROP: severe abnormal blood vessel growth, plus disease will require treatment to prevent retinal detachment Stage IV ROP: partially detached retina, traction from the scar pulls the retina away from the wall of the eye Stage V ROP: completely detached retina, end stage disease, severe visual impairment or blindness
What is the treatment for ROP? 1. Cryo/laser therapy to burn away the abnormal blood vessels in the peripheral retina -rescues central vision but can damage peripheral vision normal ROP 2. Anti-VEGF therapy (Avastin)-Stage 3 ROP patients receive intravitreal injections -significant benefit for patients -now being used in the Royal Children s hospital
Time line of treatment for ROP Conception Age @ 1 st screening 31.08± 7.05 weeks Age at birth 25.94± 1.47weeks Age @ treatment 37.9± 3.02weeks The youngest age at treatment was 33.27 weeks PMA
CVVS Queen s University Belfast
Endothelial Progenitor cells (EPCs): a new potential therapy for Retinopathy of Prematurity (ROP)
Vascular Stem Cells in ischaemic tissue -endothelial progenitor cells (EPCs) are thought to be bone marrow-derived precursors that can repair ischaemic tissue via vasculogenesis EPC CXCR4 SDF-1 Ischaemic /hypoxic tissue Decaris et al., 2009
Can Vascular Stem cells provide benefit for patients with vascular disease? Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of BM- MNCs (CD34+) Laser Doppler Tateishi-Yuyuama et al., The Lancet,360, 427-435; Aug, 2002
Vascular Stem Cells can be isolated from adult umbilical cord blood PB-MNC CB-MNC Yield typically lower than cords Best yield of cells from young, female non-smokers 20-25 ml blood High yield of EPCs
What do Vascular Stem Cells look like? Room air (21 % O 2 ) Hypoxia (1 % O 2 )
What do Vascular Stem Cells look like?
Why would vascular stem cells be useful in treating babies with ROP? -current treatments for ROP (laser and Avastin) i) are not perfect ii) do not work in every patient iii) only target Stage 3 or late stage ROP -vascular stem cells have the potential to treat patients at an earlier stage, to prevent the serious damage to the retina due to abnormal blood vessel growth -autologous therapy-babies would get their own cell injected, no need for immunosuppression
ROP project in CVVS, QUB -collect umbilical cord blood from normal-term, Caesarean section deliveries (RMH, Dr. Inez Cooke) -collect umbilical cords from premature deliveries at RMH (Dr. David Sweet) -all parents provided informed consent before collection -very difficult to isolate the vascular stem cells from premature deliveries -the earlier the gestational age, the harder it was to isolate cells
Premature Cord Blood OEC Study We have received 37 cord blood samples from Premature infants Gestational age range 24 31 weeks Weight range 740 1700grms Samples 1-21 clamped cords 15 samples 1ml 4 samples not processed due to complete lack of blood/clotted samples 1 successful isolation of OECs Samples 22-37 blood transferred from cord to heparinised tube post delivery 15 samples 3ml 3 samples not processed due to clotted sample 8 successful isolations of OEC s
What do we do with the vascular stem cells when we isolate them? -test the ability of vascular stem cells to form blood vessels in vitro -use a mouse model of ROP to test the ability of these cells to treat ROP in vivo Injection of stem cells to treat oxygen-induced damage
Comparison of normal versus premature vascular stem cells Premature Full Term -ex vivo repair of premature vascular stem cells will be necessary for optimal treatment of ROP
Tiny Life-sponsored Summer Studentship 2013-8 week project, summer 2013, CVVS Kristine Dodds (BSc Hons 2014) -assess the effect of low oxygen ( hypoxia ) on vascular stem cell function -focus on the TGFb1 pathway and Smad proteins -Kristine showed that low oxygen can alter the levels of important Smad proteins in the TGFb1 pathway -this work will contribute toward the overall effort in developing vascular stem cells as a novel, improved therapy for ROP in babies
Retinopathy of Prematurity: hope for the future -screening for ROP has improved in recent years-earlier diagnosis critical -treatments for later stage ROP are improving (Avastin) -lots of research groups working on improved treatment options for early stage ROP to minimize visual impairment in babies
Acknowledgements Patient Volunteers Prof. Alan Stitt Dr. Reinhold Medina Dr. Christina O Neill Kristine Dodds Prof. Morris White (Boston) Dr. Brian Hemmings (Basel) Alison McNulty Jenny McGowan