National Institutes of Health–Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities

Eight manufacturing facilities participating in the National Institutes of Health–sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed

Sex-Related Longitudinal Change of Motor, Non-Motor, and Biological Features in Early Parkinson’s Disease

BackgroundInvestigation of sex-related motor and non-motor differences and biological markers in Parkinson's disease (PD) may improve precision medicine approach.ObjectiveTo examine sex-related longitudinal changes in motor and non-motor features and biologic biomarkers in early PD.MethodsWe compared 5-year longitudinal changes in de novo, untreated PD men and women (at baseline N = 423; 65.5%male) of the Parkinson's Progression Markers Initiative (PPMI), assessing motor and non-motor manifestations of disease; and biologic measures in cerebrospinal fluid (CSF) and dopamine transporter deficit on DaTscanTM uptake.ResultsMen experienced greater longitudinal decline in self-reported motor (p < 0.001) and non-motor (p = 0.009) aspects of experiences of daily living, such that men had a yearly increase in MDS-UPDRS part II by a multiplicative factor of 1.27 compared to women at 0.7, while men had a yearly increase in MDS-UPDRS part I by a multiplicative factor of 0.98, compared to women at 0.67. Compared to women, men had more longitudinal progression in clinician-assessed motor features in the ON medication state (p = 0.010) and required higher dopaminergic medication dosages over time (p = 0.014). Time to reach specific disease milestones and longitudinal changes in CSF biomarkers and DaTscanTM uptake were not different by sex.ConclusionMen showed higher self-assessed motor and non-motor burden of disease, with possible contributions from suboptimal dopaminergic therapeutic response in men. However, motor features of disease evaluated with clinician-based scales in the OFF medication state, as well as biological biomarkers do not show specific sex-related progression patterns

Age dependence of glucose tolerance in adult KK-Ay mice, a model of non–insulin dependent diabetes mellitus

Yellow KK mice carrying the \u27yellow obese\u27 gene Ay are a well established polygenic model for human non-insulin dependent diabetes mellitus. These animals develop marked adiposity and decreased glucose tolerance relative to their control littermates, KK mice. The authors monitored glucose tolerance in KK-Ay mice over time and observed a significant (P ≤ 0.05) age-dependent improvement (13.3% by 175 d of age and 36.4% by 212 d of age, relative to 85 d of age). During the same time period, body weight and food and water consumption were relatively constant. The authors also measured plasma levels of endocrine hormones that are important in diabetes. Levels of insulin were approximately 8 times higher and levels of amylin 3 times higher in 220-d-old KK-Ay mice than in 180-d-old mice, whereas levels of glucagon-like peptide 1, glucagon and leptin remained relatively constant. These findings suggest that KK-Ay mice undergo an age-dependent improvement of glucose tolerance when maintained on a normal diet for 25 weeks or longer, due in part to increases in plasma levels of insulin and amylin

Assessment of heterogeneity among participants in the Parkinsons Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study.

BACKGROUND: Emerging evidence shows that α-synuclein seed amplification assays (SAAs) have the potential to differentiate people with Parkinsons disease from healthy controls. We used the well characterised, multicentre Parkinsons Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of the α-synuclein SAA and to examine whether the assay identifies heterogeneity among patients and enables the early identification of at-risk groups. METHODS: This cross-sectional analysis is based on assessments done at enrolment for PPMI participants (including people with sporadic Parkinsons disease from LRRK2 and GBA variants, healthy controls, prodromal individuals with either rapid eye movement sleep behaviour disorder (RBD) or hyposmia, and non-manifesting carriers of LRRK2 and GBA variants) from 33 participating academic neurology outpatient practices worldwide (in Austria, Canada, France, Germany, Greece, Israel, Italy, the Netherlands, Norway, Spain, the UK, and the USA). α-synuclein SAA analysis of CSF was performed using previously described methods. We assessed the sensitivity and specificity of the α-synuclein SAA in participants with Parkinsons disease and healthy controls, including subgroups based on genetic and clinical features. We established the frequency of positive α-synuclein SAA results in prodromal participants (RBD and hyposmia) and non-manifesting carriers of genetic variants associated with Parkinsons disease, and compared α-synuclein SAA to clinical measures and other biomarkers. We used odds ratio estimates with 95% CIs to measure the association between α-synuclein SAA status and categorical measures, and two-sample 95% CIs from the resampling method to assess differences in medians between α-synuclein SAA positive and negative participants for continuous measures. A linear regression model was used to control for potential confounders such as age and sex. FINDINGS: This analysis included 1123 participants who were enrolled between July 7, 2010, and July 4, 2019. Of these, 545 had Parkinsons disease, 163 were healthy controls, 54 were participants with scans without evidence of dopaminergic deficit, 51 were prodromal participants, and 310 were non-manifesting carriers. Sensitivity for Parkinsons disease was 87·7% (95% CI 84·9-90·5), and specificity for healthy controls was 96·3% (93·4-99·2). The sensitivity of the α-synuclein SAA in sporadic Parkinsons disease with the typical olfactory deficit was 98·6% (96·4-99·4). The proportion of positive α-synuclein SAA was lower than this figure in subgroups including LRRK2 Parkinsons disease (67·5% [59·2-75·8]) and participants with sporadic Parkinsons disease without olfactory deficit (78·3% [69·8-86·7]). Participants with LRRK2 variant and normal olfaction had an even lower α-synuclein SAA positivity rate (34·7% [21·4-48·0]). Among prodromal and at-risk groups, 44 (86%) of 51 of participants with RBD or hyposmia had positive α-synuclein SAA (16 of 18 with hyposmia, and 28 of 33 with RBD). 25 (8%) of 310 non-manifesting carriers (14 of 159 [9%] LRRK2 and 11 of 151 [7%] GBA) were positive. INTERPRETATION: This study represents the largest analysis so far of the α-synuclein SAA for the biochemical diagnosis of Parkinsons disease. Our results show that the assay classifies people with Parkinsons disease with high sensitivity and specificity, provides information about molecular heterogeneity, and detects prodromal individuals before diagnosis. These findings suggest a crucial role for the α-synuclein SAA in therapeutic development, both to identify pathologically defined subgroups of people with Parkinsons disease and to establish biomarker-defined at-risk cohorts. FUNDING: PPMI is funded by the Michael J Fox Foundation for Parkinsons Research and funding partners, including: Abbvie, AcureX, Aligning Science Across Parkinsons, Amathus Therapeutics, Avid Radiopharmaceuticals, Bial Biotech, Biohaven, Biogen, BioLegend, Bristol-Myers Squibb, Calico Labs, Celgene, Cerevel, Coave, DaCapo Brainscience, 4D Pharma, Denali, Edmond J Safra Foundation, Eli Lilly, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Insitro, Janssen Neuroscience, Lundbeck, Merck, Meso Scale Discovery, Neurocrine Biosciences, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, VanquaBio, Verily, Voyager Therapeutics, and Yumanity