ALBERT

Beschreibung: Parkinson’s disease (PD) is the second most prevalent late-age onset neurodegenerative disorder, affecting 1% of the population after the age of about 60 years old and 4% of those over 80 years old, causing motor impairments and cognitive dysfunction. Increasing evidence indicates that Mediterranean diet (MD) exerts beneficial effects in maintaining health, especially during ageing and by the prevention of neurodegenerative disorders. In this regard, olive oil and its biophenolic constituents like hydroxytyrosol (HT) have received growing attention in the past years. Thus, in the current study we test the health-promoting effects of two hydroxytyrosol preparations, pure HT and Hidrox® (HD), which is hydroxytyrosol in its “natural” environment, in the established invertebrate model organism Caenorhabditis elegans. HD exposure led to much stronger beneficial locomotion effects in wild type worms compared to HT in the same concentration. Consistent to this finding, in OW13 worms, a PD-model characterized by α-synuclein expression in muscles, HD exhibited a significant higher effect on α-synuclein accumulation and swim performance than HT, an effect partly confirmed also in swim assays with the UA44 strain, which features α-synuclein expression in DA-neurons. Interestingly, beneficial effects of HD and HT treatment with similar strength were detected in the lifespan and autofluorescence of wild-type nematodes, in the neuronal health of UA44 worms as well as in the locomotion of rotenone-induced PD-model. Thus, the hypothesis that HD features higher healthspan-promoting abilities than HT was at least partly confirmed. Our study demonstrates that HD polyphenolic extract treatment has the potential to partly prevent or even treat ageing-related neurodegenerative diseases and ageing itself. Future investigations including mammalian models and human clinical trials are needed to uncover the full potential of these olive compounds.

Beschreibung: Background: In developed countries, the extension of human life is increasingly accompanied by a progressive increase in neurodegenerative diseases, most of which do not yet have effective therapy but only symptomatic treatments. In recent years, plant polyphenols have aroused considerable interest in the scientific community. The mechanisms currently hypothesized for the pathogenesis of Parkinson’s disease (PD) are neuroinflammation, oxidative stress and apoptosis. Hydroxytyrosol (HT), the main component of Hidrox® (HD), has been shown to have some of the highest free radical evacuation and anti-inflammatory activities. Here we wanted to study the role of HD on the neurobiological and behavioral alterations induced by rotenone. Methods: A study was conducted in which mice received HD (10 mg/kg, i.p.) concomitantly with rotenone (5 mg/kg, o.s.) for 28 days. Results: Locomotor activity, catalepsy, histological damage and several characteristic markers of the PD, such as the dopamine transporter (DAT) content, tyrosine hydroxylase (TH) and accumulation of α-synuclein, have been evaluated. Moreover, we observed the effects of HD on oxidative stress, neuroinflammation, apoptosis and inflammasomes. Taken together, the results obtained highlight HD’s ability to reduce the loss of dopaminergic neurons and the damage associated with it by counteracting the three main mechanisms of PD pathogenesis. Conclusion: HD is subject to fewer regulations than traditional drugs to improve patients’ brain health and could represent a promising nutraceutical choice to prevent PD.

Beschreibung: The SARS-CoV-2 infection is associated with pulmonary coagulopathy, which determines the deposition of fibrin in the air spaces and lung parenchyma. The resulting lung lesions compromise patient pulmonary function and increase mortality, or end in permanent lung damage for those who have recovered from the COVID-19 disease. Therefore, local pulmonary fibrinolysis can be efficacious in degrading pre-existing fibrin clots and reducing the conversion of lung lesions into lasting scars. Plasminogen is considered a key player in fibrinolysis processes, and in view of a bench-to-bedside translation, we focused on the aerosolization of an orphan medicinal product (OMP) for ligneous conjunctivitis: human plasminogen (PLG-OMP) eye drops. As such, the sterile and preservative-free solution guarantees the pharmaceutical quality of GMP production and meets the Ph. Eur. requirements of liquid preparations for nebulization. PLG-OMP aerosolization was evaluated both from technological and stability viewpoints, after being submitted to either jet or ultrasonic nebulization. Jet nebulization resulted in a more efficient delivery of an aerosol suitable for pulmonary deposition. The biochemical investigation highlighted substantial protein integrity maintenance with the percentage of native plasminogen band 〉 90%, in accordance with the quality specifications of PLG-OMP. In a coherent way, the specific activity of plasminogen is maintained within the range 4.8–5.6 IU/mg (PLG-OMP pre-nebulization: 5.0 IU/mg). This is the first study that focuses on the technological and biochemical aspects of aerosolized plasminogen, which could affect both treatment efficacy and clinical dosage delivery. Increasing evidence for the need of local fibrinolytic therapy could merge with the availability of PLG-OMP as an easy handling solution, readily aerosolizable for a fast translation into an extended clinical efficacy assessment in COVID-19 patients.

Beschreibung: BACKGROUND Ligneous Conjunctivitis (LC) is the most common clinical manifestation of type-1 plasminogen (PLG) deficiency, a very rare autosomal recessive disorder with an estimated prevalence of ~1.6/million. LC is a membranous conjunctivitis characterized by the formation of fibrin-rich, soft/hard pseudomembranes on tarsal conjunctivae, resulting in visual impairment/loss, and commonly presents in the first weeks/months of life, but may present in childhood or any age. PLG is the precursor of plasmin; absence of plasmin activity results in impaired fibrinolysis and formation of fibrin-rich membranes. LC affects bilateral eyes in up to 51% of cases, and corneal involvement, leading to blindness, occurs in 20-30% of cases. Although non-specific therapies have been reported to result in lesion improvement/resolution, only FFP administered topically or systemically, and topical/systemic plasminogen have demonstrated more consistent efficacy. Surgery is often performed for hard membrane removal; surgical intervention can trigger regrowth without adequate medical therapy. We report the long-term results of topical ocular administration from a PLG eye drop formulation [Kedrion Biopharma, CVP, Barga, Italy] for LC. METHODS A phase 2/3, 3-segment [Fig], open label, historically controlled, clinical trial (KB046) was initiated in May 2013 at three sites (1 US; 2 Italy). Segments 1 & 2 assessed the efficacy and safety of short-term PLG treatment in pseudomembrane regression/recurrence and prevention. Subjects with residual hard membranes at Segment 1 end underwent surgical removal. Patients completing Segment 2 without pseudomembranes continued to segment 3 for long-term safety continuation. Segment 3 is ongoing. Primary and secondary Efficacy Endpoints: a) Pseudomembrane recurrence prevention at end of Segment 2 and b) Regression of surface area of existing pseudomembranes at end of Segment 1 including Time (days) to pseudomembrane recurrence post-surgery or complete regression at end Segment 2. Regression and recurrence occurring during the trial were compared to the patients' prior treatments and surgical history. Safety Endpoints of segment 1/2 included overall safety, local tolerability, immunogenicity and viral safety. RESULTS Eleven patients (15 eyes) with pseudomembranes were enrolled in segment 1 and treated for 4 weeks with PLG drops. At Segment 1 end, four patients showed regression, proceeded to Segment 2, and treated with PLG drops for 8 weeks to prevent recurrence; seven patients had residual hard pseudomembranes and underwent surgical removal followed by 8 weeks with PLG. At Segment 2 end, 10 patients compliant per protocol without recurrence, transitioned to Segment 3. The primary endpoint of no pseudomembrane recurrence was 100% in all patients compliant with the treatment regimen at end Segment 2. Regression of surface area of existing pseudomembranes at end Segment 1 was achieved in 83.3% of affected eyes. Prior to trial enrollment, all patients experienced recurrences with prior historical therapies. Eleven patients were treated in segment 3 with 3 ongoing (as of July, 2020). Eight patients exited the study: one patient due to noncompliance, and two who developed systemic manifestations requiring other therapy. No other subjects have experienced new eye lesions. No major safety concerns arose during any the 3 Segments. Final data on immunogenicity will be available at the end of 2020. CONCLUSIONS Kedrion PLG eye drops were well tolerated and effective in recurrence prevention of pseudomembranes in patients with LC due to PLG deficiency who were compliant with the study protocol with long term follow-up now at 7 years (median: 74 months, range: 37-85 months); 3 subjects are still ongoing. Disclosures Caputo: Kedrion SpA: Research Funding. Suffredini:Kedrion SpA: Current Employment. Calcinai:Kedrion SpA: Current Employment. Crea:Kedrion SpA: Current Employment. Mathew:Kedrion SpA: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nakar:Kedrion SpA: Research Funding; Prometic Biotherapeutics: Research Funding. Shapiro:Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kedrion Biopharma: Research Funding; Daiichi Sankyo: Research Funding; BioMarin: Research Funding; Novartis: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Research Funding; ProMetic Bio Therapeutics: Consultancy, Research Funding; OPKO: Research Funding; Glover Blood Therapeutics: Research Funding; Sigilon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Catalyst BioSciences: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Octapharma: Research Funding; Sangamo: Research Funding. OffLabel Disclosure: Plasminogen eye drops, for treatment of Ligneous conjunctivitis due to Plasminogen Type I deficiency