Antisense oligonucleotide (AO)‐mediated exon‐skipping therapies show promise in Duchenne muscular dystrophy (DMD), a devastating muscular disease caused by frame‐disrupting mutations in the DMD gene. However, insufficient systemic delivery remains a hurdle to clinical deployment. Here, we demonstrate that MOTS‐c, a mitochondria‐derived bioactive peptide, with an intrinsic muscle‐targeting property, augmented glycolytic flux and energy production capacity of dystrophic muscles in vitro and in vivo, resulting in enhanced phosphorodiamidate morpholino oligomer (PMO) uptake and activity in mdx mice. Long‐term repeated administration of MOTS‐c (500 μg) and PMO at the dose of 12.5 mg/kg/week for 3 weeks followed by 12.5 mg/kg/month for 3 months (PMO‐M) induced therapeutic levels of dystrophin expression in peripheral muscles, with up to 25‐fold increase in diaphragm of mdx mice over PMO alone. PMO‐M improved muscle function and pathologies in mdx mice without detectable toxicity. Our results demonstrate that MOTS‐c enables enhanced PMO uptake and activity in dystrophic muscles by providing energy and may have therapeutic implications for exon‐skipping therapeutics in DMD and other energy‐deficient disorders.
TX 75083-3836, U.S.A., fax 01-972-952-9435. AbstractIron sulfide scale deposition occurs throughout the Kaybob South field in Central Alberta. The scale typically forms directly on the tubular walls and generally results in corrosion of the metal beneath the scale crystallites. Under normal conditions, iron sulfide is soluble in hydrochloric acid. However, in sour gas and condensate environments, an asphaltene binder forms over the crystallites to limit, if not completely eliminate, the efficiency of chemical removal treatments. In such cases, the scale can only be effectively removed by mechanical means. A number of different methods of scale removal have been attempted, with an inconsistent record of success. For example, on some wells HCl Blends (7%-22% HCl) with xylene have been successful on the first attempt, on other wells this mixture required several attempts, and in some cases this technique resulted in no success. Mechanical options to resolve the problem include a tubing replacement (with an average cost of $150K -$550K CDN depending on completion complexity) or a milling treatment. The milling process, using coiled tubing, a motor and a mill, is costly and carries an element of risk.Well workovers are completed as required in this area on a regular basistypically one per year.This case study will define and present the Blaster scale removal system that has been developed to clean tubulars. The techniques have been continually improved and modified since their introduction in January 1998. Amoco Canada participated in the beta test of the system where several modifications to the process were made. Nineteen wells have been completed as part of the test program, the results of which has added valuable data to this case study.This paper will demonstrate that coiled tubing technology has provided an effective, efficient and economic method of scale removal.
Objectives/Scope Clients utilizing Coiled Tubing (CT) for straddle frac operations in multi-stage horizontal wells often encounter cement stringers preventing the frac bottomhole assembly (BHA) from reaching plug back total depth (PBTD) and the packer from sealing to the casing wall. This paper presents the learnings from a >90 well campaign of preparing for fracking operations using an electric line (e-line) milling and clean-out tool. The wells were mostly cemented, 4.5″ liners with frac sleeves. This technique reduced frac preparation costs in the cemented wells by approximately 30%. Methods, Procedures, Process The common practice in Southeast Saskatchewan (SE Sask) is to perform a “well prep” operation prior to the frac equipment's arrival to the well site. A CT unit equipped with a rotating scraper/mill—and associated fluids—is used for the clean-out, adding to the logistical coordination and well costs. Fluid has several costs associated with it: the cost of the fluid/water itself, heating for winter operations, trucking and disposal. However, “well prep” is considered “cheap insurance” by most operators working in SE Sask compared to the potential costs of a waiting frac crew. Results, Observations, Conclusions An operator in SE Sask has had success with an alternative clean-out solution to replace the use of fluid for well preps by introducing an e-line method consisting of an electric milling & clean-out tool with a casing collar locator (CCL). The mill is conveyed by e-line tractor and is equipped with a scraper mill to confirm the PBTD and ensure that there is no cement debris or sheath present that could negatively affect the frac operation. Various bailers can be added to collect the cement debris in the same run and ensure it is removed from the wellbore. In combination with the clean-out service, a CCL is deployed and logged to surface to pinpoint the exact sleeve location to be referenced during the frac operation. This new, efficient clean-out solution has proved slightly more time-consuming (~3-5 hours) but yielded significant cost savings of approximately 30% per well of prep costs. These savings come from using e-line equipment, eliminating fluid costs and offering inherently safer operations with a low carbon footprint. Novel/Additive Information Moreover, the paper will discuss the future applicability of this ‘additional application’ for pre-logging runs as a means to reduce total completion costs in cemented wells. This is achieved by using the e-line milling tool as a pre-run for casing inspections or cement evaluation logging.
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