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Objective: To continue evaluation of the long-term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy (DMD). Three-year progression of eteplirsen-treated patients was compared to matched historical controls (HC)., Methods: Ambulatory DMD patients who were ≥7 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open-label basis. The primary functional assessment in this study was the 6-Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype., Results: At 36 months, eteplirsen-treated patients (n = 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n = 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen-treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping., Interpretation: Over 3 years of follow-up, eteplirsen-treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC., (© 2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Background: AVI-7288 is a phosphorodiamidate morpholino oligomer with positive charges that targets the viral messenger RNA that encodes Marburg virus (MARV) nucleoprotein. Its safety in humans is undetermined., Methods: We assessed the efficacy of AVI-7288 in a series of studies involving a lethal challenge with MARV in nonhuman primates. The safety of AVI-7288 was evaluated in a randomized, multiple-ascending-dose study in which 40 healthy humans (8 humans per dose group) received 14 once-daily infusions of AVI-7288 (1 mg, 4 mg, 8 mg, 12 mg, or 16 mg per kilogram of body weight) or placebo, in a 3:1 ratio. We estimated the protective dose in humans by comparing pharmacokinetic variables in infected nonhuman primates, uninfected nonhuman primates, and uninfected humans., Results: Survival in infected nonhuman primates was dose-dependent, with survival rates of 0%, 30%, 59%, 87%, 100%, and 100% among monkeys treated with 0 mg, 3.75 mg, 7.5 mg, 15 mg, 20 mg, and 30 mg of AVI-7288 per kilogram, respectively (P<0.001 with the use of the log-rank test for the comparison of survival across groups). No safety concern was identified at doses up to 16 mg per kilogram per day in humans. No serious adverse events were reported. Drug exposure (the area under the curve) was dose-dependent in both nonhuman primates and humans; drug clearance was independent of dose but was higher in nonhuman primates than in humans. The protective dose in humans was initially estimated, on the basis of exposure, to be 9.6 mg per kilogram per day (95% confidence interval, 6.6 to 12.5) for 14 days. Monte Carlo simulations supported a dose of 11 mg per kilogram per day to match the geometric mean protective exposure in nonhuman primates., Conclusions: This study shows that, on the basis of efficacy in nonhuman primates and pharmacokinetic data in humans, AVI-7288 has potential as postexposure prophylaxis for MARV infection in humans. (Funded by the Department of Defense; ClinicalTrials.gov number, NCT01566877.).

Objective: In prior open-label studies, eteplirsen, a phosphorodiamidate morpholino oligomer, enabled dystrophin production in Duchenne muscular dystrophy (DMD) with genetic mutations amenable to skipping exon 51. The present study used a double-blind placebo-controlled protocol to test eteplirsen's ability to induce dystrophin production and improve distance walked on the 6-minute walk test (6MWT)., Methods: DMD boys aged 7 to 13 years, with confirmed deletions correctable by skipping exon 51 and ability to walk 200 to 400 m on 6 MWT, were randomized to weekly intravenous infusions of 30 or 50 mg/kg/wk eteplirsen or placebo for 24 weeks (n = 4/group). Placebo patients switched to 30 or 50 mg/kg eteplirsen (n=2/group) at week 25; treatment was open label thereafter. All patients had muscle biopsies at baseline and week 48. Efficacy included dystrophin-positive fibers and distance walked on the 6MWT., Results: At week 24, the 30 mg/kg eteplirsen patients were biopsied, and percentage of dystrophin-positive fibers was increased to 23% of normal; no increases were detected in placebo-treated patients (p≤0.002). Even greater increases occurred at week 48 (52% and 43% in the 30 and 50 mg/kg cohorts, respectively), suggesting that dystrophin increases with longer treatment. Restoration of functional dystrophin was confirmed by detection of sarcoglycans and neuronal nitric oxide synthase at the sarcolemma. Ambulation-evaluable eteplirsen-treated patients experienced a 67.3 m benefit compared to placebo/delayed patients (p≤0.001)., Interpretation: Eteplirsen restored dystrophin in the 30 and 50 mg/kg/wk cohorts, and in subsequently treated, placebo-controlled subjects. Duration, more than dose, accounted for dystrophin production, also resulting in ambulation stability. No severe adverse events were encountered., (© 2013 American Neurological Association.)

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations in the SMN1 gene that result in a deficiency of SMN protein. One approach to treat SMA is to use antisense oligonucleotides (ASOs) to redirect the splicing of a paralogous gene, SMN2, to boost production of functional SMN. Injection of a 2'-O-2-methoxyethyl-modified ASO (ASO-10-27) into the cerebral lateral ventricles of mice with a severe form of SMA resulted in splice-mediated increases in SMN protein and in the number of motor neurons in the spinal cord, which led to improvements in muscle physiology, motor function and survival. Intrathecal infusion of ASO-10-27 into cynomolgus monkeys delivered putative therapeutic levels of the oligonucleotide to all regions of the spinal cord. These data demonstrate that central nervous system-directed ASO therapy is efficacious and that intrathecal infusion may represent a practical route for delivering this therapeutic in the clinic.

Abnormalities of myelin are common in lysosomal and peroxisomal disorders. Most display a primary loss of myelin in which the myelin sheath and/or oligodendrocytes are selectively targeted by diverse pathogenetic processes. The most severe and, hence, clinically relevant are heritable diseases predominantly of infants and children, the leukodystrophies: metachromatic, globoid cell (Krabbe disease) and adreno-leukodystrophy. Our still limited understanding of these diseases has derived from multiple sources: originally, neurological-neuropathologic-neurochemical correlative studies of the natural disease in humans or other mammals, which has been enhanced by more sophisticated and contemporary techniques of cell and molecular biology. Transgenic mouse models seem to be the most promising methodology, allowing the examination of the cellular role of lysosomes and peroxisomes for formation and maintenance of both myelin and axons, and providing initial platforms to evaluate therapies. Treatment options are woefully inadequate and in their nascent stages, but still inspire some hope for the future.

We developed normative profiles of physical functioning (mobility and self-care) in infancy up through 14 years of age with an expanded version of the Pediatric Evaluation of Disability Inventory. Mobility and self-care reference curves were based on the original Pediatric Evaluation of Disability Inventory standardization data (n = 412) and data from an additional cross-sectional, convenience sample (n = 373) via web-based survey, telephone or in-person interviews of parents. This new sample, which included children up through 14 years-of-age, was stratified for race, age, and sex, but was primarily limited geographically to the Northeast region of the United States. Goodness of fit of male, female, and combined sex (male and female) reference curves was examined. The mobility and self-care reference curves produced efficient and well-fitting estimates of conventional percentiles (3rd, 10th, 25th, 50th, 75th, 97th). Differences between males' and females' reference curves were negligible. This study highlights the use of these reference curves for determining the functional impact of Pompe disease, a lysosomal storage disorder that affects skeletal and cardiac muscle, restricting normal expression of mobility and self-care activities. This physical functioning instrument could also be used to evaluate the impact of muscle weakness in other neuromuscular disorders.

Objective: To determine whether newborn screening by tandem mass spectrometry (MS/MS) for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is cost-effective versus not screening and to define the contributions of disease, test, and population parameters on the decision., Methods: A decision-analytic Markov model was designed to perform cost-effectiveness and cost-utility analyses measuring the discounted, incremental cost per life-year saved and per quality-adjusted life-year saved of newborn screening for MCADD compared with not screening. A hypothetical cohort of neonates made transitions among a set of health states that reflected clinical status, morbidity, and cost. Outcomes were estimated for time horizons of 20 and 70 years. Probabilities and costs were derived from a retrospective chart review of a 32-patient cohort treated over the past 30 years at the Children's Hospital of Philadelphia, clinical experience with MCADD patient management, patient-family interviews, cost surveys, state sources, and published studies. In addition to older patients who came to medical attention by symptomatic presentation, our patient group included 6 individuals whose MCADD had been diagnosed by supplemental newborn screening. Estimates of the expected net changes in costs and life expectancy for MCADD screening were used to compute the incremental cost-effectiveness ratios. Sensitivity analyses were performed on key input variables, and 95% confidence intervals (CIs) were computed through second-order Monte Carlo simulations., Results: In our base-case analysis over the first 20 years of life, the cost of newborn screening for MCADD was approximately 11,000 dollars(2001 US dollars; 95% CI: <0-33,800 dollars) per life-year saved, or 5600 dollars (95% CI: <0-17,100 dollars) per quality-adjusted life-year saved compared with not screening. Over a 70-year horizon, the respective ratios were approximately 300 dollars (95% CI: <0-13,000 dollars) and 100 dollars (95% CI: <0-6900 dollars). The results were robust when tested over plausible ranges for diagnostic test sensitivity and specificity, MCADD prevalence, asymptomatic rate, and screening cost., Conclusions: Simulation modeling indicates that newborn screening for MCADD reduces morbidity and mortality at an incremental cost below the range for accepted health care interventions. At the 70-year horizon, the model predicts that almost all of the additional costs of screening would be offset by avoided sequelae.

Maple syrup urine disease (MSUD) is an inborn error of amino acid metabolism, which affects the brain tissue resulting in impairment or death if untreated. Imaging studies have shown reversible brain edema during acute metabolic decompensation. The purpose of this paper is to describe the diffusion-weighted imaging (DWI) and spectroscopy findings during metabolic decompensation and to assess the value of these findings in the prediction of patient outcome. Six patients with the diagnosis of MSUD underwent conventional MR imaging with DWI during acute presentation with metabolic decompensation. Spectroscopy with long TE was performed in four of the six patients. Follow-up examinations were performed after clinical and metabolic recovery. DWI demonstrated marked restriction of proton diffusion compatible with cytotoxic or intramyelinic sheath edema in the brainstem, basal ganglia, thalami, cerebellar and periventricular white matter and the cerebral cortex. This was accompanied by the presence of an abnormal branched-chain amino acids (BCAA) and branched-chain alpha-keto acids (BCKA) peak at 0.9 ppm as well as elevated lactate on proton spectroscopy in all four patients. The changes in all six patients were reversed with treatment without evidence of volume loss or persistent tissue damage. The presence of cytotoxic or intramyelinic edema as evidenced by restricted water diffusion on DWI, with the presence of lactate on spectroscopy, could imply imminent cell death. However, in the context of metabolic decompensation in MSUD, it appears that changes in cell osmolarity and metabolism can reverse completely after metabolic correction.

Although great promise has been made in the field of gene therapy, a number of difficulties must be solved before successful human studies can be completed. These issues involve safety, immunological reactions to the vectors and their transgene products, persistent transgene expression, and ability to repeat administrations of the vector safely. A major hurdle that must be overcome is the ubiquitous delivery of the transgene throughout the nervous system. Significant gene delivery to the CNS of murine models of LSD has been accomplished, but we await the successful treatment of the nervous system in a larger mammalian model of LSD. As yet there is no perfect vector that can solve all of these problems. It is likely that vector technology will evolve into hybrid vectors also using synthetic components that will increase safety and efficacy of recombinant vectors. The treatment of the CNS remains complicated, but progress is being made in this area. Clinical trials already planned will give us increasing information as to the ideal gene therapy for the CNS.

Mitochondrial disease is classically associated with deep gray-matter lesions. When white matter is involved, the lesions are typically subcortical and overshadowed by more significant disease in the gray matter. We report six infants in five families who developed neurodegenerative diseases characterized primarily by abnormalities in deep white-matter structures such as the periventricular region, internal capsule, and corpus callosum. Five patients had impairments of mitochondrial enzymes, including a pre-electron transport chain defect and defects in respiratory chain complexes I, III, and IV (cytochrome-c oxidase). One patient, the sibling of one of the others, was diagnosed clinically with complex III deficiency. These six patients, along with others in the literature, appear to represent a distinct syndrome of mitochondrial infantile leukoencephalopathy. Our observations suggest that infants with leukoencephalopathies, especially leukodystrophies, who do not have one of the more common causes of white-matter disease should be evaluated for mitochondrial dysfunction.

Lysosomal storage disorders (LSDs), over 40 different diseases, are now considered treatable disorders. Only a few short years ago, Lysosomal storage disorders were seen as interesting neurodegenerative disorders without any potential for treatment. Effective treatment strategies such as bone marrow transplantation (BMT), enzyme replacement therapy (ERT), and glycolipid synthesis inhibition have been developed in the last 20 years and continue to be researched and evaluated. Bone marrow transplantation began approximately 15 years ago and has shown benefit for some of the lysosomal storage disorders. In order to be effective, the transplant must be performed early in the course of the disease, before the development of irreversible neurologic damage. Diseases such as Hurler appear to respond to BMT, however, improvement in bone disease is much less vigorous than responses in other organs. Krabbe disease responds if the transplant is performed before irreversible signs of neurologic damage appear. Metachromatic leukodystrophy may respond if the transplant can be performed early enough although peripheral nerve findings appear to progress. Other diseases, eg, GM1- and GM2-gangliosidoses do not appear to be altered by BMT. Despite its high cost, ERT has been very effective treatment for type I (non-neuronopathic) Gaucher disease. Enzyme replacement therapy for other LSDs, including ERT for Fabry and Pompe diseases, which are planned to be imminently introduced, and other enzymes such as for Morquio and Hunter diseases that are in the study phases, may be marketed in the very near future. Glycolipid inhibitors, such as N-butyldeoxynijirimycin (OGS-918), have been effective in reducing the liver and spleen volume in type I Gaucher disease. These oral inhibitors may prove to be important adjuncts to ERT and provide the advantage of being able to cross the blood/brain barrier, which limits enzyme access to brain. Currently, clinical studies are being conducted on patients with type III Gaucher disease and Fabry disease using OGS-918. Other, potentially more specific, glycolipid inhibitors are being developed.