Orphan diseases: state of the drug discovery art.

Wien Med Wochenschr. 2017 Jun;167(9-10):197-204

Authors: Volmar CH, Wahlestedt C, Brothers SP

Abstract
Since 1983 more than 300 drugs have been developed and approved for orphan diseases. However, considering the development of novel diagnosis tools, the number of rare diseases vastly outpaces therapeutic discovery. Academic centers and nonprofit institutes are now at the forefront of rare disease R&D, partnering with pharmaceutical companies when academic researchers discover novel drugs or targets for specific diseases, thus reducing the failure risk and cost for pharmaceutical companies. Considerable progress has occurred in the art of orphan drug discovery, and a symbiotic relationship now exists between pharmaceutical industry, academia, and philanthropists that provides a useful framework for orphan disease therapeutic discovery. Here, the current state-of-the-art of drug discovery for orphan diseases is reviewed. Current technological approaches and challenges for drug discovery are considered, some of which can present somewhat unique challenges and opportunities in orphan diseases, including the potential for personalized medicine, gene therapy, and phenotypic screening.

PMID: 26819216 [PubMed - indexed for MEDLINE]

Adipose tissue-derived stem cells from affected and unaffected areas in patients with multiple symmetric lipomatosis show differential regulation of mTOR pathway genes.

Clin Hemorheol Microcirc. 2018;69(1-2):141-151

Authors: Felthaus O, Schön T, Schiltz D, Aung T, Kühlmann B, Jung F, Anker A, Klein S, Prantl L

Abstract
BACKGROUND: Multiple symmetric lipomatosis is a rare disease characterized by the excessive growth of uncapsulated masses of adipose tissue. Although the etiology has yet to be elucidated, a connection to brown adipose tissue has been proposed recently. The mTOR pathway which is found to be regulated in lipomatous tissue as well as associated with brown adipose tissue can be inhibited by a compound called rapamycin.
METHODS: We isolated adipose tissue derived stem cells from both affected and unaffected tissue and treated these cells with different concentrations of rapamycin.
RESULTS: The differences in both proliferation and differentiation between adipose tissue derived stem cells (ASCs) from lipomatous and normal tissue decreased after mTOR pathway inhibition. In some patients regulation of mTOR genes was opposed in the ASCs from the two different tissues.
CONCLUSIONS: Treatment with rapamycin might be a novel therapeutical approach for patients suffering from multiple symmetric lipomatosis.

PMID: 29758934 [PubMed - indexed for MEDLINE]

Pseudoangiomatous stromal hyperplasia - a benign and rare tumor of the breast in an adolescent: a case report.

J Med Case Rep. 2017 Oct 05;11(1):284

Authors: Testori A, Alloisio M, Errico V, Bottoni E, Voulaz E, Fernandez B, Meroni S, De Simone M, Cioffi U

Abstract
BACKGROUND: Pseudoangiomatous stromal hyperplasia is an uncommon mesenchymal breast neoplasm.
CASE PRESENTATION: Here we present a case of an 11-year old hispanic girl affected by bilateral mammary nodular pseudoangiomatous stromal hyperplasia, an uncommon breast disease, with a review of the literature related to diagnostic workup, differential diagnosis, and management. A rapidly growing mass in the breast may be stressful for both parents and child as the suspicion of malignancy arises. Multiple wide excisions of both breasts were performed.
CONCLUSIONS: The purpose of this case report is to draw attention to the fact that most emerging lesions of the breast in girls during puberty are benign diseases.

PMID: 28978330 [PubMed - indexed for MEDLINE]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/06/15

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/06/15

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

[Benign aggressive vascular anomalies in children].

Bull Cancer. 2018 Jun;105(6):610-625

Authors: Boccara O, Maruani A, Léauté-Labrèze C

Abstract
Superficial vascular anomalies constitute a large group of malformative and tumoral conditions developed from all types of vessels. Vascular tumors are the result of cellular hyperplasia, whereas vascular malformations (VMs) are constituted of dysplastic vessels. The classification from International Society for the Study of Vascular Anomalies (ISSVA) is based on this pathogenic difference. The most common vascular tumor is infantile hemangioma, which treatment, when necessary, is propranolol. Congenital hemangiomas and tumors that might be complicated with Kasabach-Merritt phenomenon, i.e. deep thrombocytopenia, are much rarer. Management of Kasabach-Merritt phenomenon is now largely based on sirolimus. Low-flow VMs include capillary, venous and lymphatic malformations; arteriovenous malformations are high-flow malformations. These different types of VMs might be combined. Currently, there is an increasing work in delineating the different entities based on molecular findings. Treatment of VMs depends on the impairment linked to them, and is decided case by case, in pluridisciplinary consultations. Interventional treatments, especially surgery and sclerotherapy, are usually partially efficient, and management of patients with VMs increasingly involves medical drugs. First-line treatment of coagulation disorders associated with venous malformations is based on low molecular weight heparin; sirolimus seems efficient in hemorrhagic complications refractory to usual treatment. Sirolimus is about to become the standard treatment in painful inflammatory manifestations of mixed and/or complicated lymphatic malformations.

PMID: 29571951 [PubMed - indexed for MEDLINE]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/06/13

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

[Rare primary proximal epithelioid sarcoma in skull base: clinical analysis of four cases].

Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2018 Apr 07;53(4):263-269

Authors: Duan ZJ, Yao K, Qu YM, Ren M, Zhang YL, Qi XL

Abstract
Objective: To report the clinical and pathological features of primary proximal epithelioid sarcoma (PES) in skull base. Methods: The clinical and pathological features of four cases of PES in skull base from Sanbo Brain Institute of Capital Medical University and Kunming Sanbo Brain Institute were analysed retrospectively. Results: Three cases was female, and one male, the age ranged from 46 to 52 years.All cases occurred in skull base, and sellar region was the main site of involvement.Under the microscope, the tumor cells characterized by epithelioid cell changes, with or without rhabdoid tumor cells.Mitotic figure was active.Immunohistochemical staining showed that AE1/AE3, EMA and CD34 were variously expression in tumor cells.INI-1 protein was lost in all cases.Three cases were detected by FISH, and INI1 (22q11.2) gene locus was absent in them.Three patients died less than 3 months after surgery, and case 4 was under treatment after five months of surgery. Conclusions: Primary PES in skull base mostly occurs in sellar region and its clinical prognosis is poor.It features with epithelioid/rhabdoid tumor cells with lack granuloma structure as distal ES.It has epithelial and mesenchymal differentiation characteristics.CD34 is always positive.INI1 gene deletion and protein loss expression are characteristic molecular alteration of PES.

PMID: 29747250 [PubMed - indexed for MEDLINE]

Prevalence Estimates of Rare Congenital Anomalies by Integrating Two Population-Based Registries in Tuscany, Italy.

Public Health Genomics. 2017;20(4):229-234

Authors: Coi A, Santoro M, Pierini A, Marrucci S, Pieroni F, Bianchi F

Abstract
BACKGROUND/AIMS: Population-based registries play a key role in the epidemiological surveillance of congenital anomalies (CAs). This study is aimed at improving the epidemiological surveillance and providing prevalence estimates of rare CAs using the Registry of Rare Diseases as an added data source to the Registry of Congenital Anomalies.
METHODS: Cases of diagnosed rare CAs (2006-2013) were extracted from the Tuscany Registry of Rare Diseases and the Tuscany Registry of Congenital Anomalies in order to set up an integrated dataset. Prevalence (per 100,000 births; 95% confidence interval) was calculated for each rare CA.
RESULTS: Overall, 56 rare CAs were analyzed including 656 cases, of whom 121 (18.4%) were retrieved from the Registry of Rare Diseases that provided a major contribution for rare CAs for which a prenatal diagnosis is difficult, or for CAs more easily diagnosed in the postneonatal period. After data integration, an increased prevalence estimate was observed in particular for atresia of bile ducts (6.24; 3.57-10.14), tuberous sclerosis (2.34; 0.86-5.10), Kabuki syndrome (1.95; 0.63-4.55), and some monogenic CAs.
CONCLUSIONS: This study represents an example of integration of registries operating in the field of rare diseases. Providing the accurate prevalence of rare CAs is a key point to improving surveillance, supporting public health policies, and planning healthcare.

PMID: 29045944 [PubMed - indexed for MEDLINE]

Oculonasal Synkinesis: Video Report and Surgical Solution of a Rare Phenomenon.

Aesthet Surg J. 2017 Sep 01;37(8):879-883

Authors: Guarro G, Brunelli F, Rasile B, Alfano C

Abstract
Background: Synkinesis represents involuntary muscular movements that occur in association with voluntary contraction of other muscle groups. Oculonasal synkinesis is a rare phenomenon.
Objectives: In a series of videos, the authors present clinical findings and surgical correction of oculonasal synkinesis.
Methods: Two women who underwent surgical procedures to correct oculonasal synkinesis were evaluated in a prospective study. One patient presented with bilateral synkinesis after 2 previous rhinoplasties. She underwent open rhinoplasty in our office. The other patient had unilateral synkinesis of the left side and received endonasal rhinoplasty.
Results: The patients' mean age was 27.5 years, and follow-up was conducted for 6 months. Both patients experienced complete, stable resolution of synkinesis after surgical correction. No complications were recorded.
Conclusions: Patients with oculonasal synkinesis may not notice it preoperatively and may regard these muscle movements as an unfavorable result of rhinoplasty. Therefore, careful preoperative evaluation is crucial.

PMID: 29036940 [PubMed - indexed for MEDLINE]

Quantitative disease progression model of α-1 proteinase inhibitor therapy on computed tomography lung density in patients with α-1 antitrypsin deficiency.

Br J Clin Pharmacol. 2017 Nov;83(11):2386-2397

Authors: Tortorici MA, Rogers JA, Vit O, Bexon M, Sandhaus RA, Burdon J, Chorostowska-Wynimko J, Thompson P, Stocks J, McElvaney NG, Chapman KR, Edelman JM

Abstract
AIMS: Early-onset emphysema attributed to α-1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID-RCT/RAPID-OLE, the largest clinical trials of purified human α-1 proteinase inhibitor (A1 -PI; 60 mg kg-1  week-1 ) therapy completed to date, demonstrated for the first time that A1 -PI is clinically effective in slowing lung tissue loss in AATD. A posthoc pharmacometric analysis was undertaken to further explore dose, exposure and response.
METHODS: A disease progression model was constructed, utilizing observed A1 -PI exposure and lung density decline rates (measured by computed tomography) from RAPID-RCT/RAPID-OLE, to predict effects of population variability and higher doses on A1 -PI exposure and clinical response. Dose-exposure and exposure-response relationships were characterized using nonlinear and linear mixed effects models, respectively. The dose-exposure model predicts summary exposures and not individual concentration kinetics; covariates included baseline serum A1 -PI, forced expiratory volume in 1 s and body weight. The exposure-response model relates A1 -PI exposure to lung density decline rate at varying exposure levels.
RESULTS: A dose of 60 mg kg-1  week-1 achieved trough serum levels >11 μmol l-1 (putative 'protective threshold') in ≥98% patients. Dose-exposure-response simulations revealed increasing separation between A1 -PI and placebo in the proportions of patients achieving higher reductions in lung density decline rate; improvements in decline rates ≥0.5 g l-1  year-1 occurred more often in patients receiving A1 -PI: 63 vs. 12%.
CONCLUSION: Weight-based A1 -PI dosing reliably raises serum levels above the 11 μmol l-1 threshold. However, our exposure-response simulations question whether this is the maximal, clinically effective threshold for A1 -PI therapy in AATD. The model suggested higher doses of A1 -PI would yield greater clinical effects.

PMID: 28662542 [PubMed - indexed for MEDLINE]

Synchronous Bilateral Breast Cancer in a Patient With Nager Syndrome.

Clin Breast Cancer. 2017 06;17(3):e151-e153

Authors: Denu RA, Burkard ME

PMID: 28139434 [PubMed - indexed for MEDLINE]

10 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/06/12

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

[Acute Promyelocytic Leukemia - A Rare, Life-Threatening Disease with High Healing Chance].

Dtsch Med Wochenschr. 2018 Feb;143(3):152-156

Authors: Nolte F, Lengfelder E, Hofmann WK

Abstract
The acute promyelocytic leukemia (APL) is a rare disease. However, if diagnosed early and treated immediately high cure rates can be achieved. Signs of hematopoietic insufficiency such as cytopenias or leucocytosis can be present at first presentation of the patients. Moreover, hemorrhagic diatheses due to coagulpathy are present in approximately 80 % of cases and contribute substatially to the high early death rate in APL patients, which has been reported as high as 30 % in population based studies. In case of initial suspicion of APL treatment with all-trans retinoic acid (ATRA) should be initated immediately to reduce the risk of fatal bleeding events and confirmation or exclusion of the PML-RARA transcript should not be awaited before start of ATRA treatment. While patients with a low or intermediate risk of relapse are treated with a combination of ATRA and arsenic trioxide (ATO), those with high risk of relapse still receive a combination regimen consisting of ATRA, anthracyclines and cytosine-arabinosid. However, treatment strategies are under clinical investigation aiming at reducing the administration of conventional chemotherapy in high risk APL patients. With the current treatment approaches cure rates of approximately 90 % of the patients with low or intermeditae risk APL can be achieved. Nevertheless, particularly the high initial death rate warrants further clinical and pathiobiologic studies to identify targets and means to decrease hemorrhagic complications in patients with APL.

PMID: 29409083 [PubMed - indexed for MEDLINE]

Phenopolis: an open platform for harmonization and analysis of genetic and phenotypic data.

Bioinformatics. 2017 Aug 01;33(15):2421-2423

Authors: Pontikos N, Yu J, Moghul I, Withington L, Blanco-Kelly F, Vulliamy T, Wong TLE, Murphy C, Cipriani V, Fiorentino A, Arno G, Greene D, Jacobsen JOB, Clark T, Gregory DS, Nemeth AM, Halford S, Inglehearn CF, Downes S, Black GC, Webster AR, Hardcastle AJ, UKIRDC, Plagnol V

Abstract
Summary: Phenopolis is an open-source web server providing an intuitive interface to genetic and phenotypic databases. It integrates analysis tools such as variant filtering and gene prioritization based on phenotype. The Phenopolis platform will accelerate clinical diagnosis, gene discovery and encourage wider adoption of the Human Phenotype Ontology in the study of rare genetic diseases.
Availability and Implementation: A demo of the website is available at https://phenopolis.github.io . If you wish to install a local copy, source code and installation instruction are available at https://github.com/phenopolis . The software is implemented using Python, MongoDB, HTML/Javascript and various bash shell scripts.
Contact: n.pontikos@ucl.ac.uk.
Supplementary information: Supplementary data are available at Bioinformatics online.

PMID: 28334266 [PubMed - indexed for MEDLINE]

Epidemiology of pyoderma gangrenosum: Results from an Italian prospective multicentre study.

Int Wound J. 2018 Jun 06;:

Authors: Monari P, Moro R, Motolese A, Misciali C, Baraldi C, Fanti PA, Caccavale S, Puviani M, Olezzi D, Zampieri P, Trevisan G, Nan K, Fiorentini C, Pellacani G, Gualdi G

Abstract
Pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterised by painful, necrotic ulcerations. PG is described as a rare disease: the world-wide incidence is estimated to be around 3 to 10 cases per million population per year. These estimations are based mostly on case reports and retrospective case series; there are no prospective, multicentre studies on the matter. The apparent rarity of PG is in contrast with our clinical perception as dermatologists: in our opinion, PG is not so uncommon. Therefore, we decide to investigate the epidemiology of PG in the Italian population and confirm our clinical suspicions that it is not an orphan disease. We enrolled all patients diagnosed with PG in 8 Italian Dermatological Departments from 1st October 2014 to 1st November 2015, and we recorded their features. Our data, collected from 64 patients, are in accordance with those of the published literature regarding the epidemiology and features of PG. In an Italian population of roughly 8 million inhabitants of 7 provinces, we found an incidence of 5.17 new cases per million population per year. Unlike our predictions before the study, we confirmed the world-wide incidence of PG. To our knowledge, this is the first observational, multicentre study on PG. We hope that it provides a stimulus for further researches on PG and for the creation of an Italian register.

PMID: 29877043 [PubMed - as supplied by publisher]

A cross-sectional quantitative analysis of the natural history of free sialic acid storage disease-an ultra-orphan multisystemic lysosomal storage disorder.

Genet Med. 2018 Jun 06;:

Authors: Zielonka M, Garbade SF, Kölker S, Hoffmann GF, Ries M

Abstract
PURPOSE: Quantitative definition of the natural history of free sialic acid storage disease (SASD, OMIM 604369), an orphan disorder due to the deficiency of the proton-driven carrier SLC17A5.
METHODS: Analysis of published cases with SASD (N = 116) respecting STROBE criteria.
MAIN OUTCOME PARAMETERS: survival and diagnostic delay. Phenotype, phenotype-biomarker associations, and geographical patient distribution were explored.
RESULTS: Median age at disease onset was 0.17 years. Median age at diagnosis was 3 years with a median diagnostic delay of 2.5 years. Median survival was 11 years. The biochemical phenotype clearly predicted the disease course: patients with a urinary free sialic acid excretion below 6.37-fold or an intracellular free sialic acid storage in fibroblasts below 7.37-fold of the mean of normal survived longer than patients with biochemical values above these thresholds. Cluster analysis of disease features suggested a continuous phenotypic spectrum. Patient distribution was panethnic.
CONCLUSION: Combination of neurologic symptoms, visceromegaly, and dysmorphic features and/or nonimmune hydrops fetalis should prompt specific tests for SASD, reducing diagnostic delay. The present quantitative data inform clinical studies and may stimulate and accelerate development of specific therapies. Biomarker-phenotype association is particularly important for both counseling parents and study design.

PMID: 29875421 [PubMed - as supplied by publisher]

Improving risk equalization for individuals with persistently high costs: Experiences from the Netherlands.

Health Policy. 2017 Nov;121(11):1169-1176

Authors: Eijkenaar F, van Vliet RCJA

Abstract
BACKGROUND: Risk-equalization (RE) models in competitive health insurance markets have become increasingly sophisticated. However, these models still have important imperfections. A specific problem in the Netherlands is that insurers are insufficiently compensated for individuals who can persistently be found in the right-end tail of the cost distribution.
OBJECTIVES: The goal of this study is to explore and evaluate options for improving compensation for persistently high-cost individuals in the Dutch basic health insurance.
METHODS: Prescription drugs claims (2012) and administrative data on costs and risk-characteristics (2010-2013) for the entire Dutch population are used to identify high-cost individuals and evaluate improvement options. These options - including new risk-classes and a form of risk-sharing - are evaluated in terms of insurers' incentives for risk-selection and efficiency.
RESULTS: Three significantly undercompensated high-cost groups are identified: users of specific expensive drugs for rare diseases, hemophilia-patients, and individuals whose costs are in the top-0.50% in 3 prior years. The improvement options effectively remove the undercompensations for these groups and lead to a considerable improvement in individual-level model fit. However, the options differ in terms of their (potential) effects on insurers' efficiency incentives.
CONCLUSIONS: Although this study provides useful insights in the possibilities for improving RE-models for persistently high-cost individuals, improving compensation remains challenging and dependent on the ongoing debate regarding coverage and reimbursement of expensive drugs.

PMID: 28942090 [PubMed - indexed for MEDLINE]

Long-term metabolic follow-up and clinical outcome of 35 patients with maple syrup urine disease.

J Inherit Metab Dis. 2017 Nov;40(6):783-792

Authors: Abi-Wardé MT, Roda C, Arnoux JB, Servais A, Habarou F, Brassier A, Pontoizeau C, Barbier V, Bayart M, Leboeuf V, Chadefaux-Vekemans B, Dubois S, Assoun M, Belloche C, Alili JM, Husson MC, Lesage F, Dupic L, Theuil B, Ottolenghi C, de Lonlay P

Abstract
BACKGROUND: Maple syrup urine disease (MSUD) is a rare disease that requires a protein-restricted diet for successful management. Little is known, however, about the psychosocial outcome of MSUD patients. This study investigates the relationship between metabolic and clinical parameters and psychosocial outcomes in a cohort of patients with neonatal-onset MSUD.
METHODS: Data on academic achievement, psychological care, family involvement, and biochemical parameters were collected from the medical records of neonatal MSUD patients treated at Necker Hospital (Paris) between 1964 and 2013.
RESULTS: Thirty-five MSUD patients with a mean age of 16.3 (2.1-49.0) years participated. Metabolic decompensations (plasma leucine >380 μmol/L) were more frequent during the first year of life and after 15 years, mainly due to infection and dietary noncompliance, respectively. Leucine levels increased significantly in adulthood: 61.5% of adults were independent and achieved adequate social and professional integration; 56% needed occasional or sustained psychological or psychiatric care (8/19, with externalizing, mood, emotional, and anxiety disorders being the most common). Patients needing psychiatric care were significantly older [mean and standard deviation (SD) 22.6 (7.7) years] than patients needing only psychological follow-up [mean (SD) 14.3 (8.9) years]. Patients with psychological follow-up experienced the highest lifetime number of decompensations; 45% of families had difficulty coping with the chronic disease. Parental involvement was negatively associated with the number of lifetime decompensations.
CONCLUSION: Adults had increased levels of plasma leucine, consistent with greater chronic toxicity. Psychological care was associated with age and number of decompensations. In addition, parental involvement appeared to be crucial in the management of MSUD patients.

PMID: 28905140 [PubMed - indexed for MEDLINE]

Small-Molecule Inhibitors Disrupt let-7 Oligouridylation and Release the Selective Blockade of let-7 Processing by LIN28.

Cell Rep. 2018 Jun 05;23(10):3091-3101

Authors: Wang L, Rowe RG, Jaimes A, Yu C, Nam Y, Pearson DS, Zhang J, Xie X, Marion W, Heffron GJ, Daley GQ, Sliz P

Abstract
LIN28 is an RNA-binding protein that regulates the maturation of the let-7 family of microRNAs by bipartite interactions with let-7 precursors through its two distinct cold shock and zinc-knuckle domains. Through inhibition of let-7 biogenesis, LIN28 functions as a pluripotency factor, as well as a driver of tumorigenesis. Here, we report a fluorescence polarization assay to identify small-molecule inhibitors for both domains of LIN28 involved in let-7 interactions. Of 101,017 compounds screened, six inhibit LIN28:let-7 binding and impair LIN28-mediated let-7 oligouridylation. Upon further characterization, we demonstrate that the LIN28 inhibitor TPEN destabilizes the zinc-knuckle domain of LIN28, while LI71 binds the cold shock domain to suppress LIN28's activity against let-7 in leukemia cells and embryonic stem cells. Our results demonstrate selective pharmacologic inhibition of individual domains of LIN28 and provide a foundation for therapeutic inhibition of the let-7 biogenesis pathway in LIN28-driven diseases.

PMID: 29874593 [PubMed - in process]