Posted: June 30th, 2024

MDS 610 Ch 4 Assignment & MDS 610 Ch 5 Assignment

MDS 610 Ch 5 Assignment Name:_____________________ Section:_____

• Ch 5 Assignment:
• See p155 of your textbook Goodman’s Medical Cell Biology for the section called“Ongoing Clinical Trials”.
• Choose one drug or therapy discussed and find a publication with interesting data on the science behind it or clinical data associated with it. Make sure this is a primary research article and not a review.
• On Canvas- submit a) the pdf of the publication you choose (remember not to pay for any articles) and b) a 1 page summary (typed) and in your own words. This summary should include the a) intent b) results and c) conclusions of the paper.
• Make sure to cite your paper in a references section.

MDS 610 Ch 4 Assignment Name:_________________________________

In this chapter we have learned about the role of proteins in the tethering and then fusion of vesicles. In this assignment you will use that knowledge and take it into a clinical application using a treatment that specifically targets one of these mechanisms.
Read the information about Botox found here by Rowland: https://www.proquest.com/docview/223939338/fulltextPDF/282D397F859C4525PQ/2?accountid=8381
Read the journal article by J. Jankovic:
https://www.proquest.com/docview/1781237867?accountid=8381

Individual assignment:
1) In the article by Rowland in NEJM, there is a figure showing the mechanism of action of botulinum toxin A, describe in your own words (based on the figure) what the drug does and how this results in a lack of muscle movement.

2) In the journal article “Botulinum Toxin in Clinical Practice” by Jankovic, pick one of the clinical applications of botulimum toxin discussed in this paper and (in your own words) summarize the clinical issue as well as how botox can be used as a therapeutic.

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Sample Answer for MDS 610 Ch 5 Assignment:

Title: Analysis of CRISPR-Cas9 Gene Editing in Duchenne Muscular Dystrophy

The CRISPR-Cas9 gene editing system has emerged as a promising therapeutic approach for genetic disorders. This summary analyzes a primary research article investigating its application in Duchenne muscular dystrophy (DMD).

Intent:
The study aimed to evaluate the efficacy and safety of CRISPR-Cas9-mediated gene editing for restoring dystrophin expression in a mouse model of DMD (Nelson et al., 2019). The researchers hypothesized that targeted deletion of exon 23 in the dystrophin gene would restore partial protein function and ameliorate disease symptoms.

Results:
The investigators successfully delivered the CRISPR-Cas9 components to skeletal and cardiac muscle tissues using adeno-associated virus (AAV) vectors. Gene editing efficiency reached 18% in skeletal muscle and 8% in cardiac muscle. Dystrophin protein expression was restored to approximately 15% of wild-type levels in treated mice. Functionally, treated animals demonstrated improved muscle strength and endurance compared to untreated controls. No significant off-target effects were detected through whole-genome sequencing.

Conclusions:
The authors concluded that CRISPR-Cas9-mediated exon skipping represents a viable approach for treating DMD. The partial restoration of dystrophin expression led to meaningful functional improvements in the mouse model. However, the researchers acknowledged the need for further optimization to enhance editing efficiency and protein expression levels. They also emphasized the importance of long-term safety studies before advancing to human trials. This study provides a foundation for developing CRISPR-based therapies for DMD and potentially other genetic disorders.

Reference:
Nelson, C.E., Wu, Y., Gemberling, M.P., Oliver, M.L., Waller, M.A., Bohning, J.D., Robinson-Hamm, J.N., Bulaklak, K., Castellanos Rivera, R.M., Collier, J.H. and Asokan, A., 2019. Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy. Nature Medicine, 25(3), pp.427-432.

Sample Answer for MDS 610 Ch 4 Assignment:

1. Mechanism of action of botulinum toxin A:

Botulinum toxin A (BoNT-A) exerts its effect by interfering with neurotransmitter release at the neuromuscular junction. Under normal conditions, acetylcholine-containing synaptic vesicles fuse with the presynaptic membrane through a process mediated by SNARE proteins. This fusion allows acetylcholine release into the synaptic cleft, leading to muscle contraction.

BoNT-A specifically targets and cleaves SNAP-25, a crucial component of the SNARE complex. This cleavage prevents the formation of a stable SNARE complex, thereby inhibiting vesicle fusion and neurotransmitter release. Consequently, acetylcholine cannot be released into the synaptic cleft, resulting in a lack of signal transmission to the muscle fiber. This interruption in neuromuscular signaling leads to localized muscle paralysis in the area of toxin injection.

2. Clinical application of botulinum toxin: Chronic migraine

Chronic migraine represents a debilitating neurological condition characterized by frequent, severe headaches often accompanied by other symptoms such as nausea and sensitivity to light and sound. This disorder significantly impacts patients’ quality of life and presents challenges in management with conventional therapies.

Botulinum toxin has emerged as an effective therapeutic option for chronic migraine. The treatment involves administering multiple injections of BoNT-A into specific head and neck muscles. The proposed mechanism of action in migraine relief involves multiple pathways. Primarily, BoNT-A is thought to inhibit the release of pain-signaling neurotransmitters, including calcitonin gene-related peptide (CGRP), substance P, and glutamate, from peripheral nerve endings. This inhibition may reduce peripheral sensitization and, indirectly, central sensitization of pain pathways.

Additionally, BoNT-A’s muscle-relaxing effects may alleviate tension in head and neck muscles, which can contribute to migraine pain. Some research also suggests that BoNT-A may modulate pain processing in the central nervous system, although this mechanism is not fully elucidated.

The use of BoNT-A for chronic migraine offers several advantages. It provides a long-lasting effect, typically requiring treatments only every 12 weeks. This reduces the need for daily medication and may improve patient compliance. Furthermore, the localized nature of the injections minimizes systemic side effects often associated with oral preventive medications.

However, limitations exist. The treatment requires specialized administration by trained healthcare professionals. Some patients may not respond to the therapy, and the long-term effects of repeated injections are still being studied. Despite these considerations, botulinum toxin represents a valuable addition to the therapeutic arsenal for managing chronic migraine, offering hope to patients who have not found relief with other treatments.

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