Nassim Usman - Academia.edu (original) (raw)

Papers by Nassim Usman

Investigative Ophthalmology & Visual Science, Jul 13, 2018

Eleven to 15 million people in the US have AMD (NEI estimates, Pennington and DeAngelis 2017). Vi... more Eleven to 15 million people in the US have AMD (NEI estimates, Pennington and DeAngelis 2017). Vision is most affected in the late stages of the disease, wet age-related macular degeneration (AMD) and geographic atrophy (GA). Wet AMD accounts for approximately 10 – 15% of AMD cases (AMD alliance). Wet AMD is well treated by intravitreal VEGF blockade yielding a >$4B market. Geographic atrophy nearly as prevalent as wet AMD (amdbook.org), yet has no approved drugs.

Trends in Biochemical Sciences, Sep 1, 1992

$Research paper thumbnail of Crystallization and preliminary X-ray diffraction analysis of double-helical RNA octamers$

Acta Crystallographica Section D-biological Crystallography, Nov 1, 1995

New Drugs for Asthma, Allergy and COPD, 2001

RNA (New York, N.Y.), 1996

Proliferation of injured smooth muscle cells contributes to the reocclusion or restenosis of coro... more Proliferation of injured smooth muscle cells contributes to the reocclusion or restenosis of coronary arteries that often occurs following angioplasty procedures. We have identified and optimized nuclease-resistant ribozymes that efficiently cleave c-myb RNA. Three ribozymes targeting different sites in the c-myb mRNA were synthesized chemically and delivered to rat aortic smooth muscle cells with cationic lipids; all three inhibited serum-stimulated cell proliferation significantly. RNA molecules with two base substitutions in the catalytic core that render the ribozyme catalytically inactive had little effect on smooth muscle cell proliferation. Ribozymes with scrambled binding arm sequences also failed to affect cell cycle progression of vascular smooth muscle cells. Furthermore, inhibition of rat smooth muscle cell proliferation correlated with a reduction in intact c-myb mRNA. Efficacy of the chemically-modified ribozyme was compared directly to phosphorothioate antisense oligo...

Current Oncology Reports, 2001

Several inhibitors of angiogenesis are being developed for the treatment of cancer. One dominant ... more Several inhibitors of angiogenesis are being developed for the treatment of cancer. One dominant strategy involves disruption of the vascular endothelial growth factor (VEGF) pathway by inhibition of the receptors for VEGF. Inhibition of the VEGF receptor activity can be accomplished using catalytic RNA molecules known as ribozymes, which downregulate VEGF receptor function by specifically cleaving the mRNAs for the primary VEGF receptors, Flt-1 and KDR. Significant inhibition of angiogenesis using ribozymes against both receptors has been demonstrated. In animal tumor models, antitumor effects are most pronounced with the anti-Flt-1 ribozyme known as Angiozyme (Ribozyme Pharmaceuticals, Boulder, CO). Extensive preclinical studies have demonstrated no significant toxicities. Clinical trials of Angiozyme are currently in progress for patients with advanced malignancy. Preliminary results demonstrate Angiozyme to be well tolerated, without significant side effects. Several phase II trials are underway for patients with advanced malignancy to test therapeutic efficacy.

Science, 1991

An acceptor stem G3.U70 base pair is a major determinant of the identity of an alanine transfer R... more An acceptor stem G3.U70 base pair is a major determinant of the identity of an alanine transfer RNA. Hairpin helices and RNA duplexes consisting of complementary single strands are aminoacylated with alanine if they contain G3.U70. Chemical synthesis of RNA duplexes enabled the introduction of base analogs that tested the role of specific functional groups in the major and minor grooves of the RNA helix. The results of these experiments indicate that an unpaired guanine 2-amino group at a specific position in the minor groove of an RNA helix marks a molecule for aminoacylation with alanine.

Cancer Chemotherapy and Pharmacology, 2005

Purpose: RPI.4610 (ANGIOZYME) is a chemically stabilized ribozyme targeting vascular endothelial ... more Purpose: RPI.4610 (ANGIOZYME) is a chemically stabilized ribozyme targeting vascular endothelial growth factor receptor 1. The purpose of this study was to evaluate the safety and pharmacokinetics of RPI.4610 in combination with carboplatin and paclitaxel in patients with advanced solid tumors. Methods: The study used a sequential treatment design evaluating a single dose level for all three drugs: paclitaxel 175 mg m À2 and carboplatin AUC=6 on day 1 of a 21day cycle, and RPI.4610 100 mg m À2 day À1 beginning on day 8 and continuing daily thereafter. Pharmacokinetic samples were drawn on day 1 of courses 1 (chemotherapy alone) and 2 (chemotherapy+RPI.4610), and on day 8 of course 1 (RPI.4610 alone). Ratios were generated by comparing the pharmacokinetic parameters for the combination of carboplatin with paclitaxel when administered alone or together with RPI.4610. Results: Twelve patients were enrolled in this trial and received two to six courses of treatment each. The most common grade 3-4 toxicities were neutropenia (three patients), thrombocytopenia (three patients), pain (three patients), anemia (two patients) and fatigue (two patients). The ratio of the mean maximum plasma concentration (Cmax) for carboplatin when administered with paclitaxel alone versus when administered with paclitaxel and RPI.4610 was 1.07 (90% confidence interval, 0.77-1.37). Similarly, the ratio of the mean AUC 0-last for carboplatin was 1.04 (0.73-1.35). For paclitaxel the ratio of the mean Cmax when administered with carboplatin alone versus with carboplatin and RPI.4610 was 1.17 (1.03-1.31), and the ratio of the mean AUC 0-last was 1.17 (1.04-1.30). Objective tumor responses were observed and included one patient with a complete response (bladder cancer) and one patient with a partial response (esophageal cancer). Conclusions: These results indicate that RPI.4610, carboplatin, and paclitaxel can be administered safely in combination without substantial pharmacokinetic interactions.

Journal of the American Chemical Society, 1994

Carriers for transport of nucleotides across model membranes have been developed from lipophilic ... more Carriers for transport of nucleotides across model membranes have been developed from lipophilic quaternary ammonium salt^^^^ or from principles of molecular recognition.4 We recently introduced synthetic receptors for adenylic acids that involve molecular recognition through hydrogen bonding, aromatic stacking effects, and salt bridges.3 These molecules have now been further refined to yield highly lipophilic molecules that show good activity for selective transport of short nucleotides across liquid membranes and extraction of longer oligonucleotides into organic solvents. The molecules la, lb, and 2 were assembled from Kemp triacid derivatives: carbazole spacer subunit^,^^^ and guanidinium complements for according to described synthetic routes.5JO Optically pure guanidinium derivatives, having the S,S configuration, were used in all cases. The transport studies used a simple U-tube apparatus in which 1,2-dichloroethane (DCE) represented a liquid membrane between two aqueous phases." The source phase contained the nucleotides at the concentrations indicated in Table 1 ; transport (and active transport) was promoted by 10 mM sodium chloride in the receiving phase. Carrier 2 showed the highest selectivity for mononucleotides of adenine us guanine, but it is likely that the lower solubility of

The Journal of Clinical Pharmacology

The pharmacokinetics and tolerability of a chemically stabilized synthetic ribozyme (ANGIOZYME) t... more The pharmacokinetics and tolerability of a chemically stabilized synthetic ribozyme (ANGIOZYME) targeting the Flt-1 VEGF receptor mRNA were evaluated in healthy volunteers. In a placebo-controlled, single-dose escalation study, ribozyme was administered as a 4-hour i.v. infusion of 10 or 30 mg/m2 or as a s.c. bolus of 20 mg/m2. Peak ribozyme plasma concentrations of 1.5 and 3.8 micrograms/mL were observed after the 10 and 30 mg/m2 i.v. infusions, respectively. When normalized to dose, AUC values as well as peak concentrations increased proportionally as the dose was increased from 10 to 30 mg/m2. Peak concentrations of 0.9 microgram/mL were observed approximately 3.25 hours after a 20 mg/m2 s.c. bolus of ribozyme. The dose-normalized AUCs obtained after s.c. dosing were compared to the mean dose-normalized AUC after i.v. dosing to estimate an absolute s.c. bioavailability (f) of approximately 69%. An average elimination half-life of 28 to 40 minutes was observed after i.v. administration, which increased to 209 minutes after s.c. administration. Only 4 of 12 reported adverse events were possibly related to administration of ribozyme (headache and somnolence). Thus, ribozyme administration was well tolerated after a single 4-hour i.v. infusion of up to 30 mg/m2 or a single s.c. bolus of 20 mg/m2.

La presente invention concerne des compositions et des methodes permettant d'inhiber l'ex... more La presente invention concerne des compositions et des methodes permettant d'inhiber l'expression d'un gene cible dans une cellule. Le procede consiste a introduire des constructions d'ARNi double brin a structure tripartite dans les cellules et a reduire l'expression de l'ARN messager correspondant dans ces cellules. Les constructions, qui peuvent etre encapsulees ou administrees sous forme de constructions d'ARNi sequestrees, different du petit ARN interferent canonique etant donne qu'elles presentent une structure tripartite dont la formule generale comprend (1) un noyau d'ARNi (natif ou raccourci), (2) une ou plusieurs fractions terminales fixees au noyau d'ARNi, et eventuellement (3) un lieur situe entre le noyau d'ARNi et la fraction terminale. Une fois encapsulees dans des vehicules de sequestration, les constructions sont activees en vue d'une regulation genetique par application de certaines formes d'energie.

L'invention concerne des molecules detectrices a acides nucleiques et des methodes de detecti... more L'invention concerne des molecules detectrices a acides nucleiques et des methodes de detection et d'amplification d'agents de signalisation a l'aide de constructions d'acides nucleiques enzymatiques, notamment des molecules d'acides nucleiques enzymatiques a tete de marteau, des inozymes, des molecules d'acides nucleiques enzymatiques G-cleaver, des zinzymes, des amberzymes et ADNzymes; des materiels de detection et d'amplification; leur utilisation en diagnostic, dans des circuits d'acides nucleiques, les ordinateurs a acides nucleiques ainsi que d'autres utilisations.

A nucleic acid molecule ENZYME CONTAINING ONE OR MORE MIMIC NO NUCLEOTIDE AND HAVING ACTIVITY TO ... more A nucleic acid molecule ENZYME CONTAINING ONE OR MORE MIMIC NO NUCLEOTIDE AND HAVING ACTIVITY TO ADHERE TO A DNA molecule or RNA