{"id":6367,"date":"2026-10-19T09:48:49","date_gmt":"2026-10-19T09:48:49","guid":{"rendered":"https:\/\/phd.hi.is\/doktorsvorn\/doktorsvorn-i-lyfjafraedi-raul-oswaldo-perez-garcia\/"},"modified":"2026-10-19T09:48:49","modified_gmt":"2026-10-19T09:48:49","slug":"doktorsvorn-i-lyfjafraedi-raul-oswaldo-perez-garcia","status":"publish","type":"phd_defence","link":"https:\/\/phd.hi.is\/en\/doktorsvorn\/doktorsvorn-i-lyfjafraedi-raul-oswaldo-perez-garcia\/","title":{"rendered":"Doktorsv\u00f6rn \u00ed lyfjafr\u00e6\u00f0i – Raul Oswaldo Perez Garcia"},"content":{"rendered":"
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M\u00e1nudaginn 16. september 2024 ver Raul Oswaldo Perez Garcia doktorsritger\u00f0 s\u00edna \u00ed lyfjafr\u00e6\u00f0i vi\u00f0 Lyfjafr\u00e6\u00f0ideild H\u00e1sk\u00f3la \u00cdslands. Ritger\u00f0in ber heiti\u00f0: \u00der\u00f3un \u00e1 n\u00fdrri lyfjame\u00f0fer\u00f0 vi\u00f0 sj\u00f3nufreknum. Toward a first drug therapy for the treatment of retinitis pigmentosa. Andm\u00e6lendur eru dr. Eugen Stulz, pr\u00f3fessor vi\u00f0 University of Southhampton og dr. Kerstin Forsberg, pr\u00f3fessor vi\u00f0 KTH Royal institute of technology. Umsj\u00f3narkennari og lei\u00f0beinandi voru \u00deorsteinn Loftsson, pr\u00f3fessor vi\u00f0 Lyfjafr\u00e6\u00f0ideild og Nicolaas Schipper, Head of Manufacture vi\u00f0 RISE, Research Institutes of Sweden. Auk \u00feeirra s\u00e1tu \u00ed doktorsnefnd H\u00e1kon Hrafn Sigur\u00f0sson, pr\u00f3fessor og Per H. Svensson, pr\u00f3fessor.<\/p>\n

Elvar \u00d6rn Viktorsson, varadeildarforseti Lyfjafr\u00e6\u00f0ideildar, stj\u00f3rnar ath\u00f6fninni sem fer fram \u00ed H\u00e1t\u00ed\u00f0asal H\u00e1sk\u00f3la \u00cdslands og hefst kl. 13.00.<\/p>\n

\u00c1grip<\/strong><\/p>\n

Markmi\u00f0 verkefnisins var a\u00f0 \u00fer\u00f3a lyf sem byggja \u00e1 efnasameindinni CN03 til me\u00f0h\u00f6ndlunar \u00e1 retinitis pigmentosa (RP) og \u00f6\u00f0rum arfgengum sj\u00f3nhimnuhr\u00f6rnunarsj\u00fakd\u00f3mum. Fyrri ranns\u00f3knir h\u00f6f\u00f0u s\u00fdnt a\u00f0 CN03 hefur \u00e1hrif \u00e1 PR og a\u00f0ra skylda sj\u00fakd\u00f3ma. Fyrst var \u00fer\u00f3a\u00f0 efnaferli til framlei\u00f0slu \u00e1 CN03. A\u00f0fer\u00f0in byggir \u00e1 H-fosf\u00f3nat efnaferlum. T\u00f3kst a\u00f0 framlei\u00f0a 125 g af CN03 sem haf\u00f0i >99,9% hreinleika. \u00de\u00e1 var mynda\u00f0 torleysanlegt s\u00f6lt af CN03. \u00c1tta saltform af CN03 voru myndu\u00f0 og af \u00feeim voru 21 kristalform au\u00f0kennd, me\u00f0al annars me\u00f0 XRPD og NMR. S\u00f6lt af kals\u00edum, benetham\u00edni og benzat\u00edni (\u00fe.e. CN03-Ca, CN03-Bnet og CN03-BZ) h\u00f6f\u00f0u minnstu leysni e\u00f0a 300, 50 og 10 \u00b5g\/mL, og var CN03-BZ vali\u00f0 til frekari ranns\u00f3kna. A\u00f0 lokum voru \u00ferj\u00e1r n\u00e1skyldar hli\u00f0st\u00e6\u00f0ur CN03 samtengdar og virkni \u00feeirra ranns\u00f6ku\u00f0 in vitro. Ranns\u00f3knirnar s\u00fdndu a\u00f0 SP-CN03 haf\u00f0i svi\u00f0u\u00f0 l\u00edffr\u00e6\u00f0ileg \u00e1hrif \u00e1 lj\u00f3svi\u00f0taka og m\u00f3\u00f0urefni\u00f0 CN03 \u00e1n \u00feess a\u00f0 valda markt\u00e6kum eitur\u00e1hrifum \u00e1 fumurnar. Oxo-CN03 var \u00f3virkt. Virkasust af \u00feessum \u00feremur aflei\u00f0un var d\u00ed\u00f0\u00ed\u00f3-CN03. D\u00ed\u00f0\u00ed\u00f3-CN03 haf\u00f0i mestu l\u00edffr\u00e6\u00f0ilega virkni, olli minnstum eiturverkunum og haf\u00f0i mj\u00f6g litla vatnsleysni, allt eiginleikar sem gagnast lyfi til me\u00f0fer\u00f0ar \u00e1 RP og gefa \u00e1 me\u00f0 innd\u00e6lingu \u00ed glerhlaup augans.<\/p>\n

Abstract<\/strong><\/p>\n

The goal of this project was to contribute to the pharmaceutical development of CN03, the lead candidate for drug treatment of retinitis pigmentosa (RP) and other inherited retinal degenerations (IRDs). RP is an inherited neurodegeneration of the retina with with currently no treatments available on the market. The first task was to develop a chemical process to manufacture large quantities of CN03. A synthetic strategy was designed which makes use of H-phosphonate chemistry to construct the required 3\u2032,5\u2032-cyclic RP-phosphorothioate. The internal cyclization and sulfurization of the nucleoside 5\u2032-H-phosphonate monoester to afford the 3\u2032,5\u2032-cyclic phosphorothioate could be steered to obtain the desired RP-diastereomer with 90% selectivity over the thermodynamically favored SP-phosphorothioate. About 125 g of the CN03, purity >99.9%, were prepered. Access to larger amouts of the drug compound enabled further pharmaceutical development. Next, solid forms of CN03 with low aqueous solubility were investigated. This was sought in order to extend the half-life of the drug compound in the eye, which is critical to aid in reducing the frequency of intravitreal injections \u2013 the most likely route of administration. Eight salt forms of CN03 were synthesized. A total of 21 crystal modifications were identified with XRPD, some of which were characterized further with NMR. The calcium, benethamine, and benzathine salts of CN03 (i.e., CN03-Ca, CN03-Bnet, and CN03-BZ) possessed sub-milligram solubilities in water, or 300, 50, and 10 \u00b5g\/mL, respectively. CN03-BZ was identified as the most promising CN03 solid form based on the lowest solubility as well as lowest hygroscopicity. Finally, three closely related analogues of CN03 were prepared and their biological effects studied in in vitro RP model. The phosphate analogue and the SP-phosphorothioate diastereomer (oxo-CN03 and SP-CN03) were expected to promote photoreceptor cell degeneration, while the activity of the corresponding phosphorodithioate (dithio-CN03) was unknown. In vitro studies found that SP-CN03 was not toxic to photoreceptors, but instead preserved photoreceptors to a similar level as CN03 itself. Oxo-CN03 was not significantly more toxic than CN03 or SP-CN03, and as expected provided no neuroprotection. The most promising compound was the novel dithio-CN03, which was identified as the least toxic and provided significantly more protection to photoreceptors than current drug candidate CN03. The solubility of dithio-CN03 as a triethylammonium salt was determined to be 1.8 mM, compared to 13.7 mM for the same salt of CN03, which further establishes dithio-CN03 as a potentially more effective drug compound as part of sustained-release formulations for treatment of RP via intravitreal injections.<\/p>\n

Um doktorsefni\u00f0 <\/strong><\/p>\n

Raul Oswaldo Perez Garcia f\u00e6ddist \u00ed Maracaibo \u00e1 Venezuela \u00e1ri\u00f0 1993 og flutti til Noregs \u00feegar hann var 14 \u00e1ra. Hann hlaut BA-gr\u00e1\u00f0u \u00ed Biochemistry & Biotechnology fr\u00e1 H\u00e1sk\u00f3lanum \u00ed Stavanger \u00ed Noregi \u00e1ri\u00f0 2015. Raul stunda\u00f0i meistaran\u00e1m \u00ed Biochemistry vi\u00f0 \u00ed Mohali \u00e1 Indlandi fr\u00e1 2015 og lauk meistaran\u00e1mi \u00e1ri\u00f0 2017. Hann hefur stunda\u00f0 doktorsn\u00e1m vi\u00f0 RISE Research Institutes of Sweden og vi\u00f0 H\u00e1sk\u00f3la \u00cdslands fr\u00e1 \u00e1rinu 2018, undir handlei\u00f0slu dr. Nicolaas Schippers og \u00deorsteins Loftssonar, pr\u00f3fessors emeritus, vi\u00f0 Lyfjafr\u00e6\u00f0ideild H\u00e1sk\u00f3la \u00cdslands.<\/p>\n<\/div><\/div>","protected":false},"featured_media":5699,"template":"","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"default","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","ast-disable-related-posts":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"_phd_date_start":"2024-09-16T13:00:00+00:00","_phd_date_end":"2024-09-16T16:00:00+00:00","_phd_location":"A\u00f0albygging H\u00e1t\u00ed\u00f0asalur","_phd_admission":"A\u00f0gangur \u00f3keypis","_phd_thesis_title":"","_phd_source_url":"https:\/\/gamli.hi.is\/vidburdir\/doktorsvorn_i_lyfjafraedi_raul_oswaldo_perez_garcia","_phd_source_node_id":"434988","_phd_source_type":"vidburdir","_phd_member_id":904,"footnotes":""},"phd_school":[60,64],"phd_discipline":[66],"class_list":["post-6367","phd_defence","type-phd_defence","status-publish","has-post-thumbnail","hentry","phd_school-heilbrigdisvisindasvid","phd_school-lyfjafraedideild","phd_discipline-phd-i-lyfjafraedi"],"_links":{"self":[{"href":"https:\/\/phd.hi.is\/en\/wp-json\/wp\/v2\/phd_defence\/6367","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/phd.hi.is\/en\/wp-json\/wp\/v2\/phd_defence"}],"about":[{"href":"https:\/\/phd.hi.is\/en\/wp-json\/wp\/v2\/types\/phd_defence"}],"version-history":[{"count":0,"href":"https:\/\/phd.hi.is\/en\/wp-json\/wp\/v2\/phd_defence\/6367\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/phd.hi.is\/en\/wp-json\/wp\/v2\/media\/5699"}],"wp:attachment":[{"href":"https:\/\/phd.hi.is\/en\/wp-json\/wp\/v2\/media?parent=6367"}],"wp:term":[{"taxonomy":"phd_school","embeddable":true,"href":"https:\/\/phd.hi.is\/en\/wp-json\/wp\/v2\/phd_school?post=6367"},{"taxonomy":"phd_discipline","embeddable":true,"href":"https:\/\/phd.hi.is\/en\/wp-json\/wp\/v2\/phd_discipline?post=6367"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}