Development and validation of TreatHSP-QoL: a patient-reported outcome measure for health-related quality of life in hereditary spastic paraplegia.

BACKGROUND: Hereditary spastic paraplegia (HSP) is a rare neurodegenerative disease that lacks specific and validated patient-centered outcome measures (PCOMs). We aimed to develop and validate a health-related quality of life (HRQoL) questionnaire specific to HSP ("TreatHSP-QoL") that could be used as a PCOM. RESULTS: The pilot-items of the TreatHSP-QoL (45 five-level Likert scale items, with values per item between 0 and 4) were developed based on a qualitative data analysis of 54 semi-structured interviews, conducted in person with 36 HSP patients and 18 caregivers. It was then reduced and modified through the validation process to 25 items. The main validation was performed using the online questionnaire in 242 HSP patients and 56 caregivers. The exploratory factor analysis defined five subdomains. Cronbach's alpha ranged from 0.57 to 0.85 for the subdomains and reached 0.85 for the total score. The test-retest Pearson correlation reached 0.86 (95% Confidence Interval (CI) [0.79, 0.91]). Pearson correlations with the EuroQol-5 Dimension (5 levels) (EQ-5D-5L) and Friedreich Ataxia Rating Scale-Activities of Daily Living (FARS-ADL) questionnaires varied strongly among the subdomains, with the total scores reaching 0.53 (95% CI [0.42, 0.61]) and -0.45 (95% CI [- 0.55, - 0.35]), respectively. The caregiver-patient response Pearson correlation ranged between 0.64 and 0.82 for subdomains and reached 0.65 (95% CI [0.38, 0.81]) for the total score. CONCLUSIONS: TreatHSP-QoL can be used in high-quality clinical trials and clinical practice as a disease-specific PCOM (i.e., HRQoL measure) and is also applicable as a proxy questionnaire. Score values between 0 and 100 can be reached, where higher value represents better HRQoL. The Pearson correlations to the EQ-5D-5L and FARS-ADL support the additional value and need of HSP-specific PCOM, while non-specific QoL-assessment and specific clinical self-assessment tools already exist. All in all, the results demonstrate good validity and reliability for this new patient-centered questionnaire for HSP.

Prevention of medication overuse and medication overuse headache in patients with migraine: a randomized, controlled, parallel, allocation-blinded, multicenter, prospective trial using a mobile software application.

BACKGROUND: Overall, 55% of the German population suffers from primary episodic headaches according to recent studies. Inadequate management of headache disorders is a significant medical problem. The prevalence of medication overuse headache (MOH) is about 1% with an estimated number of 800,000 people in Germany. Medication overuse (MO) and MOH are usually managed through a complex process of medication withdrawal and initiating of prophylaxis. However, patients who were successfully treated for MO or MOH have a high relapse rate in the following 2 years. Previously, continued monitoring of self-reported medication intake demonstrated lower relapse rates. The prevalence and burden of MO and MOH are high, and effective strategies to prevent the development of a relapse into MOH or de novo MOH are still missing. Therefore, the MOH trial was designed to assess the effects of combining self-reported medication intake with daily monitoring of the entered data and a personalized patient-specific medication intake feedback system in an easy-accessible app-based platform in order to prevent the development and relapse of MO(H). METHODS: The MOH trial is a randomized, controlled, parallel, multicenter, prospective trial. A total of 624 migraine patients with frequent migraine attacks and 336 patients who underwent treatment for MO(H) will be randomly allocated to use either a customized app with or without individual feedback regarding their self-reported medication intake for 12 months. The primary outcome will be the proportion of patients developing MO or MOH for at least 3 consecutive months between baseline and end of study visits. DISCUSSION: This trial will assess the effects of providing patients with feedback regarding their self-reported use of migraine medications and migraine days using a mobile software on the development or prevention of MO(H). We hypothesize that the development of MO(H) in patients with frequent episodic migraine (EM) or chronic migraine (CM) and relapse after treatment of MO(H) can be reduced by a feedback system. If this trial proves that using an app with specific and unspecific messaging to the patient is successful, this method, which is now investigated mainly in specialized headache centers, could later be extended to primary care, thus providing benefits for a broader patient group. TRIAL REGISTRATION: German Clinical Trials Register DRKS00025961 . Registered on 04 August 2021.

Pro-inflammatory immunity supports fibrosis advancement in epidermolysis bullosa: intervention with Ang-(1-7).

Recessive dystrophic epidermolysis bullosa (RDEB), a genetic skin blistering disease, is a paradigmatic condition of tissue fragility-driven multi-organ fibrosis. Here, longitudinal analyses of the tissue proteome through the course of naturally developing disease in RDEB mice revealed that increased pro-inflammatory immunity associates with fibrosis evolution. Mechanistically, this fibrosis is a consequence of altered extracellular matrix organization rather than that of increased abundance of major structural proteins. In a humanized system of disease progression, we targeted inflammatory cell fibroblast communication with Ang-(1-7)-an anti-inflammatory heptapeptide of the renin-angiotensin system, which reduced the fibrosis-evoking aptitude of RDEB cells. In vivo, systemic administration of Ang-(1-7) efficiently attenuated progression of multi-organ fibrosis and increased survival of RDEB mice. Collectively, our study shows that selective down-modulation of pro-inflammatory immunity may mitigate injury-induced fibrosis. Furthermore, together with published data, our data highlight molecular diversity among fibrotic conditions. Both findings have direct implications for the design of therapies addressing skin fragility and fibrosis.

Proteomic Profiling of Fibroblasts Isolated from Chronic Wounds Identifies Disease-Relevant Signaling Pathways.

Chronic skin wounds accompany many prevalent age-related diseases and are a major cause of morbidity and mortality. Both keratinocytes and fibroblasts contribute to the pathomechanisms in chronic skin wounds. Dysregulated pathways in the epidermis have been extensively studied, but little is known of the influence of dermal fibroblasts on chronic wounding. We isolated fibroblasts from chronic wounds, propagated them in vitro, and analyzed them using proteomic profiling in combination with functional characterization of the proteomic changes. Chronic wound-associated fibroblasts exhibit a unique proteome profile characteristic of lysosomal dysfunction and dysregulated TGFß signaling. They display a decreased propensity for cell proliferation and migration, combined with an enhanced ability to contract the extracellular matrix. With these properties, chronic wound-associated fibroblasts actively contribute to pathological inabilities to close wounds and represent potential targets for pharmacological interference for changing cellular phenotypes.

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa.

Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB), a skin fragility disorder that, unexpectedly, manifests also with elevated colonization of commensal bacteria and frequent wound infections. Here, we describe an unprecedented systemic function of collagen VII as a member of a unique innate immune-supporting multiprotein complex in spleen and lymph nodes. In this complex, collagen VII specifically binds and sequesters the innate immune activator cochlin in the lumen of lymphoid conduits. In genetic mouse models, loss of collagen VII increased bacterial colonization by diminishing levels of circulating cochlin LCCL domain. Intraperitoneal injection of collagen VII, which restored cochlin in the spleen, but not in the skin, reactivated peripheral innate immune cells via cochlin and reduced bacterial skin colonization. Systemic administration of the cochlin LCCL domain was alone sufficient to diminish bacterial supercolonization of RDEB mouse skin. Human validation demonstrated that RDEB patients displayed lower levels of systemic cochlin LCCL domain with subsequently impaired macrophage response in infected wounds. This study identifies an intrinsic innate immune dysfunction in RDEB and uncovers a unique role of the lymphoid extracellular matrix in systemic defense against bacteria.

Cell therapy for basement membrane-linked diseases.

For most disorders caused by mutations in genes encoding basement membrane (BM) proteins, there are at present only limited treatment options available. Genetic BM-linked disorders can be viewed as especially suited for treatment with cell-based therapy approaches because the proteins that need to be restored are located in the extracellular space. In consequence, complete and permanent engraftment of cells does not necessarily have to occur to achieve substantial causal therapeutic effects. For these disorders cells can be used as transient vehicles for protein replacement. In addition, it is becoming evident that BM-linked genetic disorders are modified by secondary diseases mechanisms. Cell-based therapies have also the ability to target such disease modifying mechanisms. Thus, cell therapies can simultaneously provide causal treatment and symptomatic relief, and accordingly hold great potential for treatment of BM-linked disorders. However, this potential has for most applications and diseases so far not been realized. Here, we will present the state of cell therapies for BM-linked diseases. We will discuss use of both pluripotent and differentiated cells, the limitation of the approaches, their challenges, and the way forward to potential wider implementation of cell therapies in the clinics.

Analysis of the functional consequences of targeted exon deletion in COL7A1 reveals prospects for dystrophic epidermolysis bullosa therapy.

Genetically evoked deficiency of collagen VII causes dystrophic epidermolysis bullosa (DEB)-a debilitating disease characterized by chronic skin fragility and progressive fibrosis. Removal of exons carrying frame-disrupting mutations can reinstate protein expression in genetic diseases. The therapeutic potential of this approach is critically dependent on gene, protein, and disease intrinsic factors. Naturally occurring exon skipping in COL7A1, translating collagen VII, suggests that skipping of exons containing disease-causing mutations may be feasible for the treatment of DEB. However, despite a primarily in-frame arrangement of exons in the COL7A1 gene, no general conclusion of the aptitude of exon skipping for DEB can be drawn, since regulation of collagen VII functionality is complex involving folding, intra- and intermolecular interactions. To directly address this, we deleted two conceptually important exons located at both ends of COL7A1, exon 13, containing recurrent mutations, and exon 105, predicted to impact folding. The resulting recombinantly expressed proteins showed conserved functionality in biochemical and in vitro assays. Injected into DEB mice, the proteins promoted skin stability. By demonstrating functionality of internally deleted collagen VII variants, our study provides support of targeted exon deletion or skipping as a potential therapy to treat a large number of individuals with DEB.

Collagen VII Half-Life at the Dermal-Epidermal Junction Zone: Implications for Mechanisms and Therapy of Genodermatoses.

The tissue half-life of proteins largely determines treatment frequency of non-gene-editing-based therapies targeting the cause of genodermatoses. Surprisingly, such knowledge is missing for a vast number of proteins involved in pathologies. The dermal-epidermal junction zone is believed to be a rather static structure, but to our knowledge no detailed analysis of the stability of proteins within this zone has been performed. Here, we addressed the in vivo half-life of collagen type VII using genetic ablation of its expression and therapeutic introduction of exogenous collagen VII in a preclinical model. A similar in vivo stability of collagen VII was observed in the skin, tongue, and esophagus, with a half-life of about 1 month. Collagen VII expressed by intradermally injected mesenchymal stromal cells also exhibited a similar half-life. Our study provides key information needed for the development of protein replacement or cell-based therapies for dystrophic epidermolysis bullosa caused by genetic deficiency of collagen VII. Moreover, by showing what we define as an intermediate half-life of collagen VII, our study challenges the view of the dermal-epidermal junction zone as a static structure with very slow turnover.

High Local Concentrations of Intradermal MSCs Restore Skin Integrity and Facilitate Wound Healing in Dystrophic Epidermolysis Bullosa.

Dystrophic epidermolysis bullosa (DEB) is an incurable skin fragility disorder caused by mutations in the COL7A1 gene, coding for the anchoring fibril protein collagen VII (C7). Life-long mechanosensitivity of skin and mucosal surfaces is associated with large body surface erosions, chronic wounds, and secondary fibrosis that severely impede functionality. Here, we present the first systematic long-term evaluation of the therapeutic potential of a mesenchymal stromal cell (MSC)-based therapy for DEB. Intradermal administration of MSCs in a DEB mouse model resulted in production and deposition of C7 at the dermal-epidermal junction, the physiological site of function. The effect was dose-dependent with MSCs being up to 10-fold more potent than dermal fibroblasts. MSCs promoted regeneration of DEB wounds via normalization of dermal and epidermal healing and improved skin integrity through de novo formation of functional immature anchoring fibrils. Additional benefits were gained by MSCs' anti-inflammatory effects, which led to decreased immune cell infiltration into injured DEB skin. In our setting, the clinical benefit of MSC injections lasted for more than 3 months. We conclude that MSCs are viable options for localized DEB therapy. Importantly, however, the cell number needed to achieve therapeutic efficacy excludes the use of systemic administration.

Quantitative assessment of left ventricular systolic wall thickening using multidetector computed tomography.

BACKGROUND: Multidetector computed tomography (MDCT) of the heart provides both anatomical and functional information. The objective of this study was to evaluate the accuracy of quantitative assessment of left ventricular contractile function in relation to two-dimensional transthoracic echocardiography (TTE). MATERIALS AND METHODS: Sixty-four patients with known or suspected coronary artery disease underwent ECG-gated 64-slice MDCT and TTE. Regional left ventricular contractile function was measured by percent systolic wall thickening (SWT) in 16 myocardial segments using MDCT, and compared with visual evaluation of wall motion score (WMS) by TTE. Global SWT by MDCT was calculated as the mean SWT of all myocardial segments and compared with wall motion index (WMI) by TTE. RESULTS: Eight hundred and eleven segments (81%) were classified as normokinetic, 142 (14%) as hypokinetic, 41 (4%) as akinetic and 5 (0.5%) as dyskinetic by TTE. A significant inverse linear trend was found between regional SWT by MDCT and WMS by TTE (p<0.001). Sensitivity and specificity for the identification of regional abnormalities of contractile function were 76% and 78%, respectively. A linear correlation between global SWT by MDCT and WMI by TTE was found (r=-0.8, p<0.001). Sensitivity and specificity for the identification of WMI>1.5 using global SWT was 91% and 94%, respectively. CONCLUSION: Quantification of systolic wall thickening by MDCT provides functional information, which is well correlated to visual assessment of global left ventricular contractile function by TTE.