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Treatment of Retinitis Induced by Cytomegalovirus Using Intravitreal Fomivirsen (ISIS 2922)
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
To better understand the mechanisms of fomivirsen antiviral activities, additional studies were performed. To avoid non-antisense effects and to avoid binding to viral coat proteins in the antiviral assays, U373 cells were transformed with a cDNA that encoded only the fomivirsen target, a CMV immediate-early 55 kDa protein. The activities of fomivirsen and other phosphorothioate oligonucleotides in this assay were compared to those observed in a traditional antiviral assay to dissect out potential mechanisms of action. A direct assay of inhibition of production of the 55 kDa protein revealed that fomivirsen displayed potent, sequence-dependent effects consistent with an antisense mechanism. Treatment of these cells with fomivirsen also resulted in loss of the message for the 55 kDa protein, consistent with RNase H mediated degradation. Thus, in U373 cells transformed with the antisense target, the drug displayed potent antisense activity (Anderson et al., 1996).
Biotechnology products and indications II
Published in Ronald P. Evens, Biotechnology, 2020
Inhibition of aberrant mRNA and replacing nonfunctional mutated genes as causes of serious disease has been a very major development challenge especially regarding and requiring intracellular delivery and optimal cell targeting. Improvement in oligonucleotide delivery has resulted in very promising products in the last few years. Eleven products have been approved for patient care, see Table 9.4, The first antisense molecule (fomivirsen) was used to treat Cytomegalovirus (CMV) retinitis in HIV patients, but it has been removed from the market because of low usage related to improved anti-HIV treatments and little CMV retinitis. Difficult administration (multiple intra-vitreal injections) limits Macugen use for its ophthalmologic indication. In the rare disease area, severe familial hypercholesterolemia, transthyretin amyloidosis and Duchenne’s muscle atrophy now have treatments. Gene therapies with curative potential finally have become available for Duchenne’s muscular dystrophy and spinal muscle atrophy.
Cytomegalovirus
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Fomivirsen is a phosphorothioate oligonucleotide that inhibits CMV replication through an antisense mechanism [112]. The drug has activity against strains of CMV that are resistant to ganciclovir and foscarnet. It is administered by intravitreal injection for treatment of CMV retinitis. Like other anti-CMV therapy, it must be given in induction doses followed by maintenance therapy. Fomivirsen is approved for the local treatment of CMV retinitis in patients unable to take other anti-CMV drugs or who have failed treatment. Side effects of fomivirsen include ocular inflammation (which may require therapy with topical steroids) and increased intraocular pressure.
Lipoplex-based therapeutics for effective oligonucleotide delivery: a compendious review
Published in Journal of Liposome Research, 2020
Pirthi Pal Singh, Veena Vithalapuram, Sunita Metre, Ravinder Kodipyaka
Of all the NAs evaluated clinically as of January 2019, the regulatory authorities assessed that seven provided clear clinical benefit in rigorously controlled trials leading to the market approval. Table 2 summarizes the nucleic acid formulations clinically approved and marketed so far. Fomivirsen (Vitravene™) was the first ASO approved for marketing by FDA in 1998 and by EMEA in 1999 for the treatment of patients with cytomegalovirus (CMV) retinitis. This 21-mer phosphorothioate oligodeoxynucleotide (containing a CpG motif-cytosine being 5-prime to the guanine base separated by only one phosphate group), was developed in a collaboration of Isis Pharmaceuticals with Novartis Ophthalmics. Treatment consisted of weekly vitreal injections of 165 mg of fomivirsen followed by maintenance injections. Subsequently, due to the development of high-activity anti-retroviral therapy, marketing the drug was stopped in Europe (in 2002) followed by United States (in 2006) as the number of CMV cases decreased dramatically (Group 2002).
Strategies for improving the specificity of siRNAs for enhanced therapeutic potential
Published in Expert Opinion on Drug Discovery, 2018
Aditya Kiran Gatta, Raghu Chandrashekhar Hariharapura, Nayanabhirama Udupa, Meka Sreenivasa Reddy, Venkata Rao Josyula
Several researchers have explored the option of backbone modification to increase the efficacy of the siRNA. The basic backbone containing the phosphodiester bonds is substituted with the phosphorothioate or the boranophosphate. This modification improved the serum stability of the siRNA [90]. Fomivirsen is marketed under the brand name Vitravene. It is an oligonucleotide drug consisting of a phosphorothioate modification. Interestingly, it is the only oligonucleotide that was approved by the FDA in 1998 to treat retinitis [103,104]. However, this drug is currently withdrawn [105]. This modification is studied in great detail as it has nuclease stability and reduces renal clearance by enhancing binding with plasma proteins and improves the pharmacokinetic profiles. Although it was observed to have significant nuclease stability, it had a negative impact on silencing the activity. The boranophosphate modification is a substitution with BH3 (borane moiety) in the position of nonbridging phosphate oxygen atom. Unlike the phosphorothioate modification, this modification retains the functionality and the serum nuclease stability [90]. Apart from the chemical modifications, other nucleoside modifications like dihydrouridine, pseudouridine, and 2ʹ-thiouridine were also evaluated for the potency of the siRNA [106]. Recently, a database ‘siRNAmod’ is developed, which provides information about 128 types of modifications and on more than 5000 chemically modified siRNAs and their biological activities. The database is maintained on the LAMP (Linux Apache MySQL PHP) software. This database provides good evidence for the experimentally validated siRNAs, but it is yet to integrate to the designing algorithm [107].
Antisense Oligonucleotide Therapy for Ophthalmic Conditions
Published in Seminars in Ophthalmology, 2021
Kevin Ferenchak, Iris Deitch, Rachel Huckfeldt
In 1998, fomivirsen was the first AON therapy approved by the FDA.33 This drug was administered by intravitreal injection to treat cytomegalovirus (CMV) retinitis for patients who either had failed or were ineligible for conventional therapy. Fomivirsen was a first generation AON that required multiple injections per month typically beginning with weekly dosing for 3 weeks followed by every other week for three more injections for peripheral disease.10,11 Its mechanism was limiting viral replication by blocking the formation of an essential viral protein and limiting CMV adsorption into host cells.34 Preclinical studies demonstrated that it had at least 30-fold more antiviral activity than ganciclovir.9 Primate models demonstrated maximum retinal concentration after 2 days with a half-life of 78 days, and human studies had a vitreous half-life of 55 h. 34 In a randomized clinical trial, eyes treated with fomivirsen had no retinal detachments and also demonstrated a statistically significant delay in progression of peripheral disease from 13 days in the delayed treatment group to 71 days in the immediate treatment group.10,11 There were no observed systemic side effects, and the ocular side effects were transient elevated intraocular pressure and inflammation that improved with topical corticosteroids.10,11,35 Fomivirsen was a potent and effective treatment which it was first discovered, but by the time it was approved for clinical use there was a significant decrease in the prevalence of AIDS and CMV retinitis with the advent of antiretroviral therapy. Given the low demand for fomivirsen, it was removed from the market in 2001.