ORCID Profile
0000-0002-4132-7646
Current Organisation
University of Oxford
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Publisher: Cold Spring Harbor Laboratory
Date: 13-11-2020
DOI: 10.1101/2020.11.12.379701
Abstract: N-acetyl-DL-leucine is an analogue of the alpha amino acid leucine with a chiral stereocenter. The active L-enantiomer of the racemate is currently under development for rare neurological disorders. Here we present evidence that a selective recognition of N-acetyl-L-leucine versus L-leucine by different uptake transporters significantly contributes to the therapeutic effects of N-acetyl-L-leucine. A previous study of the pharmacokinetics of racemic N-acetyl-DL-leucine and N-acetyl-L-leucine revealed D-L enantiomer competition and saturation kinetics, best explained by carrier-mediated uptake. The strategy we used was to first analyze the physicochemical properties associated with good oral bioavailable drugs and how these are alerted by N-acetylation by comparing N-acetyl-L-leucine with L-leucine. Using in silico computational chemistry we found that N-acetylation has a profound impact on certain physicochemical properties that can rationalize why N-acetyl-L-leucine is drug-like compared to L-leucine. Our calculations show that at physiological pH, L-leucine is a zwitterion, whereas N-acetyl-L-leucine is present as mainly an anion. Specifically, N-acetylation removes a charge from the nitrogen at physiological pH and N-acetyl-L-leucine is an anion that is then a substrate for the organic anion transporters. We examined N-acetyl-L-leucine uptake in human embryonic kidney cells overexpression candidate organic anion transporters (OAT) and pharmacological inhibitors. We found that N-acetyl-L-leucine is a translocated substrate for OAT1 and OAT3 with low affinity (Km ~10 mM). In contrast, L-leucine is known to be transported by the L-type Amino Acid Transporter (LAT) with high affinity (Km ~0.2 mM) and low capacity. The clinical consequence is that L-leucine uptake becomes saturated at 50-fold lower concentration than N-acetyl-L-leucine. These results demonstrate a mechanism of action that explains why N-acetyl-L-leucine is effective as a drug and L-leucine itself is not.
Publisher: Cold Spring Harbor Laboratory
Date: 16-03-2020
DOI: 10.1101/2020.03.11.20034256
Abstract: The lack of approved treatments for the majority of rare diseases is reflective of the unique challenges of orphan drug development. Novel methodologies, including new functionally relevant endpoints, are needed to render the development process more feasible and appropriate for these rare populations, and thereby expedite the approval of promising treatments to address patients’ high unmet medical need. Here, we describe the development of an innovative master protocol and primary outcome assessment to investigate the modified amino acid N-acetyl-L-leucine (Sponsor Code: IB1001) in three seperate, multinational, phase II trials for three ultra-rare, autosomal-recessive, neurodegenerative disorders: Niemann-Pick disease type C (NPC), GM2 Gangliosidoses (Tay-Sachs and Sandhoff disease “GM2”), and Ataxia Telangiectasia (A-T). The innovative IB1001 master protocol and novel CI-CS primary endpoints were developed through a close collaboration between the Industry Sponsor, Key Opinion Leaders, representatives of the Patient Communities, and National Regulatory Authorities. As a result, the open-label, rater-blinded study design is considerate of the practical limitations of recruitment and retention of subjects in these ultra-orphan populations. The novel primary endpoint, the Clinical Impression of Change in Severity © (CI-CS), accommodates the heterogenous clinical presentation of NPC, GM2, and A-T: at screening, the Principal Investigator appoints for each patient a primary anchor test (either the 8 Meter Walk Test (8MWT) or 9 Hole Peg Test of the Dominant Hand (9HPT-D)) based on his/her unique clinical symptoms. The anchor tests are videoed in a standardized manner at each visit to capture all aspects related to the patient’s functional performance. The CI-CS assessment is ultimately performed by independent, blinded raters who compare videos of the primary anchor test from three periods: baseline, the end of treatment, and the end of a post-treatment washout. Blinded to the timepoint of each video, the raters make an objective comparison scored on a 7-point Likert scale of the change in the severity of the patient’s neurological signs and symptoms from Video A to Video B. To investigate both the symptomatic and disease-modifying effects of treatment, N-acetyl-L-leucine is assessed during two treatment sequences: a 6-week parent study, and one-year extension phase. The novel CI-CS assessment, developed through a collaboration of all stakeholders, is advantageous in that it better ensures the primary endpoint is functionally relevant for each patient, is able to capture small but meaningful clinical changes critical to the patients’ quality of life (fine-motor skills gait), and blinds the primary outcome assessment. The results of these three trials will inform whether N-acetyl-L-leucine is an effective treatment for NPC, GM2, and A-T, and can also serve as a new therapeutic paradigm for the development of future treatments for other orphan diseases. The three trials (IB1001-201 for Niemann-Pick disease type C (NPC) IB1001-202 for GM2 Gangliosidoses (Tay-Sachs and Sandhoff) IB1001-203 for Ataxia-Telangiectasia (A-T)) have been registered at www.clinicaltrials.gov ( NCT03759639 NCT03759665 NCT03759678 ), www.clinicaltrialsregister.eu (EudraCT: 2018-004331-71 2018-004406-25 2018-004407-39) and www.germanctr.de (DR KS-ID: DRKS00016567 DRKS00017539 DRKS00020511).
Publisher: F1000 Research Ltd
Date: 05-01-2021
DOI: 10.12688/HRBOPENRES.13131.1
Abstract: Background : The number of older adults with complex medical comorbidities and functional impairment is increasing throughout the world. Frail older adults frequently attend the Emergency Department (ED) and are at increased risk of adverse outcomes following presentation. A number of screening tools exist that aim to screen older adults for frailty and identify those at risk of functional decline, unscheduled readmission, institutionalisation and mortality. We propose to determine the predictive accuracy of four commonly used screening tools, namely the Identification of Seniors at Risk Screening (ISAR), Clinical Frailty Scale (CFS), Program of Research to Integrate Services for the Maintenance of Autonomy (PRISMA 7) and InterRAI ED, to determine adverse events at 30 days and six months among older adults who present to the ED. Methods and analysis : This is a prospective cohort study where patients over the age of 65 will have four screening tools (ISAR, CFS, PRISMA 7, interRAI ED) performed by face-to-face interview with a research nurse during their index visit to one Irish ED. Older adults will be included if they are willing and able to provide written informed consent, have a Manchester Triage Category 2-5 and are resident in the hospital catchment area. Demographic information will be collected at the index visit. A telephone follow up will occur at 30 days and six months, completed by a research nurse who is blinded to the initial assessment. Outcome data will include mortality rates, ED re-attendance, hospital readmission, functional decline and institutionalisation. We will analyse the risk of adverse outcomes using multivariable logistic regression and we will report adjusted risk ratios (RR) with 95% CI. Dissemination : Study findings will be disseminated through publication in peer-reviewed journals and presentations at relevant academic and clinical conferences. National and International gerontology conferences will be targeted.
Publisher: Elsevier BV
Date: 11-1997
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Antony Galione.