Gene Editing For Muscular Dystrophy

Here is a paper from several years ago discussing promising results with gene therapy in a mouse model of muscular dystrophy.  Abstract:

Gene replacement therapies utilizing adeno-associated viral (AAV) vectors hold great promise for treating Duchenne muscular dystrophy (DMD). A related approach uses AAV vectors to edit specific regions of the DMD gene using CRISPR/Cas9. Here we develop multiple approaches for editing the mutation in dystrophic mdx4cv mice using single and dual AAV vector delivery of a muscle-specific Cas9 cassette together with single-guide RNA cassettes and, in one approach, a dystrophin homology region to fully correct the mutation. Muscle-restricted Cas9 expression enables direct editing of the mutation, multi-exon deletion or complete gene correction via homologous recombination in myogenic cells. Treated muscles express dystrophin in up to 70% of the myogenic area and increased force generation following intramuscular delivery. Furthermore, systemic administration of the vectors results in widespread expression of dystrophin in both skeletal and cardiac muscles. Our results demonstrate that AAV-mediated muscle-specific gene editing has significant potential for therapy of neuromuscular disorders.

That's very promising.  What's going on more recently? Future posts here will explore the progress in this and other similar projects using gene therapy tested in mouse models. This is why basic science research is so important, as the methods utilized are ultimately derived from such research.

Exercise Type And Neuromuscular Adaptions

Can the type of exercise influence what kind of neuromuscular adaptions result?  Does high intensity training cause different types of adaptions than does lower-intensity endurance training, as the “gym gurus: tell us?  The answer seems to be yes.  Abstract:

PURPOSE:
Using a novel technique of high-density surface electromyography (HDEMG) decomposition and motor unit (MU) tracking, we compared changes in the properties of vastus medialis (VM) and vastus lateralis (VL) MUs following endurance (END) and high-intensity interval training (HIIT).
METHODS:
Sixteen men were assigned to an END or HIIT group (n=8 each) and performed six training sessions over 14 days. Each session consisted of 8-12×60s intervals at 100% peak power output (PPO) separated by 75s of recovery (HIIT) or 90-120min continuous cycling at ~65% VO2peak (END). Pre and post intervention, participants performed: 1) incremental cycling to determine VO2peak and PPO and 2) maximal (MVC), submaximal (10, 30, 50 and 70% MVC) and sustained (until task failure at 30% MVC) isometric knee extensions while HDEMG signals were recorded from the VM and VL. EMG signals were decomposed (submaximal contractions) into individual MUs by convolutive blind source separation. Finally, MUs were tracked across sessions by semi-blind source separation.
RESULTS:
After training, END and HIIT improved VO2peak similarly (by 5.0 and 6.7%, respectively). The HIIT group showed enhanced maximal knee extension torque by ~7% (p=0.02) and was accompanied by an increase in discharge rate for high-threshold MUs (≥50% knee extension MVC) (p<0.05). In contrast, the END group increased their time to task failure by ~17%, but showed no change in MU discharge rates (p>0.05).
CONCLUSIONS:
HIIT and END induce different adjustments in MU discharge rate despite similar improvements in cardiopulmonary fitness. Moreover, the changes induced by HIIT are specific for high-threshold motor units. For the first time we show that HIIT and END induce specific neuromuscular adaptations, possibly related to differences in exercise load intensity and training volume.

Therefore, the findings of this study show that high-intensity HIIT and endurance-oriented END result in exercise type-specific neuromuscular adaptions, which is completely consistent with the “gym info” popular conception that different types of exercise can induce specific types of nervous system and muscular adaptions and therefore one can tailor exercise type for the desired effect.

Spinal Muscular Atrophy Gene Therapy Clinical Trial

By Kashmiri, based on earlier work by Domaina - Own work based on Autosomal dominant - en.svg and Autorecessive.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=19018894

Spinal muscular atrophy is an extremely serious neurological disease of childhood that is inherited in an autosomal recessive manner.  There has recently been an encouraging gene therapy clinical trial for this disease.  Families of children with this disorder need to be made aware of these findings.  Note: "...a single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN resulted in longer survival, superior achievement of motor milestones, and better motor function than in historical cohorts."  Abstract:

BACKGROUND:

Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease.

METHODS:

Fifteen patients with SMA1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. Three of the patients received a low dose (6.7×1013 vg per kilogram of body weight), and 12 received a high dose (2.0×1014 vg per kilogram). The primary outcome was safety. The secondary outcome was the time until death or the need for permanent ventilatory assistance. In exploratory analyses, we compared scores on the CHOP INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scale of motor function (ranging from 0 to 64, with higher scores indicating better function) in the two cohorts and motor milestones in the high-dose cohort with scores in studies of the natural history of the disease (historical cohorts).

RESULTS:

As of the data cutoff on August 7, 2017, all 15 patients were alive and event-free at 20 months of age, as compared with a rate of survival of 8% in a historical cohort. In the high-dose cohort, a rapid increase from baseline in the score on the CHOP INTEND scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort. Of the 12 patients who had received the high dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Elevated serum aminotransferase levels occurred in 4 patients and were attenuated by prednisolone.

CONCLUSIONS:

In patients with SMA1, a single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN resulted in longer survival, superior achievement of motor milestones, and better motor function than in historical cohorts. Further studies are necessary to confirm the safety and efficacy of this gene therapy. (Funded by AveXis and others; ClinicalTrials.gov number, NCT02122952 .).