Biomarker candidates of neurodegeneration in Parkinson’s disease for the evaluation of disease-modifying therapeutics

Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of the development of disease-modifying treatments for Parkinson’s disease (PD). The German Society of Experimental and Clinical Neurotherapeutics (GESENT) has convened a Working Group to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD. The criteria proposed are that the biomarker should be linked to fundamental features of PD neuropathology and mechanisms underlying neurodegeneration in PD, should be correlated to disease progression assessed by clinical rating scales, should monitor the actual disease status, should be pre-clinically validated, and confirmed by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. To date, available data have not yet revealed one reliable biomarker to detect early neurodegeneration in PD and to detect and monitor effects of drug candidates on the disease process, but some promising biomarker candidates, such as antibodies against neuromelanin, pathological forms of α-synuclein, DJ-1, and patterns of gene expression, metabolomic and protein profiling exist. Almost all of the biomarker candidates were not investigated in relation to effects of treatment, validated in experimental models of PD and confirmed in independent studies

Beyond humanization and de-immunization: tolerization as a method for reducing the immunogenicity of biologics

Immune responses to some monoclonal antibodies (mAbs) and biologic proteins interfere with their efficacy due to the development of anti-drug antibodies (ADA). In the case of mAbs, most ADA target ‘foreign’ sequences present in the complementarity determining regions (CDRs). Humanization of the mAb sequence is one approach that has been used to render biologics less foreign to the human immune system. However, fully human mAbs can also drive immunogenicity. De-immunization (removing epitopes) has been used to reduce biologic protein immunogenicity. Here, we discuss a third approach to reducing the immunogenicity of biologics: introduction of Treg epitopes that stimulate Treg function and induce tolerance to the biologic protein. Supplementing humanization (replacing xenosequences with human) and de-immunization (reducing T effector epitopes) with tolerization (introducing Treg epitopes) where feasible, as a means of improving biologics ‘quality by design’, may lead to the development of ever more clinically effective, but less immunogenic, biologics

Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy.

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. Pathogenic mechanisms remain obscure but the neuropathological hallmark is the presence of alpha-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the alpha-synuclein gene, SNCA, are thus strong candidates for genetic association with MSA. One follow-up to a genome-wide association of Parkinson's disease has identified association of a SNP in SNCA with MSA

The cystathionine beta-synthase variant c.844_845ins68 protects against CNS demyelination in X-linked adrenoleukodystrophy

The clinical course of X-linked adrenoleukodystrophy (X-ALD) is of unexplained heterogeneity. Major X-ALD phenotypes are the progressive childhood cerebral form (CCALD) with early confluent cerebral demyelination and the adult-onset adrenomyeloneuropathy (AMN). Adult AMN may present with demyelinated foci of the CNS (adrenoleukomyeloneuropathy, ALMN) or without ("pure" AMN). Activated methionine is essential for CNS myelination, and methionine metabolism is important for glutathione synthesis, which may influence neurodegeneration. Cystathionine beta-synthase (CBS) is a key enzyme of methionine metabolism. The CBS variant c.844_845ins68 (p.-) may influence the availability of activated methionine as well as of glutathione. In this study, we analyzed this variant in genomic DNA samples of 86 X-ALD patients. We observed the allele carrying the insertion in 12 of 49 patients without CNS demyelination ("pure" AMN), but in none of the 37 patients with CNS demyelination (CCALD or ALMN; chi(2)=10.531; p=0.001). We conclude that the insertion allele of CBS c.844_845ins68 protected X-ALD patients against CNS demyelination in our study sample. These data suggest that the individual conditions in methionine metabolism may be a disease modifier of X-ALD. Since methionine metabolism can easily be influenced by vitamin and amino acid substitution, this observation could be a basis of novel treatment strategies in this yet untreatable disease. (c) 2006 Wiley-Liss, In