Therapeutic potential of valproic acid for 2010.10.27 초독회 Therapeutic potential of valproic acid for retinitis pigmentosa 본 논문은 valproic acid 를 이용하여 RP의 치료를 시도 한 2010년 7월 Br J Ophthalmol지에 실린 논문입니다. Pf. 배선량 / R2 이재형

Purpose To examine the efficacy and safety of valproic acid (VPA) in patients with retinitis pigmentosa(RP) 치료효과와 안전성을 분석하고자 하였습니다

Introduction Retinitis pigmentosa (RP) a severe neurodegenerative disease of the retina constitutes many retinal & RPE dystrophies caused by molecular defects in more than 100 different genes A few new approaches for RP treatment Nutritional supplementation(Vitamin A), light reduction and gene therapy Pharmacological chaperones Recently we demonstrated the use of retinoids and other small molecules as pharmacological chaperones to increase the yield of properly folded RP mutant rhodopsins in heterologous cell culture 합성중이거나 삼차원 구조가 풀린 폴리펩타이드(폴리펩티드)에 붙어 제 구조를 회복시키거나, 폴리펩타이드(폴리펩티드)가 세포막을 잘 통과하도록 안내하는 단백질. 대표적인 것으로 셰퍼로닌(chaperonins), hsp70, hsp90이 알려져 있음.

Introduction Valproic acid (VPA) : broad-spectrum anticonvulsant : acute and maintenance therapy of mania in bipolar disease and for migraine prophylaxis affect gamma-aminobutyric acid (GABA) levels - Pharmacological chaperones to increase the yield of properly folded RP mutant rhodopsins in heterologous cell culture translation 과정에서 polypeptide를 정확하게 folding 시킬 물질 이에 저자들은 short –trtm VPA 치료가 RP 환자들의 시기능에 어떤 영향을 주는지에 대한 예비 분석 결과를 보고하였습니다

Materials and Methods Visual Field Visual Acuity 13 eyes of 7 RP patients before and after brief treatment (average 4 months) with VPA The dosage of VPA : 500 ~ 750 mg/day (half the dosage prescribed for other indications) Visual Field digitised Goldmann Kinetic Perimetry tracings - log-transformed ,VF loss/gain relative to baseline was calculated Visual Acuity using a Snellen chart at a distance of 20 feet (6.1 m) - converted to the logMAR score

Materials and Methods VF : corresponding areas of functioning retina (in mm2) were calculated based on the method used by Dagnelie VF areas(mm2) logVF ΔlogVF Improvement in VF : >2% increase Loss in VF : >2% decrease Unchanged : within 2% of baseline. VF loss in RP does not occur at a linear rate, and Massoff et al demonstrated that it may decline exponentially, with an estimated loss of about 0.10 loge units per year.15 VF areas (mm2) were loge-transformed (logVF) and the difference between follow-up and baseline was calculated (DlogVF).

Results VA : 20/47 to 20/32 (p<0.02) Most patients (n¼6,86%) had a family history or reported genotyping suggestive of an autosomal dominant form of RP (ADRP). The length of treatment on VPA was short, with a range from 2 to 6 months. Overall, average visual acuity was 20/47 per eye (range 20/20 tocount fingers at 3 feet (0.9 m) or 20/4000). 314 mm2 (the average baseline of subjects in this study translates to a positive change in Snellen score of approximately 20/47 to 20/32. Assuming no loss in visual acuity without treatment this change in acuity was significant (p<0.02). VA : 20/47 to 20/32 (p<0.02)

Results Visual field after treatment with valproic acid (VPA). (A) Goldmann kinetic perimetry tracings (B) VF area 의 변화를 각환자마다 우안, 좌안 두눈의 평균값으로 계산하여 나타낸 직선그래프입니다 위에서 말한 바와 같이 면적의 변화 기준을 2%로 잡았을 때 5명증가, 2명 감소, 2명 변화없음 Change in visual field: baseline and follow-up visual field areas are plotted for each individual patient (length offollow-up varied for each patient).

Results VF area 를 baseline 수치와 비교하였을 때 % 변화와 를 로그변환한 값의 차이를 계산한 표로서 The average change for all 13 eyes over the course of treatment was +0.16460.298 (range 0.012 to +0.942) logemm2, corresponding to an average increase of about 35 mm2. Assuming a baseline area of 314 mm2 (the average baseline of subjects in this study), this translates to an 11% increase in area of functioning retina.

Results The average change for all 13 eyes over the course of treatment was +0.16460.298 (range 0.012 to +0.942) logemm2, corresponding to an average increase of about 35 mm2. Assuming a baseline area of 314 mm2 (the average baseline of subjects in this study), this translates to an 11% increase in area of functioning retina. Vf 변화를 로그변환한 값을 사용하여 Scatterplot으로 나타낸 표입니다 좌안 우안 양안 을 Mean value SD

Results the Wilcoxon signed rank test 1.5% for 4 months 그러면 이러한 변화가 얼마나 통계학적으로 의의가 있는지 알아보기 위하여 분석Some studies estimated an average visual field loss of 0.10 loge units per year (equivalent to w10.5%/year) or about 0.033 loge units (w3.52%) for 4 months Natutal course 연간 0.1로그 유닛 감소

Discussion Valproic acid (VPA) potent inhibitor of histone deacetylase (HDAC) downregulate complement proteins and increase the levels of various neurotrophic factors downregulate the photoreceptor-specific inflammatory response pathway via apoptosis of microglial cells translation 과정에서 polypeptide를 정확하게 folding 시킬 물질 여러 작용 기전 중에서 망막 치료제로서의

Discussion In vitro data.. - VPA can induce cells to differentiate in culture. - Moreover, VPA has been shown to stimulate glial cells to differentiate into photoreceptor-like cells VPA may be an effective treatment for photoreceptor loss associated with RP. improvement of visual function in patients with RP as a result of pharmacological treatment. limited delay of progression of photoreceptor loss in RP patients have been reported with nutritional supplementation such as vitamin A3e5 본 논문의 예비 분석과

Discussion Limitation Small number of patients Brief follow-up period not genetically characterised placebo-controlled clinical trial with patients with well characterised RP genotypes genetic variation in known RP genes might account for the variability in therapeutic response to VPA

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