Substrate Reduction Augments the Efficacy of Enzyme Therapy in a Mouse Model of Fabry Disease

Fabry disease is an X-linked glycosphingolipid storage disorder caused by a deficiency in the activity of the lysosomal hydrolase α-galactosidase A (α-gal). This deficiency results in accumulation of the glycosphingolipid globotriaosylceramide (GL-3) in lysosomes. Endothelial cell storage of GL-3 frequently leads to kidney dysfunction, cardiac and cerebrovascular disease. The current treatment for Fabry disease is through infusions of recombinant α-gal (enzyme-replacement therapy; ERT). Although ERT can markedly reduce the lysosomal burden of GL-3 in endothelial cells, variability is seen in the clearance from several other cell types. This suggests that alternative and adjuvant therapies may be desirable. Use of glucosylceramide synthase inhibitors to abate the biosynthesis of glycosphingolipids (substrate reduction therapy, SRT) has been shown to be effective at reducing substrate levels in the related glycosphingolipidosis, Gaucher disease. Here, we show that such an inhibitor (eliglustat tartrate, Genz-112638) was effective at lowering GL-3 accumulation in a mouse model of Fabry disease. Relative efficacy of SRT and ERT at reducing GL-3 levels in Fabry mouse tissues differed with SRT being more effective in the kidney, and ERT more efficacious in the heart and liver. Combination therapy with ERT and SRT provided the most complete clearance of GL-3 from all the tissues. Furthermore, treatment normalized urine volume and uromodulin levels and significantly delayed the loss of a nociceptive response. The differential efficacies of SRT and ERT in the different tissues indicate that the combination approach is both additive and complementary suggesting the possibility of an improved therapeutic paradigm in the management of Fabry disease

Substrate reduction therapy in mouse models of the glycosphingolipidoses.

Substrate reduction therapy uses small molecules to slow the rate of glycolipid biosynthesis. One of these drugs, N-butyldeoxynojirimycin (NB-DNJ), shows efficacy in mouse models of Tay-Sachs, Sandhoff and Fabry diseases. This offers the prospect that NB-DNJ may be of therapeutic benefit, at least in the juvenile and adult onset variants of these disorders. The infantile onset variants will require an additional enzyme-augmenting modality if the pathology is to be significantly improved. A second drug, N-butyldeoxyglactonojirimycin, looks very promising for treating storage diseases with neurological involvement as high systemic dosing is achievable without any side-effects

Phenolic compounds from nutmeg (<i>Myristica fragrans</i> Houtt.) inhibit the endocannabinoid-modulating enzyme fatty acid amide hydrolase

Abstract Objectives The study aimed to identify nutmeg compounds that indirectly interact with the endocannabinoid system through inhibition of the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) enzymes. Methods Thirteen compounds were screened for FAAH and MAGL inhibition. Compounds demonstrating significant FAAH inhibition were evaluated to determine the halfmaximal inhibitory concentration (IC50). The most potent compound was investigated in the elevated plus maze (EPM) rodent anxiety model. Key findings Three compounds, licarin A (9), 5′-methoxylicarin A (8) and malabaricone C (6) were most active in inhibiting FAAH with IC50 of 7.02 μm ± 2.02, 4.57 μm ± 0.66 and 38.29 μm ± 6.18, respectively. None of the purified compounds showed significant MAGL inhibition. Because of its relative high potency and selectivity, compound 8 was further evaluated in the EPM animal model of anxiety. The compound showed significant increase in number of open arm entries (P &amp;lt; 0.05) when administered at 120 mg/kg dose. No effect was observed on the locomotor activity. Conclusions Results collected introduce active nutmeg compounds as potential leads for further development. Of the three compounds, 8 possesses highest potency and FAAH selectivity as well as anxiolytic activity. Furthermore, in vivo testing in appropriate behavioural animal paradigms is warranted. </jats:sec

Delay to Reconstruction of the Adolescent Anterior Cruciate Ligament

Background: A delay in pediatric and adolescent anterior cruciate ligament (ACL) reconstruction is associated with an increase in the number of concomitant meniscal and chondral injuries. Factors that contribute to this delay have not been well described. Hypothesis: Socioeconomic and demographic factors are related to ACL surgery timing. Study Methods: Cohort study; Level of evidence, 3. Methods: All subjects who underwent primary ACL reconstruction at a single tertiary pediatric hospital between 2005 and 2012 were retrospectively reviewed. Variables included concomitant knee injuries (cartilage or meniscus injuries requiring additional operative treatment) and chronologic, demographic, and socioeconomic factors. Multivariable Cox proportional-hazards analyses were used to identify factors related to ACL surgery timing. Results: The mean age of the 272 subjects was 15.2 ± 2.12 years. Time to surgery was significantly different among subjects who required multiple additional surgical procedures at time of ACL reconstruction (median, 3.3 months) compared with subjects with 1 (median, 2.0 months) or no additional injuries (median, 1.6 months). Subjects underwent ACL reconstruction significantly sooner if they were older at the time of injury (hazard ratio [HR], 1.2 per 1 year; 95% CI, 1.1-1.2; P &lt; .0001) or were covered by a commercial insurance plan (HR, 2.0; 95% CI, 1.6-2.6; P &lt; .0001). Median time to ACL surgery was 1.5 months (95% CI, 1.3-1.7) for subjects with commercial insurance plans compared with 3.0 months (95% CI, 2.3-3.3) for subjects with noncommercial insurance coverage. Conclusion: The risk of delayed ACL surgery was significantly higher among pediatric and adolescent subjects who were less affluent, who were covered by a noncommercial insurance plan, and who were younger. This study also confirms previous studies that have reported an association between a delay in ACL surgery and the presence of additional knee injuries requiring operative treatment, accentuating the importance of timely care. Clinical Relevance: Access to care is a current area of research interest and health policy formation. Information in this arena drives 2 important aspects of health: most immediately, care provided to patients, and over a broader scope, the policy that directs health care. The orthopaedic surgeon should be aware of the association between socioeconomic and demographic factors and ACL surgery timing to optimize outcomes. </jats:sec

Factors Predictive of Concomitant Injuries Among Children and Adolescents Undergoing Anterior Cruciate Ligament Surgery

Background: The timing of treatment for pediatric anterior cruciate ligament (ACL) injuries remains controversial. The risks of delaying reconstruction and the differences between age groups are poorly defined. Purpose: To investigate factors that contribute to the prevalence and severity of concomitant chondral and meniscal injuries among patients aged 14 to 19 years versus those aged ≤14 years at the time of ACL reconstruction. The hypothesis was that concomitant injuries would be more prevalent in older versus younger subjects. Also, a delay in surgery would be predictive of the presence and severity of concomitant knee injuries requiring additional operative procedures. Study Methods: Cohort study; Level of evidence, 3. Methods: All subjects who underwent primary ACL reconstruction at a single tertiary pediatric hospital between 2005 and 2012 were retrospectively reviewed. The location, severity, and treatment of all concomitant knee injuries were recorded. Chi-square tests were used to compare the prevalence of chondral and meniscal injuries in the older (age, 14-19 years; n = 165) versus younger (age, ≤14 years; n = 66) cohorts. A multivariable logistic regression analysis was used to identify factors related to the presence of a concomitant injury that required additional treatment. Kaplan-Meier analyses were used to explore the relation between time to surgery and meniscal injury severity. Results: There was a significant relationship between time to surgery and the development of an irreparable meniscal injury ( P &lt; .05 for all) in both the younger and older groups. Time to surgery correlated with severity of chondral injury in the younger cohort ( P = .0343) but not in the older cohort ( P = .8877). In the younger cohort, only a delay in surgery &gt;3 months (odds ratio [OR] = 4.8; 95% CI, 1.7-14.4; P = .0027) was significantly predictive of the presence of an injury that required additional operative procedures. In the older patients, a return to activity before surgery (OR = 3.8; 95% CI, 1.52-11.9; P = .0034) and obesity (OR = 2.5; 95% CI, 1.1-7.4; P = .0381) were significantly predictive of an injury that required additional operative procedures. Conclusion: Compared with younger subjects, the prevalence of concomitant knee injuries as well as the need for additional operative procedures was greater among older subjects. A delay to surgery correlated with increased severity of injury among both older and younger populations. A delay in surgery &gt;3 months was the strongest predictor of the development of a concomitant injury in the younger cohort. A return to activity and obesity were significantly related to the presence of a concomitant knee injury in the older cohort. </jats:sec