Guangzhou KangRui Biological Pharmaceutical Technology Co.

Guangzhou, China

Guangzhou KangRui Biological Pharmaceutical Technology Co.

Guangzhou, China
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Patent
The Regents Of The University Of California and Guangzhou Kangrui Biological Pharmaceutical Technology Co. | Date: 2017-06-28

The present invention provides sterols and uses thereof to treat vision disorders. In one embodiment, composition comprising pharmaceutically effective amount of lanosterol is used to treat and/or prevent vision disorders in a subject. In another embodiment, composition comprising pharmaceutically effective amount of lanosterol is used to treat cataract or blindness/impaired vision in a subject. In yet another embodiment, composition comprising lanosterol is used to dissolve amyloid-like fibrils of crystallin proteins.


Patent
Guangzhou KangRui Biological Pharmaceutical Technology Co. | Date: 2016-10-20

Disclosed are an anti-abnormal proliferation of angiogenesis compound represented by formula I, use and intermediate thereof. The compound has good effect against abnormal proliferation of angiogenesis, and the activity of the compound is produced by inhibiting VEGFR2. The compound can be used for treating diseases, such as wet macular degeneration, inflammation, malignant tumor and the like, caused by abnormity of angiogenesis and protein kinases such as VEGFR2, FGFR2 and the like.


Zhao L.,University of Sichuan | Zhao L.,Sun Yat Sen University | Zhao L.,University of California at San Diego | Zhao L.,Peking University | And 50 more authors.
Nature | Year: 2015

The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment. © 2015 Macmillan Publishers Limited. All rights reserved.


Lin H.,Sun Yat Sen University | Ouyang H.,Sun Yat Sen University | Zhu J.,University of California at San Diego | Huang S.,Sun Yat Sen University | And 44 more authors.
Nature | Year: 2016

The repair and regeneration of tissues using endogenous stem cells represents an ultimate goal in regenerative medicine. To our knowledge, human lens regeneration has not yet been demonstrated. Currently, the only treatment for cataracts, the leading cause of blindness worldwide, is to extract the cataractous lens and implant an artificial intraocular lens. However, this procedure poses notable risks of complications. Here we isolate lens epithelial stem/progenitor cells (LECs) in mammals and show that Pax6 and Bmi1 are required for LEC renewal. We design a surgical method of cataract removal that preserves endogenous LECs and achieves functional lens regeneration in rabbits and macaques, as well as in human infants with cataracts. Our method differs conceptually from current practice, as it preserves endogenous LECs and their natural environment maximally, and regenerates lenses with visual function. Our approach demonstrates a novel treatment strategy for cataracts and provides a new paradigm for tissue regeneration using endogenous stem cells. © 2016 Macmillan Publishers Limited.


Skowronska-Krawczyk D.,University of California at San Diego | Zhao L.,University of California at San Diego | Zhao L.,Sun Yat Sen University | Zhao L.,Peking University | And 43 more authors.
Molecular Cell | Year: 2015

Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age, and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. Here, we demonstrate that the genetic effect of the SIX6 risk variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene, p16INK4a (cyclin-dependent kinase inhibitor 2A, isoform INK4a). We further show that the upregulation of homozygous SIX6 risk alleles (CC) leads to an increase in p16INK4a expression, with subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and in human POAG eyes. Our data indicate that SIX6 and/or IOP promotes POAG by directly increasing p16INK4a expression, leading to RGC senescence in adult human retinas. Our study provides important insights linking genetic susceptibility to the underlying mechanism of RGC death and provides a unified theory of glaucoma pathogenesis. Zhang et al. report p16INK4a as a downstream integrator of diverse signals, such as inherited genetic risk, age, and intraocular pressure, in the pathogenesis of glaucoma. They demonstrate that upregulation of SIX6 upon stress directly increases p16INK4a, leading to retinal ganglion cell senescence and death. © 2015 Elsevier Inc.


Ghazi N.G.,King Khaled Eye Specialist Hospital | Ghazi N.G.,University of Virginia | Abboud E.B.,King Khaled Eye Specialist Hospital | Nowilaty S.R.,King Khaled Eye Specialist Hospital | And 26 more authors.
Human Genetics | Year: 2016

MERTK is an essential component of the signaling network that controls phagocytosis in retinal pigment epithelium (RPE), the loss of which results in photoreceptor degeneration. Previous proof-of-concept studies have demonstrated the efficacy of gene therapy using human MERTK (hMERTK) packaged into adeno-associated virus (AAV2) in treating RCS rats and mice with MERTK deficiency. The purpose of this study was to assess the safety of gene transfer via subretinal administration of rAAV2-VMD2-hMERTK in subjects with MERTK-associated retinitis pigmentosa (RP). After a preclinical phase confirming the safety of the study vector in monkeys, six patients (aged 14 to 54, mean 33.3 years) with MERTK-related RP and baseline visual acuity (VA) ranging from 20/50 to <20/6400 were entered in a phase I open-label, dose-escalation trial. One eye of each patient (the worse-seeing eye in five subjects) received a submacular injection of the viral vector, first at a dose of 150 µl (5.96 × 1010vg; 2 patients) and then 450 µl (17.88 × 1010vg; 4 patients). Patients were followed daily for 10 days at 30, 60, 90, 180, 270, 365, 540, and 730 days post-injection. Collected data included (1) full ophthalmologic examination including best-corrected VA, intraocular pressure, color fundus photographs, macular spectral domain optical coherence tomography and full-field stimulus threshold test (FST) in both the study and fellow eyes; (2) systemic safety data including CBC, liver and kidney function tests, coagulation profiles, urine analysis, AAV antibody titers, peripheral blood PCR and ASR measurement; and (3) listing of ophthalmological or systemic adverse effects. All patients completed the 2-year follow-up. Subretinal injection of rAAV2-VMD2-hMERTK was associated with acceptable ocular and systemic safety profiles based on 2-year follow-up. None of the patients developed complications that could be attributed to the gene vector with certainty. Postoperatively, one patient developed filamentary keratitis, and two patients developed progressive cataract. Of these two patients, one also developed transient subfoveal fluid after the injection as well as monocular oscillopsia. Two patients developed a rise in AAV antibodies, but neither patient was positive for rAAV vector genomes via PCR. Three patients also displayed measurable improved visual acuity in the treated eye following surgery, although the improvement was lost by 2 years in two of these patients. Gene therapy for MERTK-related RP using careful subretinal injection of rAAV2-VMD2-hMERTK is not associated with major side effects and may result in clinical improvement in a subset of patients. © 2016, Springer-Verlag Berlin Heidelberg.


Gross A.M.,University of California at San Diego | Jaeger P.A.,University of California at San Diego | Kreisberg J.F.,University of California at San Diego | Licon K.,University of California at San Diego | And 13 more authors.
Molecular Cell | Year: 2016

HIV-infected individuals are living longer on antiretroviral therapy, but many patients display signs that in some ways resemble premature aging. To investigate and quantify the impact of chronic HIV infection on aging, we report a global analysis of the whole-blood DNA methylomes of 137 HIV+ individuals under sustained therapy along with 44 matched HIV- individuals. First, we develop and validate epigenetic models of aging that are independent of blood cell composition. Using these models, we find that both chronic and recent HIV infection lead to an average aging advancement of 4.9 years, increasing expected mortality risk by 19%. In addition, sustained infection results in global deregulation of the methylome across >80,000 CpGs and specific hypomethylation of the region encoding the human leukocyte antigen locus (HLA). We find that decreased HLA methylation is predictive of lower CD4 / CD8 T cell ratio, linking molecular aging, epigenetic regulation, and disease progression. Gross et al. investigate the impact of chronic HIV infection by profiling the DNA methylomes of HIV+ individuals and matched HIV- controls. Using epigenetic models of aging, they observe that HIV+ individuals show an age advancement of 4.9 years in whole blood and validate these results in pure cell samples. © 2016 Elsevier Inc.


Li G.,University of Sichuan | Xu F.,Sun Yat Sen University | Zhu J.,Institute for Engineering in Medicine | Krawczyk M.,Institute for Engineering in Medicine | And 28 more authors.
Journal of Biological Chemistry | Year: 2015

PAX6 is a master regulatory gene involved in neuronal cell fate specification. It also plays a critical role in early eye field and subsequent limbal stem cell (LSC) determination during eye development. Defects in Pax6 cause aniridia and LSC deficiency in humans and the Sey (Small eye) phenotype in mice (Massé, K., Bhamra, S., Eason, R., Dale, N., and Jones, E. A. (2007) Nature 449, 1058-1062). However, how PAX6 specifies LSC and corneal fates during eye development is not well understood. Here, we show that PAX6 is expressed in the primitive eye cup and later in corneal tissue progenitors in early embryonic development. In contrast, p63 expression commences after that of PAX6 in ocular adnexal and skin tissue progenitors and later in LSCs. Using an in vitro feeder-free culture system, we show that PAX6 knockdown in LSCs led to up-regulation of skin epidermis-specific keratins concomitant with differentiation to a skin fate. Using gene expression analysis, we identified the involvement of Notch, Wnt, and TGF-β signaling pathways in LSC fate determination. Thus, loss of PAX6 converts LSCs to epidermal stem cells, as demonstrated by a switch in the keratin gene expression profile and by the appearance of congenital dermoid tissue. © 2015, American Society for Biochemistry and Molecular Biology Inc. All rights reserved.


PubMed | Howard Hughes Medical Institute, Shanghai JiaoTong University, China Pharmaceutical University, University of Sichuan and 4 more.
Type: Journal Article | Journal: Molecular cell | Year: 2015

Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age, and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. Here, we demonstrate that the genetic effect of the SIX6 risk variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene, p16INK4a (cyclin-dependentkinase inhibitor 2A, isoform INK4a). Wefurther show that the upregulation of homozygous SIX6 risk alleles (CC) leads to an increase in p16INK4a expression, with subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and inhuman POAG eyes. Our data indicate that SIX6 and/or IOP promotes POAG by directly increasing p16INK4a expression, leading to RGC senescence in adult human retinas. Our study provides important insights linking genetic susceptibility to the underlying mechanism of RGC death and provides a unified theory of glaucoma pathogenesis.

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