Precompetitive Consensus Building to Facilitate the Use of Digital Health Technologies to Support Parkinson Disease Drug Development through Regulatory Science.

Innovative tools are urgently needed to accelerate the evaluation and subsequent approval of novel treatments that may slow, halt, or reverse the relentless progression of Parkinson disease (PD). Therapies that intervene early in the disease continuum are a priority for the many candidates in the drug development pipeline. There is a paucity of sensitive and objective, yet clinically interpretable, measures that can capture meaningful aspects of the disease. This poses a major challenge for the development of new therapies and is compounded by the considerable heterogeneity in clinical manifestations across patients and the fluctuating nature of many signs and symptoms of PD. Digital health technologies (DHT), such as smartphone applications, wearable sensors, and digital diaries, have the potential to address many of these gaps by enabling the objective, remote, and frequent measurement of PD signs and symptoms in natural living environments. The current climate of the COVID-19 pandemic creates a heightened sense of urgency for effective implementation of such strategies. In order for these technologies to be adopted in drug development studies, a regulatory-aligned consensus on best practices in implementing appropriate technologies, including the collection, processing, and interpretation of digital sensor data, is required. A growing number of collaborative initiatives are being launched to identify effective ways to advance the use of DHT in PD clinical trials. The Critical Path for Parkinson's Consortium of the Critical Path Institute is highlighted as a case example where stakeholders collectively engaged regulatory agencies on the effective use of DHT in PD clinical trials. Global regulatory agencies, including the US Food and Drug Administration and the European Medicines Agency, are encouraging the efficiencies of data-driven engagements through multistakeholder consortia. To this end, we review how the advancement of DHT can be most effectively achieved by aligning knowledge, expertise, and data sharing in ways that maximize efficiencies.

Impact of an exercise intervention on DNA methylation in skeletal muscle from first-degree relatives of patients with type 2 diabetes.

To identify epigenetic patterns, which may predispose to type 2 diabetes (T2D) due to a family history (FH) of the disease, we analyzed DNA methylation genome-wide in skeletal muscle from individuals with (FH(+)) or without (FH(-)) an FH of T2D. We found differential DNA methylation of genes in biological pathways including mitogen-activated protein kinase (MAPK), insulin, and calcium signaling (P ≤ 0.007) and of individual genes with known function in muscle, including MAPK1, MYO18B, HOXC6, and the AMP-activated protein kinase subunit PRKAB1 in skeletal muscle of FH(+) compared with FH(-) men. We further validated our findings from FH(+) men in monozygotic twin pairs discordant for T2D, and 40% of 65 analyzed genes exhibited differential DNA methylation in muscle of both FH(+) men and diabetic twins. We further examined if a 6-month exercise intervention modifies the genome-wide DNA methylation pattern in skeletal muscle of the FH(+) and FH(-) individuals. DNA methylation of genes in retinol metabolism and calcium signaling pathways (P < 3 × 10(-6)) and with known functions in muscle and T2D including MEF2A, RUNX1, NDUFC2, and THADA decreased after exercise. Methylation of these human promoter regions suppressed reporter gene expression in vitro. In addition, both expression and methylation of several genes, i.e., ADIPOR1, BDKRB2, and TRIB1, changed after exercise. These findings provide new insights into how genetic background and environment can alter the human epigenome.

Increased DNA methylation and decreased expression of PDX-1 in pancreatic islets from patients with type 2 diabetes.

Mutations in pancreatic duodenal homeobox 1 (PDX-1) can cause a monogenic form of diabetes (maturity onset diabetes of the young 4) in humans, and silencing Pdx-1 in pancreatic ß-cells of mice causes diabetes. However, it is not established whether epigenetic alterations of PDX-1 influence type 2 diabetes (T2D) in humans. Here we analyzed mRNA expression and DNA methylation of PDX-1 in human pancreatic islets from 55 nondiabetic donors and nine patients with T2D. We further studied epigenetic regulation of PDX-1 in clonal ß-cells. PDX-1 expression was decreased in pancreatic islets from patients with T2D compared with nondiabetic donors (P = 0.0002) and correlated positively with insulin expression (rho = 0.59, P = 0.000001) and glucose-stimulated insulin secretion (rho = 0.41, P = 0.005) in the human islets. Ten CpG sites in the distal PDX-1 promoter and enhancer regions exhibited significantly increased DNA methylation in islets from patients with T2D compared with nondiabetic donors. DNA methylation of PDX-1 correlated negatively with its gene expression in the human islets (rho = -0.64, P = 0.0000029). Moreover, methylation of the human PDX-1 promoter and enhancer regions suppressed reporter gene expression in clonal ß-cells (P = 0.04). Our data further indicate that hyperglycemia decreases gene expression and increases DNA methylation of PDX-1 because glycosylated hemoglobin (HbA1c) correlates negatively with mRNA expression (rho = -0.50, P = 0.0004) and positively with DNA methylation (rho = 0.54, P = 0.00024) of PDX-1 in the human islets. Furthermore, while Pdx-1 expression decreased, Pdx-1 methylation and Dnmt1 expression increased in clonal ß-cells exposed to high glucose. Overall, epigenetic modifications of PDX-1 may play a role in the development of T2D, given that pancreatic islets from patients with T2D and ß-cells exposed to hyperglycemia exhibited increased DNA methylation and decreased expression of PDX-1. The expression levels of PDX-1 were further associated with insulin secretion in the human islets.

Decreased expression of genes involved in oxidative phosphorylation in human pancreatic islets from patients with type 2 diabetes.

OBJECTIVE: Gene expression alterations, especially in target tissues of insulin, have been associated with type 2 diabetes (T2D). In this study, we examined if genes involved in oxidative phosphorylation (OXPHOS) show differential gene expression and DNA methylation in pancreatic islets from patients with T2D compared with non-diabetic donors. DESIGN AND METHODS: Gene expression was analyzed in human pancreatic islets from 55 non-diabetic donors and nine T2D donors using microarray. RESULTS: While the expected number of OXPHOS genes with reduced gene expression is 7.21, we identified 21 downregulated OXPHOS genes in pancreatic islets from patients with T2D using microarray analysis. This gives a ratio of observed over expected OXPHOS genes of 26.37 by a χ(2)-test with P=2.81 × 10(-7). The microarray data was validated by qRT-PCR for four selected OXPHOS genes: NDUFA5, NDUFA10, COX11, and ATP6V1H. All four OXPHOS genes were significantly downregulated in islets from patients with T2D compared with non-diabetic donors using qRT-PCR (P ≤ 0.01). Furthermore, HbAlc levels correlated negatively with gene expression of NDUFA5, COX11, and ATP6V1H (P<0.05). Gene expression of NDUFA5, NDUFA10, COX11, and ATP6V1H correlated positively with glucose-stimulated insulin secretion (P<0.03). Finally, DNA methylation was analyzed upstream of the transcription start for NDUFA5, COX11, and ATP6V1H. However, none of the analyzed CpG sites in the three genes showed differences in DNA methylation in islets from donors with T2D compared with non-diabetic donors. CONCLUSION: Pancreatic islets from patients with T2D show decreased expression of a set of OXPHOS genes, which may lead to impaired insulin secretion.

Reductive openings of benzylidene acetals. Kinetic studies of borane and alane activation by Lewis acids.

The reaction kinetics for a number of reductive openings of methyl 2,3-di-O-benzyl-4,6-O-benzylidene-alpha-D-glucopyranoside have been investigated. Openings to give free HO-6 (using BH(3) x THF-AlCl(3)-THF or LiAlH(4)-AlCl(3)-Et(2)O) follow first order kinetics, while reactions yielding free HO-4 (using BH(3) x NMe(3)-AlCl(3)-THF or BH(3) x NMe(3)-BF(3) x OEt(2)-THF) follow higher order kinetics. The addition of water to the BH(3) x NMe(3)-AlCl(3)-THF results in faster reactions. The BH(3) x SMe(2)-AlCl(3)-THF system constitutes a borderline case, yielding both free HO-6 (by a first order reaction) and free HO-4 (by a higher order reaction). These results correlate well with the concept of regioselectivity by activation of borane complexes.