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"Arnold, W. David"
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What to expect when you're expecting
A look at love through the eyes of five interconnected couples experiencing the thrills and surprises of having a baby, and ultimately coming to understand the universal truth that no matter what you plan for, life doesn't always deliver what's expected.
DVD
Efficient precise in vivo base editing in adult dystrophic mice
Recent advances in base editing have created an exciting opportunity to precisely correct disease-causing mutations. However, the large size of base editors and their inherited off-target activities pose challenges for in vivo base editing. Moreover, the requirement of a protospacer adjacent motif (PAM) nearby the mutation site further limits the targeting feasibility. Here we modify the NG-targeting adenine base editor (iABE-NGA) to overcome these challenges and demonstrate the high efficiency to precisely edit a Duchenne muscular dystrophy (DMD) mutation in adult mice. Systemic delivery of AAV9-iABE-NGA results in dystrophin restoration and functional improvement. At 10 months after AAV9-iABE-NGA treatment, a near complete rescue of dystrophin is measured in
mdx
4cv
mouse hearts with up to 15% rescue in skeletal muscle fibers. The off-target activities remains low and no obvious toxicity is detected. This study highlights the promise of permanent base editing using iABE-NGA for the treatment of monogenic diseases.
Base editing is one approach used to correct mutations causing cause Duchenne muscular dystrophy (DMD), but limitations are in the requirement for a specific PAM motif and the large size beyond the packaging capacity of adeno-associated virus (AAV). Here, the authors modify the NG-targeting adenine base editor to recognize a broader PAM, devise an intein split strategy to package the otherwise oversized adenine base editor into AAV, and show it efficiently restores dystrophin expression in muscle and heart when systemically injected in a mouse model of DMD
Journal Article
The m6A methyltransferase METTL3 regulates muscle maintenance and growth in mice
Skeletal muscle serves fundamental roles in organismal health. Gene expression fluctuations are critical for muscle homeostasis and the response to environmental insults. Yet, little is known about post-transcriptional mechanisms regulating such fluctuations while impacting muscle proteome. Here we report genome-wide analysis of mRNA methyladenosine (m
6
A) dynamics of skeletal muscle hypertrophic growth following overload-induced stress. We show that increases in METTL3 (the m
6
A enzyme), and concomitantly m
6
A, control skeletal muscle size during hypertrophy; exogenous delivery of METTL3 induces skeletal muscle growth, even without external triggers. We also show that METTL3 represses activin type 2 A receptors (ACVR2A) synthesis, blunting activation of anti-hypertrophic signaling. Notably, myofiber-specific conditional genetic deletion of METTL3 caused spontaneous muscle wasting over time and abrogated overload-induced hypertrophy; a phenotype reverted by co-administration of a myostatin inhibitor. These studies identify a previously unrecognized post-transcriptional mechanism promoting the hypertrophic response of skeletal muscle via control of myostatin signaling.
Muscle undergoes hypertrophy and atrophy in response to physiological stimuli or in pathological conditions, which is partially controlled through altered gene expression. Here the authors report that m
6
A methyltransferase METTL3 and mRNA m
6
A post-transcriptional modifications as a mechanism that regulates muscle hypertrophy and atrophy via myostatin signalling in mice.
Journal Article
Myotonic Dystrophies: Targeting Therapies for Multisystem Disease
Myotonic dystrophy is an autosomal dominant muscular dystrophy not only associated with muscle weakness, atrophy, and myotonia but also prominent multisystem involvement. There are 2 similar, but distinct, forms of myotonic dystrophy; type 1 is caused by a CTG repeat expansion in the DMPK gene, and type 2 is caused by a CCTG repeat expansion in the CNBP gene. Type 1 is associated with distal limb, neck flexor, and bulbar weakness and results in different phenotypic subtypes with variable onset from congenital to very late-onset as well as variable signs and symptoms. The classically described adult-onset form is the most common. In contrast, myotonic dystrophy type 2 is adult-onset or late-onset, has proximal predominant muscle weakness, and generally has less severe multisystem involvement. In both forms of myotonic dystrophy, the best characterized disease mechanism is a RNA toxic gain-of-function during which RNA repeats form nuclear foci resulting in sequestration of RNA-binding proteins and, therefore, dysregulated splicing of premessenger RNA. There are currently no disease-modifying therapies, but clinical surveillance, preventative measures, and supportive treatments are used to reduce the impact of muscular impairment and other systemic involvement including cataracts, cardiac conduction abnormalities, fatigue, central nervous system dysfunction, respiratory weakness, dysphagia, and endocrine dysfunction. Exciting preclinical progress has been made in identifying a number of potential strategies including genome editing, small molecule therapeutics, and antisense oligonucleotide-based therapies to target the pathogenesis of type 1 and type 2 myotonic dystrophies at the DNA, RNA, or downstream target level.
Journal Article
Current Challenges in Elucidating ALS Disease Mechanisms and Therapeutic Advances
As a researcher and a physician working together to combat amyotrophic lateral sclerosis (ALS), we are acutely aware of both the urgent need for innovation and the persistent divide between laboratory discoveries and clinical care [...]
Journal Article
Sex differences in body composition but not neuromuscular function following long-term, doxycycline-induced reduction in circulating levels of myostatin in mice
Age-related declines in muscle function result from changes in muscle structure and contractile properties, as well as from neural adaptations. Blocking myostatin to drive muscle growth is one potential therapeutic approach. While the effects of myostatin depletion on muscle characteristics are well established, we have very little understanding of its effects on the neural system. Here we assess the effects of long-term, post-developmental myostatin reduction on electrophysiological motor unit characteristics and body composition in aging mice. We used male (N = 21) and female (N = 26) mice containing a tetracycline-inducible system to delete the myostatin gene in skeletal muscle. Starting at 12 months of age, half of the mice were administered doxycycline (tetracycline) through their chow for one year. During that time we measured food intake, body composition, and hindlimb electromyographic responses. Doxycycline-induced myostatin reduction had no effect on motor unit properties for either sex, though significant age-dependent declines in motor unit number occurred in all mice. However, treatment with doxycycline induced different changes in body composition between sexes. All female mice increased in total, lean and fat mass, but doxycycline-treated female mice experienced a significantly larger increase in lean mass than controls. All male mice also increased total and lean mass, but administration of doxycycline had no effect. Additionally, doxycycline-treated male mice maintained their fat mass at baseline levels, while the control group experienced a significant increase from baseline and compared to the doxycycline treated group. Our results show that long-term administration of doxycycline results in body composition adaptations that are distinctive between male and female mice, and that the effects of myostatin reduction are most pronounced during the first three months of treatment. We also report that age-related changes in motor unit number are not offset by reduced myostatin levels, despite increased lean mass exhibited by female mice.
Journal Article
YTHDF2 governs muscle size through a targeted modulation of proteostasis
The regulation of proteostasis is fundamental for maintenance of muscle mass and function. Activation of the TGF-β pathway drives wasting and premature aging by favoring the proteasomal degradation of structural muscle proteins. Yet, how this critical post-translational mechanism is kept in check to preserve muscle health remains unclear. Here, we reveal the molecular link between the post-transcriptional regulation of m
6
A-modified mRNA and the modulation of SMAD-dependent TGF-β signaling. We show that the m
6
A-binding protein YTHDF2 is essential to determining postnatal muscle size. Indeed, muscle-specific genetic deletion of YTHDF2 impairs skeletal muscle growth and abrogates the response to hypertrophic stimuli. We report that YTHDF2 controls the mRNA stability of the ubiquitin ligase ASB2 with consequences on anti-growth gene program activation through SMAD3. Our study identifies a post-transcriptional to post-translational mechanism for the coordination of gene expression in muscle.
This study highlights the role of YTHDF2, a protein that recognizes m6A-modified RNA, in determining muscle size. The authors show a post-transcriptional mechanism regulating muscle catabolism and growth, prompting interest to address muscle wasting.
Journal Article
Treatment preference among patients with spinal muscular atrophy (SMA): a discrete choice experiment
Objective
To examine patient/caregiver preference for key attributes of treatments for spinal muscular atrophy (SMA).
Background
In the rapidly evolving SMA treatment landscape, it is critically important to understand how attributes of potential treatments may impact patient/caregiver choices.
Design/methods
A discrete choice experiment survey was developed based on qualitative interviews. Patients with SMA (≥ 18 years) and caregivers of patients were recruited through a U.S. patient organization. Respondents made choices in each of 12 sets of hypothetical treatments. The relative importance of five treatment characteristics was compared (measured by regression coefficients [RC] of conditional logit models): (1) improvement or stabilization of motor function, (2) improvement or stabilization of breathing function, (3) indication for all ages or pediatric patients only, (4) route of administration [repeated intrathecal (IT) injections, one-time intravenous (IV) infusion, daily oral delivery] and (5) potential harm (mild, moderate, serious/life threatening).
Results
Patient ages ranged from less than 1 to 67 years (n = 101, 65 self-reported and 36 caregiver-reported) and 64 were female. Total SMA subtypes included: type 1 (n = 21), type 2 (n = 48), type 3 (n = 29), other (n = 3). Prior spinal surgery was reported in 47 patients. Nusinersen and onasemnogene abeparvovec-xioi use were reported in 59 and 10 patients, respectively. Improvement in motor and breathing function was highly valued [RC: 0.65, 95% confidence interval (CI): 0.47–0.83 and RC: 0.79, 95% CI: 0.60–0.98, respectively]. Oral medication and one-time infusion were strongly preferred over repeated IT injections (RC: 0.80, 95% CI: 0.60–0.98 and RC: 0.51, 95% CI: 0.30–0.73, respectively). Patients least preferred an age-restricted label/approved use (≤ 2 years of age) (RC: − 1.28, 95% CI: − 1.47 to − 1.09). Cross-attributes trade-off decision suggested a lower willingness for a high-risk therapy despite additional efficacy gain. For some patients, there may be willingness to trade off additional gains in efficacy for a change in route of administration from repeated intrathecal administration to oral medication.
Conclusions
Improvements in motor/breathing function, broad indication, oral or one-time infusion, and minimal risk were preferred treatment attributes. Treatment decisions should be made in clinical context and be tailored to patient needs.
Journal Article
OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity
Paclitaxel is among the most widely used anticancer drugs and is known to cause a dose-limiting peripheral neurotoxicity, the initiating mechanisms of which remain unknown. Here, we identified the murine solute carrier organic anion-transporting polypeptide B2 (OATP1B2) as a mediator of paclitaxel-induced neurotoxicity. Additionally, using established tests to assess acute and chronic paclitaxel-induced neurotoxicity, we found that genetic or pharmacologic knockout of OATP1B2 protected mice from mechanically induced allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes. The function of this transport system was inhibited by the tyrosine kinase inhibitor nilotinib through a noncompetitive mechanism, without compromising the anticancer properties of paclitaxel. Collectively, our findings reveal a pathway that explains the fundamental basis of paclitaxel-induced neurotoxicity, with potential implications for its therapeutic management.
Journal Article