L.N. Alfano

Proof of Concept of the Ability of the Kinect to Quantify Upper Extremity Function in Dystrophinopathy

Introduction: Individuals with dystrophinopathy lose upper extremity strength in proximal muscles followed by those more distal. Current upper extremity evaluation tools fail to fully capture changes in upper extremity strength and function across the disease spectrum as they tend to focus solely on distal ability. The Kinect by Microsoft is a gaming interface that can gather positional information about an individual’s upper extremity movement which can be used to determine functional reaching volume, velocity of movement, and rate of fatigue while playing an engaging video game. The purpose of this study was to determine the feasibility of using the Kinect platform to assess upper extremity function in individuals with dystrophinopathy across the spectrum of abilities. Methods: Investigators developed a proof-of-concept device, ACTIVE (Abilities Captured Through Interactive Video Evaluation), to measure functional reaching volume, movement velocity, and rate of fatigue. Five subjects with dystrophinopathy and 5 normal controls were tested using ACTIVE during one testing session. A single subject with dystrophinopathy was simultaneously tested with ACTIVE and a marker-based motion analysis system to establish preliminary validity of measurements. Results: ACTIVE proof-of-concept ranked the upper extremity abilities of subjects with dystrophinopathy by Brooke score, and also differentiated them from performance of normal controls for the functional reaching volume and velocity tests. Preliminary test-retest reliability of the ACTIVE for 2 sequential trials was excellent for functional reaching volume (ICC=0.986, p<0.001) and velocity trials (ICC=0.963, p<0.001). Discussion: The data from our pilot study with ACTIVE proof-of-concept demonstrates that newly available gaming technology has potential to be used to create a low-cost, widely-accessible and functional upper extremity outcome measure for use with children and adults with dystrophinopathy.

A prospective one-year natural history study of mucopolysaccharidosis types IIIA and IIIB: Implications for clinical trial design.

Mucopolysaccharidosis type III is a group of four autosomal recessive enzyme deficiencies leading to tissue accumulation of heparan sulfate. Central nervous system disease is prominent, with initial normal development followed by neurocognitive decline leading to death. In order to define outcome measures suitable for gene transfer trials, we prospectively assessed disease progression in MPS IIIA and IIIB subjects >2years old at three time points over one year (baseline, 6 and 12months). Fifteen IIIA (9 male, 6 female; age 5.0±1.9years) and ten IIIB subjects (8 male, 2 female; age 8.6±3years) were enrolled, and twenty subjects completed assessments at all time points. Cognitive function as assessed by Mullen Scales maximized at the 2.5 to 3year old developmental level, and showed a significant age-related decline over a 6month interval in three of five subdomains. Leiter nonverbal IQ (NVIQ) standard scores declined toward the test floor in the cohort by 6 to 8years of age, but showed significant mean declines over a 6month interval in those <7years old (p=0.0029) and in those with NVIQ score≥45 (p=0.0313). Parental report of adaptive behavior as assessed by the Vineland-II composite score inversely correlated with age and showed a significant mean decline over 6month intervals (p=0.0004). Abdominal MRI demonstrated increased volumes in liver (mean 2.2 times normal) and spleen (mean 1.9 times normal) without significant change over one year; brain MRI showed ventriculomegaly and loss of cortical volume in all subjects. Biochemical measures included urine glycosaminoglycan (GAG) levels, which although elevated showed a decline correlating with age (p<0.0001) and approached normal values in older subjects. CSF protein levels were elevated in 32% at enrollment, and elevations of AST and ALT were frequent. CSF enzyme activity levels for either SGSH (in MPS IIIA subjects) or NAGLU (in MPS IIIB) significantly differed from normal controls. Several other behavioral or functional measures were found to be uninformative in this population, including timed functional motor tests. Our results suggest that cognitive development as assessed by the Mullen and Leiter-R and adaptive behavior assessment by the Vineland parent interview are suitable functional outcomes for interventional trials in MPS IIIA or IIIB, and that CSF enzyme assay may be a useful biomarker to assess central nervous system transgene expression in gene transfer trials.

The 2-min walk test is sufficient for evaluating walking abilities in sporadic inclusion body myositis.

Sporadic inclusion body myositis causes progressive functional loss due to declining muscle strength. Although the underlying cause is unknown, clinical trials are underway to improve strength and function. Selection of appropriate outcome measures is critical for the success of these trials. The 6-min walk test has been the de facto standard for assessing function in neuromuscular disease; however, the optimal walking test has not been determined in this disease. In this study, 67 individuals with sporadic inclusion body myositis completed a battery of quantitative strength and functional tests including timed walking tests, patient-reported outcomes, and other tasks. The 2-min and 6-min walk tests are highly correlated to each other (r=0.97, p<0.001) and to all lower extremity strength, patient-reported, and functional measures in this population. All subjects completed the 2-min walk test, but 7% of subjects were unable to walk the full 6-min of the 6-min walk test due to fatigue. The 2-min walk test demonstrates similar correlation to all outcomes compared to the 6-min walk test, is less fatiguing and better tolerated. Results suggest that the 2-min walk test is a better alternative to tests of longer duration. Further research is needed to determine longitudinal changes on this outcome.

Correlation of knee strength to functional outcomes in becker muscular dystrophy

Introduction: The correlation of strength with performance on functional outcomes has not been evaluated in Becker muscular dystrophy (BMD), yet the determination of proper outcome measures is critical to the success of upcoming trials designed to improve strength. Methods: Lower extremity strength and performance on functional outcome measures were tested in 25 ambulatory subjects with BMD. Results: All subjects demonstrated marked knee extensor and flexor muscle weakness. Knee extensor strength was correlated with performance on the Berg Balance Scale and stair climbing. Knee flexor strength was highly correlated with performance on all functional outcomes, including timed walking distances. Conclusions: This profile differs from that previously reported in other neuromuscular diseases and demonstrates the importance of designing outcome measures for clinical trials in muscle disorders with considerations for the disease process, the mode, and the target of intervention. The findings emphasize that 1 set of outcomes is not appropriate for all neuromuscular diseases. Muscle Nerve, 2013

Reliability and validity of active-seated: An outcome in dystrophinopathy.

Traditional upper extremity measures typically focus on distal abilities and do not quantify the unique progression of decline in dystrophinopathy. We designed ACTIVE‐seated to meet this need. Our objective was to establish the tools validity and reliability.

The 100-meter timed test: Normative data in healthy males and comparative pilot outcome data for use in Duchenne muscular dystrophy clinical trials

Timed walking tests are often used to measure function in boys with Duchenne muscular dystrophy (DMD). Our objective was to evaluate the 100 meter timed test (100m), a fixed distance test of maximal performance, for use in DMD. To this end, we sought to establish normative 100m performance in healthy controls, compare DMD performance to controls, and evaluate the reliability of 100m. Seventy-two boys with DMD (18 steroid-naïve, 54 on steroids) and 599 controls (4-14 years) completed the 100m as speedily as possible on a 25-meter track. Repeat testing was completed between 1 and 42 days later and again at 1 year in a subgroup of 96 control boys. Additionally 35 DMD boys were followed longitudinally (5-19 months). Descriptive statistics are presented by age and cohort. There was a significant difference in performance between groups (p < 0.01). Age and body mass index (BMI) significantly influenced 100m (p < 0.0001) in the control cohort. Test-retest reliability was excellent for both cohorts (ICC > 0.90, p < 0.001). Normative data can be used to determine percent-predicted 100m times to quantify the severity of running impairment in children with a motor deficit. Performance of 100m follows the natural history established by other outcome measures in DMD.

Modeling functional decline over time in sporadic inclusion body myositis.

Introduction: The ability to individualize recommendations or expectations of disease progression based on a patients unique characteristics has merit for use in sporadic inclusion body myositis (sIBM). Methods: Fifty‐five subjects with sIBM completed a battery of strength and functional outcomes at 2 study visits. These were used to develop mathematical models of disease progression in patients with sIBM for use in clinical and research settings. Results: The 6‐minute walk test (6MWT) distance declined by an average of 27.5 meters (12%) per year. Significant factors that predict 6MWT were knee extension and plantarflexion strength and body weight, whereas the ability to stand from a chair was impacted by elbow extension strength. Stepping up on a curb was influenced by the patients age at diagnosis and by knee extension. Statistical models to predict functional decline in sIBM were developed. Conclusion: Statistical models help explain the complex factors that influence decreased walking ability and other functional activities in sIBM. Muscle Nerve 55: 526–531, 2017

497. Follistatin Gene Therapy Improves Six Minute Walk Distance in Sporadic Inclusion Body Myositis (sIBM)

Treatment of sIBM poses many challenges. The cause of this disease is enigmatic, and although considered to be an inflammatory myopathy, there is resistance to anti-inflammatory and immunosuppressive agents. sIBM muscle biopsies show vacuolated muscle fibers, widespread inflammation, and intracellular amyloid deposits. Follistatin is a potent inhibitor of the myostatin pathway and its potential as a therapeutic vehicle is enhanced by a pathway independent of the activin IIB receptor. We have demonstrated both safety and efficacy following direct intramuscular injection of follistatin in the quadriceps muscle in a previously reported gene therapy trial in Becker muscular dystrophy (Mendell JR, et al Mol Ther 2015). No off target effects were encountered attributed to the use of an alternatively spliced follistatin isoform, FS344, also used in the current sIBM gene therapy trial. Enrollment in the current gene therapy trial included 6 subjects with either definite or possible sIBM (Griggs RC, et al. Ann Neurol 1995). Pretreatment MRIs were obtained to determine areas of relative muscle sparing/lack of fibrosis. The intramuscular injections of AAV1.CMV.FS344 to 12 to 14 sites in the quadriceps muscle delivered 1.2X1012 vg/kg. Injections were performed with direct ultrasound guidance to target the most normal appearing muscle bundles, and intramuscular position was confirmed with simultaneous EMG. A three-patient, single limb, safety trial preceded the Phase I/IIA trial reported here. During the ongoing gene therapy trial, a control sIBM group (n=20) was prospectively studied by performance of the 6MWT with follow up from 9-28 months.The 6MWT was the primary functional outcome (See table below). sIBM patients treated with AAV1.CMV.FS344 increased the 6MWT distance by 46.5m (457 to 503.5, p =0.001). Untreated sIBM controls lost 38.5m over a similar time period resulting in net difference of 85.0m between groups (p=0.0007). To validate findings and confirm the lack of selection bias we compared a subgroup of untreated sIBM controls (n=8), matched for age, gender, and 6MWD at baseline. Matched controls lost 39m (p=0.0036) in the 6MWD, a virtually identical loss to the larger control group.The results of this study demonstrate that sIBM can benefit from follistatin gene therapy based on improvement in distance walked in the 6MWT. We did find a hierarchy of response based on muscle preservation and avoiding gene delivery to areas of fibrosis. In this study, gene delivery was limited to the quadriceps muscle, but in future trials more widespread delivery could potentially be more effective.Six Minute Walk Distance Pre- and Post-Treatment* [median values (interquartile ranges provided)]GroupBaseline (m)Final Compared to Baseline (m)Change from Baseline (m)Change per Month (m)sIBM Gene Therapy Pts (n =6)457 (431,475)Improved to 503.5 (443, 573)+46.5 (2,117)+3.09 (0.39, 8.9)Untreated sIBM Controls (n =20)393 (356.5,.451.5)Declined to 354.5 (303.5,410.5)−38.5 (−73,−22) p =0.0007−2.3 (−4,−1. 1) P =0.0032Matched sIBM Controls for age, gender, and 6MWD (n = 8)459 (439.5,469)Declined to 420 (388.5,447.5)−39.0 (−77,−8) p = 0.0036−2.2 (−4.8. −0.7) P=0.0118 View Table in HTML Data analysis used SAS 9.3 (SAS Institute, Cary NC) with two-sided p-values.