Role of nonhuman primate models in the discovery and clinical development of selective progesterone receptor modulators (SPRMs)

Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands that exert clinically relevant tissue-selective progesterone agonist, antagonist, partial, or mixed agonist/antagonist effects on various progesterone target tissues in an in vivo situation depending on the biological action studied. The SPRM asoprisnil is being studied in women with symptomatic uterine leiomyomata and endometriosis. Asoprisnil shows a high degree of uterine selectivity as compared to effects on ovulation or ovarian hormone secretion in humans. It induces amenorrhea and decreases leiomyoma volume in a dose-dependent manner in the presence of follicular phase estrogen concentrations. It also has endometrial antiproliferative effects. In pregnant animals, the myometrial, i.e. labor-inducing, effects of asoprisnil are blunted or absent. Studies in non-human primates played a key role during the preclinical development of selective progesterone receptor modulators. These studies provided the first evidence of uterus-selective effects of asoprisnil and structurally related compounds, and the rationale for clinical development of asoprisnil

Treatment of IgG4-related disease-associated hypertrophic pachymeningitis with intrathecal rituximab: a case report

IgG4-related disease-associated hypertrophic pachymeningitis (IgG4RD-HP) is a fibroinflammatory autoimmune disorder in which diagnosis is difficult without biopsy. Guidance on management of disease refractory to glucocorticoids and intravenous rituximab is limited. We present the case of a 68-year-old woman with IgG4RD-HP who developed sensorineural hearing loss with associated bulky basilar pachymeningeal enhancement. Her cerebrospinal fluid was inflammatory and had an elevated IgG4 concentration, strongly suggestive of IgG4RD-HP. Biopsy of involved meninges was not possible due to surgical risk. Over years she developed bilateral optic neuropathies and hydrocephalus, requiring intravenous rituximab and ventriculoperitoneal shunt. Her disease was refractory to glucocorticoids. Despite maintenance intravenous rituximab, she developed slowly progressive symptoms of intracranial hypertension and hydrocephalus with persistently inflammatory spinal fluid. Switching to intrathecal rituximab therapy led to dramatic improvement in gait and headache and reduced pachymeningeal bulk and metabolic activity. In patients with IgG4RD-HP refractory to glucocorticoids and intravenous rituximab, intrathecal rituximab may be an efficacious therapy

Safety of lenadogene nolparvovec gene therapy over 5 years in 189 patients with Leber hereditary optic neuropathy

Purpose: Evaluate the safety profile of lenadogene nolparvovec (Lumevoq®) in patients with Leber hereditary optic neuropathy. Design: Pooled analysis of safety data from 5 clinical studies. Methods: A total of 189 patients received single unilateral or bilateral intravitreal injections of a recombinant adeno-associated virus 2 (rAAV2/2) vector encoding the human wild-type ND4 gene. Adverse events (AEs) were collected throughout the studies, up to 5 years. Intraocular inflammation and increased intraocular pressure (IOP) were ocular AEs of special interest. Other assessments included ocular examinations, vector bio-dissemination and systemic immune responses against rAAV2/2. Results: Almost all patients (95.2%) received 9 × 1010 viral genomes and 87.8% had at least 2 years of follow-up. Most patients (75.1%) experienced at least one systemic AE, but systemic treatment-related AEs occurred in 3 patients, none was serious. Intraocular inflammation was reported in 75.6% of lenadogene nolparvovec-treated eyes. Almost all intraocular inflammations occurred in the anterior chamber (58.8%) or in the vitreous (40.3%) and was of mild (90.3%) or moderate (8.8%) intensity; most resolved with topical corticosteroids alone. All IOP increases were mild to moderate in intensity. No AE led to study discontinuation. Bio-dissemination of lenadogene nolparvovec and systemic immune response were limited. The safety profile was comparable for patients treated bilaterally and unilaterally. Conclusions: Lenadogene nolparvovec has a good overall safety profile with excellent systemic tolerability, consistent with limited bio-dissemination. The product is well tolerated, with mostly mild ocular side effects responsive to conventional ophthalmologic treatments

A Mutation in Myo15 Leads to Usher-Like Symptoms in LEW/Ztm-ci2 Rats

The LEW/Ztm-ci2 rat is an animal model for syndromal deafness that arose from a spontaneous mutation. Homozygous animals show locomotor abnormalities like lateralized circling behavior. Additionally, an impaired vision can be observed in some animals through behavioral studies. Syndromal deafness as well as retinal degeneration are features of the Usher syndrome in humans. In the present study, the mutation was identified as a base substitution (T->C) in exon 56 of Myo15, leading to an amino acid exchange from leucine (Leu) to proline (Pro) within the carboxy-terminal MyTH4 domain in the proteins' tail region. Myo15 mRNA was expressed in the retina as demonstrated for the first time with the help of in-situ hybridization and PCR. To characterize the visual phenotype, rats were examined by scotopic and photopic electroretinography and, additionally, histological analyses of the retinas were conducted. The complete loss of sight was detected along with a severe degeneration of photoreceptor cells. Interestingly, the manifestation of the disease does not solely depend on the mutation, but also on environmental factors. Since the LEW/Ztm-ci2 rat features the entire range of symptoms of the human Usher syndrome we think that this strain is an appropriate model for this disease. Our findings display that mutations in binding domains of myosin XV do not only cause non-syndromic hearing loss but can also lead to syndromic disorders including retinal dysfunction

Genome-Wide Progesterone Receptor Binding: Cell Type-Specific and Shared Mechanisms in T47D Breast Cancer Cells and Primary Leiomyoma Cells

Progesterone, via its nuclear receptor (PR), exerts an overall tumorigenic effect on both uterine fibroid (leiomyoma) and breast cancer tissues, whereas the antiprogestin RU486 inhibits growth of these tissues through an unknown mechanism. Here, we determined the interaction between common or cell-specific genome-wide binding sites of PR and mRNA expression in RU486-treated uterine leiomyoma and breast cancer cells.ChIP-sequencing revealed 31,457 and 7,034 PR-binding sites in breast cancer and uterine leiomyoma cells, respectively; 1,035 sites overlapped in both cell types. Based on the chromatin-PR interaction in both cell types, we statistically refined the consensus progesterone response element to G•ACA• • •TGT•C. We identified two striking differences between uterine leiomyoma and breast cancer cells. First, the cis-regulatory elements for HSF, TEF-1, and C/EBPα and β were statistically enriched at genomic RU486/PR-targets in uterine leiomyoma, whereas E2F, FOXO1, FOXA1, and FOXF sites were preferentially enriched in breast cancer cells. Second, 51.5% of RU486-regulated genes in breast cancer cells but only 6.6% of RU486-regulated genes in uterine leiomyoma cells contained a PR-binding site within 5 kb from their transcription start sites (TSSs), whereas 75.4% of RU486-regulated genes contained a PR-binding site farther than 50 kb from their TSSs in uterine leiomyoma cells. RU486 regulated only seven mRNAs in both cell types. Among these, adipophilin (PLIN2), a pro-differentiation gene, was induced via RU486 and PR via the same regulatory region in both cell types.Our studies have identified molecular components in a RU486/PR-controlled gene network involved in the regulation of cell growth, cell migration, and extracellular matrix function. Tissue-specific and common patterns of genome-wide PR binding and gene regulation may determine the therapeutic effects of antiprogestins in uterine fibroids and breast cancer

Study Design and Baseline Characteristics for the Reflect Gene Therapy Trial ofm.11778g\u3eA/ND4-LHON

Objective REFLECT is the first randomised, double-masked, placebo-controlled multicentre phase 3 clinical trial that evaluated the efficacy and safety of bilateral intravitreal (IVT) injection of lenadogene nolparvovec in subjects with Leber hereditary optic neuropathy carrying the m.11778G\u3eA mutation. Methods and analysis A total of 98 subjects were enrolled with vision loss of ≤12 months. The subjects were randomised to one of two treatment arms with all subjects receiving an intravitreal (IVT) injection of lenadogene nolparvovec in their first affected eye and the second-affected eye randomised to receive IVT of either lenadogene nolparvovec or placebo. Results The majority of subjects were male with a mean duration of vision loss of 8.3 months. All but one subject experienced bilateral loss of vision at the time of injection. The mean best-corrected visual acuity of first-affected eyes was worse compared with second/not-yet-affected eyes. Analysis of retinal anatomical parameters showed increased thinning in the first-affected eyes when compared with the second/not-yet-affected eyes with both treatment arms showing significant changes compared with unaffected individuals. Conclusion The REFLECT trial is the third and the largest phase 3 clinical study evaluating lenadogene nolparvovec in m.11778G\u3eA Leber hereditary optic neuropathy (LHON) subjects. The observed demographics in REFLECT are consistent with previous reports in LHON subjects in the acute and dynamic phases of LHON disease. Combined with the visual function and anatomical parameters obtained in the previous RESCUE and REVERSE trials, REFLECT has provided a uniformly collected data set that should help direct future LHON clinical trials

Medical Therapies for Uterine Fibroids - A Systematic Review and Network Meta-Analysis of Randomised Controlled Trials

BACKGROUND: Uterine fibroids are common, often symptomatic and a third of women need repeated time off work. Consequently 25% to 50% of women with fibroids receive surgical treatment, namely myomectomy or hysterectomy. Hysterectomy is the definitive treatment as fibroids are hormone dependent and frequently recurrent. Medical treatment aims to control symptoms in order to replace or delay surgery. This may improve the outcome of surgery and prevent recurrence. PURPOSE: To determine whether any medical treatment can be recommended in the treatment of women with fibroids about to undergo surgery and in those for whom surgery is not planned based on currently available evidence. STUDY SELECTION: Two authors independently identified randomised controlled trials (RCT) of all pharmacological treatments aimed at the treatment of fibroids from a list of references obtained by formal search of MEDLINE, EMBASE, Cochrane library, Science Citation Index, and ClinicalTrials.gov until December 2013. DATA EXTRACTION: Two authors independently extracted data from identified studies. DATA SYNTHESIS: A Bayesian network meta-analysis was performed following the National Institute for Health and Care Excellence-Decision Support Unit guidelines. Odds ratios, rate ratios, or mean differences with 95% credible intervals (CrI) were calculated. RESULTS AND LIMITATIONS: A total of 75 RCT met the inclusion criteria, 47 of which were included in the network meta-analysis. The overall quality of evidence was very low. The network meta-analysis showed differing results for different outcomes. CONCLUSIONS: There is currently insufficient evidence to recommend any medical treatment in the management of fibroids. Certain treatments have future promise however further, well designed RCTs are needed