INTRAVITREAL INJECTION OF AUTOLOGOUS BONE MARROW–DERIVED MONONUCLEAR CELLS(ABMC) FOR HEREDITARY RETINAL DYSTROPHY A Phase I Trial RETINA, 2011;31;(6);1207~1214 가톨릭대학교 의과대학 안과 및 시과학 교실 R2정현진 /Pf.배선량

Introduction Hereditary retinal dystrophies: RP, cone–rod dystrophy 1 in 3,500 individuals progressive visual field and visual acuity loss, night blindness, optic nerve atrophy, arteriolar attenuation, altered vascular permeability Molecular genetic analysis: * identified mutations in more than 110 different genes accounting for only a relatively small percentage of the known affected individuals *many mutations are associated with enzymatic and structural components of the phototransduction machinery(rhodopsin, cGMP, peripherin, RPE65) ->But, still no effective treatments to slow or reverse the progression of these dystrophies.

Introduction neurotrophic factor *intraocular adenovirus-mediated gene transfer of ciliary neurotrophic factor(calcium channel blockers, electrical stimulation) may reduce photoreceptor loss in an RP model Neural stem cell transplantation * limited by cell rejection and by political and ethical controversies related to the use of embryonic stem cells bone marrow–derived stem cells intravitreal administration *improving perfusion through angiogenesis and replacing damaged cells in animal model study *Jonas et al, demonstrated the clinical feasibility of intravitreal administration of autologous bone marrow–derived mononuclear cells (ABMC) in patients with advanced degenerative retinopathies

Purpose Phase I Trial To evaluate the short-term (10 months) safety of a single intravitreal injection of autologous bone marrow–derived mononuclear cells in patients with RP or cone–rod dystrophy

Methods prospective, nonrandomized, open-label study including 3 patients with RP and 2 patients with cone–rod dystrophy(≤BCVA 20/200) intravitreal injection of 10 x106 autologous bone marrow–derived mononuclear cells (0.1 mL) into 1 study eye of each patient BCVA, full-field ERG, Goldman kinetic VF, FAG, ICG, OCT were performed at baseline and 1, 7, 13, 18, 22, and 40 weeks after intravit. Inj Safety Outcome Measures 1) severe VA loss, loss of 15 letters on the ETDRS VA scale 2) decrease in ERG a wave amplitude of 100 mV 3) decrease in visual field seeing area of 1 square radians 4) genesis of abnormal tissues (teratomas) or tumors.

Results F/23 F/31 M/33 M/35 M/35 Classic RP Cone-rod dystrophy Con-rod dystrophy M/35 Classic RP M/35

Results *No patient demonstrated a reduction in BCVA at any study visit. In 4 patients, a 1-line improvement in BCVA was measured 1 week after injection and was maintained throughout follow up *No reduction in residual visual field area

Results * dark-adapted standard flash a and b wave amplitude and implicit times for all visits. *showed no detectable response for light-adapted stimuli at baseline

Results * Macular thickness : 51 ~169 mm, macular volume: 5,718~110,007 mm3 at baseline. * No significant changes in macular thickness or volume measurements FAG, ICG : No change in retinal perfusion status compared with baseline

Disscusion Hematopoietic cells have been reported to play an active role in the formation of blood vessels ABMC may have the ability to differentiate into retinal neuronal cells Interleukins & other important mediators may be produced by stem cells, a paracrine effect, contributing to the rescue of retinal neurons patients’ own bone marrow cells may provide retinal rescue, which allows for avoiding unwanted potential side effects associated with the use of viral vectors in long-term gene therapy and rejection of embryonic stem cells

Conclusion The present study has important limitations such as a few patients and short follow-up However, this is the first report of the safety of intravitreal ABMC injection in patients Further studies are required to investigate the role of autologous bone marrow–derived mononuclear cell therapy in the management of retinal dystrophies hereditary retinal dystrophies