Kenny Walter

Findings from an open-label gene transfer study in adolescent patients with Duchenne muscular dystrophy (DMD) suggest that Microdystrophin gene transfer using recombinant adeno-associated virus serotype rh74 (rAAVrh74), driven by a skeletal and cardiac muscle-specific promoter with enhanced cardiac expression (MHCK7), known as SRP-9001 (Sarepta Therapeutics), is an effective therapeutic option for patients with DMD.

Led by Rebecca J. Willcocks, PhD, Department of Physical Therapy, University of Florida, the Systemic Gene Delivery Clinical Trial for DMD showed robust transgene expression on muscle biopsy (74% to 96%) of fibers, but biopsy data reflects a small sample of muscle where muscle quality in large muscle groups can be objectively and noninvasively measured using quantitive MRI (qMRI) and spectroscopy (qMRS), 2 tools used for monitoring disease progression and therapeutic response.

The researchers noted that between qMRI and qMRS data—including muscle fat fraction and bulk MRI transverse relaxation time—could be reduced in children treated with SRP-9001 compared to an age-matched natural history cohort treated with standard of care, as well as a control group of individuals without DMD.

In the case-control trial, 3 patients received qMRI and qMRS evaluation at the University of Florida between 2018-2020, with each imaged 1–2 times, 6–24 months post systemic delivery of SRP-9001, using the MR protocols implemented in the multicenter Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy (Imaging DMD) study. A natural history comparison cohort was used retrospectively from the ImagingDMD study (54 individuals; 110 study visits between 2011-2018). The investigators also retrospectively identified 17 age-matched individuals without DMD for the comparison control cohort.

Out-of-Pocket Costs Steadily Increasing for Neurologic Care

In total, minimal fat infiltration was observed on MR images from the SRP-9001 arm compared to participants from the natural history cohort, whose muscles have dark patterning throughout, especially in the biceps femoris long head and adductor magnus.

Additionally, the investigators found spectra from the vastus lateralis (VL) showed a visible fat peak, reflecting an accumulation of intramuscular fat (value, 0.13) in the natural history cohort. In the control and SRP-9001 arms of the trial, this was minimal. Mean VL MRS fat faction in the treatment cohort was lower than what was observed in the natural history cohort. Overall, there were 100 data points (0.02 [0.01] vs 0.11 [0/11]) which were similar to the control group, which included 17 data points (0.02 [0.01]).

VL fat faction was stable over the course of 12 months in 2 participants who received SRP-9001 who had repeated measurements (mean change, 0.00 [0.01]), though, this was not seen in the 42 participants of the natural history cohort with repeated measurements (mean change, 0.05 [0.07]).

Wilcocks et al. also found qT2 across 5 upper and lower leg muscles was greater in the natural history cohort than it was in the SRP-9001 or control cohorts (mean qT2 for VL: natural history, 44.7 [7.7] ms; SRP-9001, 37.3 [2.2] ms; control, 35.1 [3.7] ms).

“These MR data indicate marked sparing and minimal fat infiltration in boys with DMD who received SRP-9001 compared with an age-matched natural history cohort,” they concluded. “qMRI and qMRS biomarkers are valuable adjuncts to clinical assessments because of their sensitivity to subclinical disease progression and lack of dependence on participant growth, maturation, and motivation.”

Last year, results from Study 101, a phase 1/2a nonrandomized controlled trial (NCT03375164) revealed that treatment with SRP-9001 was well-tolerated and had minimal adverse events (AEs) in ambulatory men with Duchenne muscular dystrophy (DMD) without preexisting AAVrh74 antibodies and a stable corticosteroid dose.

Lead author Jerry Mendell, MD, neurologist, Nationwide Children’s Hospital, and colleagues found that among the 4 patients included in the study, all 53 AEs recorded were either considered mild (n = 33; 62%) or moderate (n = 20; 38%), while also reporting no serious AEs as well. Conducted at the Nationwide Children’s Hospital in Columbus, Ohio, researchers found 18 AEs were considered treatment-related, the most common of which was vomiting (9 of 18 events; 50%). Additionally, 3 patients had transiently elevated y-glutamyltransferase, which resolved with corticosteroids.

With safety as the primary outcome, secondary outcomes included micro-dystrophin expression by Western blot and immunohistochemistry. After 12 weeks, immunohistochemistry of gastrocnemius muscle biopsy specimens revealed robust transgene expression in all patients, with a mean of 81.2% of muscle fiber micro-dystrophin with a mean intensity of 96% at the sarcolemma.

A version of this story originally appeared on 

REFERENCES
1. Wilcocks RJ, Forbes SC, Walter GA, et al. Assessment of rAAVrh.74.MHCK7.micro-dystrophin Gene Therapy Using Magnetic Resonance Imaging in Children With Duchenne Muscular Dystrophy. 

. 2021;4(1):e2031851. doi: 10.1001/jamanetworkopen.2020.31851.
2. 2. Mendell JR, Sahenk Z, Lehman K. Assessment of systemic delivery of rAAVrh74.MHCK7.micro-dystrophin in children with Duchenne muscular dystrophy: a nonrandomized controlled trial. 

. Published online June 15, 2020. doi: 10.1001/jamaneurol.2020.1484.

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MR imaging revealed minimal fat infiltration in the SRP-9001 arm compared to participants with DMD from the natural history cohort.

SRP-9001 Holds Promise as DMD Treatment, MRI Data Suggest

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While there are many assumptions as to how the ongoing 

 around the world, there is not much known how sleep has ultimately been impacted for parents and children.

A team, led by Ghadir Zreik, PhD, Psychology Department, The Center for Psychobiological Research, The Max Stern Yezreel Valley College, examined the possible consequences the pandemic and home confinement is having on maternal anxiety, maternal insomnia, and maternal reports of sleep problems among 264 children between 6-72 months in Israel.

The study population included 120 male children, with a mean age of 31.27 months. Approximately 38% of the infants in the study were firstborns, while families had a mean of 2.15 children. The mean age of mothers in the study was 33.97 years old and their mean duration of education was 16.37 years. In addition, 54.2% of mothers reported a change in the family income because of the crisis.

Zreik and colleagues specifically explored whether mothers experience change in their own insomnia symptoms and child’s sleep between pre-crisis and crisis. Furthermore, they conducted a web-based study 4 weeks into the national lockdown in Israel.

The investigators found a high frequency of maternal clinical insomnia in recent months—23% during the pandemic compared to 11% in the 1-2 months prior to the pandemic. Additionally, approximately 80% of mothers reported no change in their child’s sleep quality, duration, and sleeping arrangement during the COVID-19 pandemic.

On the other hand, approximately 30% of these mothers reported a negative change in their child’s sleep quality, as well as a decrease in sleep duration. There was also mothers who reported a positive change.

"These findings suggest that the changes in sleep patterns during the COVID‐19 pandemic are varied and that no unified change for the worse should be expected,” the authors wrote. “Further consideration of changes in sleep within the family context during this ongoing crisis is needed.”

The ongoing pandemic has been linked to a number of psychiatric and other issues, including depression, anxiety, and sleep. The disruption of traditional work and school hours has only exacerbated those issues.

Researchers have long believed sleep is critical for both adult and child psychical and psychosocial well-being.

“The current stressful circumstances of home confinement and major changes to daily routines, higher levels of anxiety, decrease in daylight exposure, increased blue light exposure due to massive reliance on digital media, changes in diet, and reduced physical activity may all have negative implications for sleep quality,” the authors wrote.

Recently, researchers in Greece found 37.6% of participants scored above the cut-off score for insomnia, significantly higher than the 10% worldwide prevalence estimated prior to the pandemic.

Maternal perceptions of sleep problems among children and mothers during the coronavirus disease 2019 (COVID‐19) pandemic in Israel,

The rate of maternal clinical insomnia increased from 11% pre-pandemic to 23% during the COVID-19 pandemic. 

COVID-19 Pandemic Associated With Sleep Issues

 on HCPLive, part of the HCPLive Network.

The FDA has given 510(k) clearance for Synaptive Medical's Evry, a point-of-care head magnetic resonance imaging (MRI) system designed to provide immediate access to diagnostic imaging for patients in need of emergency care, including potential complications arising from COVID-19, ischemic stroke, neurological damage or potential head trauma. 

The device features a mid-field 0.5T superconducting magnet that is small enough to reduce the footprint currently allotted to MRI machines. Evry also includes  predefined imaging protocols, automated series planning including volume section, a detachable stretcher to support bedside transfers and a multichannel head coil with patient-specific customized fitting intended to optimize image quality.

Because of its small size, Evry can be delivered without cranes and forgoes yearly cryogen refills, a cryogen pipe and reinforced flooring, providing significant cost-savings for healthcare systems.

“As medical professionals, our goal is to utilize every tool at our disposal that will improve outcomes for our patients in a variety of situations, Gustavo Pradilla, MD, Chief of Neurosurgery, Grady Memorial Hospital, said in a statement. “With the availability of Evry in the US, we will now be able to provide critical diagnostic information in settings beyond where traditional MRIs are offered, which can significantly expedite the speed at which we make actionable decisions that positively impact patient care.” 

All of Synaptive’s products, including Evry, can be used independently or with outside systems.

Evry will soon be commercially available in the US and will provide MRI imaging to patients in critical care settings. 

Kenny Walter

Articles

SRP-9001 Holds Promise as DMD Treatment, MRI Data Suggest

COVID-19 Pandemic Associated With Sleep Issues

FDA Clears Point-of-Care MRI System