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Treatment of Myotonic Dystrophy Mous...

Cisco, Lily,

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Treatment of Myotonic Dystrophy Mouse Models With Calcium Channel Blockers and Anti-Myotonics /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Treatment of Myotonic Dystrophy Mouse Models With Calcium Channel Blockers and Anti-Myotonics // Lily Cisco.
Author:	Cisco, Lily,
Description:	1 electronic resource (537 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-11, Section: B.
Contained By:	Dissertations Abstracts International86-11B.
Subject:	Physiology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31937118
ISBN:	9798315738497

Treatment of Myotonic Dystrophy Mouse Models With Calcium Channel Blockers and Anti-Myotonics /
Cisco, Lily,

Treatment of Myotonic Dystrophy Mouse Models With Calcium Channel Blockers and Anti-Myotonics /Lily Cisco. - 1 electronic resource (537 pages)

Source: Dissertations Abstracts International, Volume: 86-11, Section: B.

Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. It is caused by a trinucleotide repeat expansions that ultimately leads to the altered splicing of hundreds of transcripts throughout the body. Downstream, this manifests as a multisystem disorder that varies patient to patient in severity of symptoms presented, age of onset and time of progression. With the complex splice background and other confounding mechanisms present in DM1, connecting aberrant splicing events to clinical manifestation has proven difficult. Muscle weakness and muscle wasting are the leading causes of morbidity and mortality in DM1, but the mechanism that underlies this is poorly understood. However, a significant correlation between muscle weakness in the tibialis anterior of DM1 patients and proteins central to excitation-contraction coupling (ECC) and Ca2+ handling.From this, we found that the combination of chloride channel myotonia with the deletion of an exon 29 in the L-type voltage gate calcium channel CaV1.1 (CaV1.1Δe29) in skeletal muscle resulted in synthetically lethality in mice. Since myotonic CaV1.1Δe29 mice do not survive beyond 14-weeks-old and have severe and significant muscle weakness and respiratory dysfunction, we have tangible readouts for therapeutic intervention. We tested if blocking CaV1.1Δe29 in the context of myotonia improved survival and other metrics of health. To do so, we investigated FDA-approved calcium channel blockers verapamil and amlodipine in in vitro and in vivo studies. We saw significantly improved muscle force and respiratory function and extend the lifespan and in the myotonic CaV1.1Δe29 mice with both verapamil and amlodipine. Further, we tested if long term treatment with an FDA approved anti-myotonic, ranolazine, would also improve survival and health in the myotonic CaV1.1Δe29 mice with great success.Based on the robust impact verapamil had on time of righting reflex, muscle strength, myotonia, and transient weakness in the myotonic CaV1.1Δe29 mice, we tested if verapamil could be used as an anti-myotonic in a myotonia congenita (MC) mouse model that has a frameshift mutation in the skeletal muscle chloride channel gene Clcn1, and is devoid of the channel (ClC-1-/- ). In the ClC-1-/- mice, verapamil significantly improved survival, respiration, muscle strength, righting, myotonia, and transient weakness, thus identifying verapamil as a treatment option for MC patients.Moving forward, we wanted to determine if amlodipine, verapamil, and ranolazine treatments were effective in a DM1 mouse model that has the full panoply of aberrant splice defects seen in severe DM1. This model combines loss of Mbnl1 with CTG-repeat expansion in the Human Skeletal Actin transgene (HSALR/Mbnl1-/- ). Untreated, these mice are characterized by reduced survival, low body weight, respiratory dysfunction, prolonged myotonia and a significant loss in muscle force generation. We found that treating HSALR/Mbnl1-/- mice with amlodipine or verapamil, blocking Ca2+ entry through CaV1.1, significantly improved survival and health. Additionally, long-term treatment with the anti-myotonic ranolazine improved survival and health, which suggests myotonia contributes to the skeletal muscle phenotype seen in DM1. Overall, by repurposing an already FDA approved drug, we hope to move quickly into the clinic. While there are other avenues being explored to treat DM1, many are novel, and configuring new drug applications requiring a long time before implementation, conveying high costs to patients. With FDA repurposing, it is expected that the path to the clinic is relatively short, without monetary burden.

English

ISBN: 9798315738497Subjects--Topical Terms:

518431
Physiology.
Subjects--Index Terms:

Myotonic dystrophy type 1

Treatment of Myotonic Dystrophy Mouse Models With Calcium Channel Blockers and Anti-Myotonics /
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500 $a Source: Dissertations Abstracts International, Volume: 86-11, Section: B.
500 $a Advisors: Lueck, John D. Committee members: Dirksen, Robert; Boutz, Paul; Orlandi, Cesare; Falsetta, Megan L.; Portman, Douglas.
502 $b Ph.D. $c University of Rochester $d 2025.
520 $a Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. It is caused by a trinucleotide repeat expansions that ultimately leads to the altered splicing of hundreds of transcripts throughout the body. Downstream, this manifests as a multisystem disorder that varies patient to patient in severity of symptoms presented, age of onset and time of progression. With the complex splice background and other confounding mechanisms present in DM1, connecting aberrant splicing events to clinical manifestation has proven difficult. Muscle weakness and muscle wasting are the leading causes of morbidity and mortality in DM1, but the mechanism that underlies this is poorly understood. However, a significant correlation between muscle weakness in the tibialis anterior of DM1 patients and proteins central to excitation-contraction coupling (ECC) and Ca2+ handling.From this, we found that the combination of chloride channel myotonia with the deletion of an exon 29 in the L-type voltage gate calcium channel CaV1.1 (CaV1.1Δe29) in skeletal muscle resulted in synthetically lethality in mice. Since myotonic CaV1.1Δe29 mice do not survive beyond 14-weeks-old and have severe and significant muscle weakness and respiratory dysfunction, we have tangible readouts for therapeutic intervention. We tested if blocking CaV1.1Δe29 in the context of myotonia improved survival and other metrics of health. To do so, we investigated FDA-approved calcium channel blockers verapamil and amlodipine in in vitro and in vivo studies. We saw significantly improved muscle force and respiratory function and extend the lifespan and in the myotonic CaV1.1Δe29 mice with both verapamil and amlodipine. Further, we tested if long term treatment with an FDA approved anti-myotonic, ranolazine, would also improve survival and health in the myotonic CaV1.1Δe29 mice with great success.Based on the robust impact verapamil had on time of righting reflex, muscle strength, myotonia, and transient weakness in the myotonic CaV1.1Δe29 mice, we tested if verapamil could be used as an anti-myotonic in a myotonia congenita (MC) mouse model that has a frameshift mutation in the skeletal muscle chloride channel gene Clcn1, and is devoid of the channel (ClC-1-/- ). In the ClC-1-/- mice, verapamil significantly improved survival, respiration, muscle strength, righting, myotonia, and transient weakness, thus identifying verapamil as a treatment option for MC patients.Moving forward, we wanted to determine if amlodipine, verapamil, and ranolazine treatments were effective in a DM1 mouse model that has the full panoply of aberrant splice defects seen in severe DM1. This model combines loss of Mbnl1 with CTG-repeat expansion in the Human Skeletal Actin transgene (HSALR/Mbnl1-/- ). Untreated, these mice are characterized by reduced survival, low body weight, respiratory dysfunction, prolonged myotonia and a significant loss in muscle force generation. We found that treating HSALR/Mbnl1-/- mice with amlodipine or verapamil, blocking Ca2+ entry through CaV1.1, significantly improved survival and health. Additionally, long-term treatment with the anti-myotonic ranolazine improved survival and health, which suggests myotonia contributes to the skeletal muscle phenotype seen in DM1. Overall, by repurposing an already FDA approved drug, we hope to move quickly into the clinic. While there are other avenues being explored to treat DM1, many are novel, and configuring new drug applications requiring a long time before implementation, conveying high costs to patients. With FDA repurposing, it is expected that the path to the clinic is relatively short, without monetary burden.
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590 $a School code: 0188
650 4 $a Physiology. $3 518431
650 4 $a Pharmacology. $3 634543
650 4 $a Biology. $3 522710
653 $a Myotonic dystrophy type 1
653 $a Excitation-contraction coupling
653 $a Muscular dystrophy
653 $a Amlodipine
690 $a 0719
690 $a 0419
690 $a 0306
710 2 $a University of Rochester. $b School of Medicine and Dentistry. $e degree granting institution. $3 3827292
720 1 $a Lueck, John D. $e degree supervisor.
773 0 $t Dissertations Abstracts International $g 86-11B.
790 $a 0188
791 $a Ph.D.
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