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Research
Human Laminin-111 and Laminin-211 protein therapy prevents muscle disease progression in an immune deficient mouse model of LAMA2-CMD
Dean J. Burkin
University of Nevada Reno
Corresponding Author
ORCiD: https://orcid.org/0000-0001-9228-5258
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Laminin-α2 related Congenital Muscular dystrophy (LAMA2-CMD) is a devastating genetic disease caused by mutations in the LAMA2 gene. These mutations result in progressive muscle wasting and inflammation leading to delayed milestones, and reduced lifespan in affected patients. There is currently no cure or treatment for LAMA2-CMD. Preclinical studies have demonstrated that mouse Laminin-111 can serve as an effective protein replacement therapy in a mouse model of LAMA2-CMD.
Methods
In this study, we generated a novel immunocompromised dy W mouse model of LAMA2-CMD to study the role the immune system plays in muscle disease progression. We used this immune deficient dy W mouse model to test the therapeutic benefits of recombinant human laminin-111 and laminin-211 protein therapy on Laminin-α2 deficient muscle disease progression.
Results
We show that immune deficient Laminin-α2 null mice demonstrate subtle differences in muscle regeneration compared to immune competent animals during early disease stages, but overall exhibit a comparable muscle disease progression. We found human laminin-111 and laminin-211 could serve as effective protein replacement strategies with mice showing improvements in muscle pathology and function. We observed that human laminin-111 and laminin-211 exhibit differences on satellite and myoblast cell populations and differentially affect muscle repair.
Conclusions
This study describes the generation of a novel immune deficient mouse model that allows investigation of the role the immune system plays in LAMA2-CMD. This model can be used to assess the therapeutic potential of heterologous therapies that would illicit an immune response. Using this model, we show that recombinant human Laminin-111 can serve as effective protein replacement therapy for the treatment of LAMA2-CMD.
Keywords
LAMA2-CMD, MDC1A, Laminin-111, immune system
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Posted 20 May, 2020
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On 14 May, 2020
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This preprint is under consideration at Skeletal Muscle. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Human Laminin-111 and Laminin-211 protein therapy prevents muscle disease progression in an immune deficient mouse model of LAMA2-CMD
Dean J. Burkin
University of Nevada Reno
Corresponding Author
ORCiD: https://orcid.org/0000-0001-9228-5258
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 20 May, 2020
No community comments so far
First submitted
On 14 May, 2020
Editor assigned
On 14 May, 2020
Submission checks complete
On 13 May, 2020
Editor invited
On 13 May, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Orthopedics
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Laminin-α2 related Congenital Muscular dystrophy (LAMA2-CMD) is a devastating genetic disease caused by mutations in the LAMA2 gene. These mutations result in progressive muscle wasting and inflammation leading to delayed milestones, and reduced lifespan in affected patients. There is currently no cure or treatment for LAMA2-CMD. Preclinical studies have demonstrated that mouse Laminin-111 can serve as an effective protein replacement therapy in a mouse model of LAMA2-CMD.
Methods
In this study, we generated a novel immunocompromised dy W mouse model of LAMA2-CMD to study the role the immune system plays in muscle disease progression. We used this immune deficient dy W mouse model to test the therapeutic benefits of recombinant human laminin-111 and laminin-211 protein therapy on Laminin-α2 deficient muscle disease progression.
Results
We show that immune deficient Laminin-α2 null mice demonstrate subtle differences in muscle regeneration compared to immune competent animals during early disease stages, but overall exhibit a comparable muscle disease progression. We found human laminin-111 and laminin-211 could serve as effective protein replacement strategies with mice showing improvements in muscle pathology and function. We observed that human laminin-111 and laminin-211 exhibit differences on satellite and myoblast cell populations and differentially affect muscle repair.
Conclusions
This study describes the generation of a novel immune deficient mouse model that allows investigation of the role the immune system plays in LAMA2-CMD. This model can be used to assess the therapeutic potential of heterologous therapies that would illicit an immune response. Using this model, we show that recombinant human Laminin-111 can serve as effective protein replacement therapy for the treatment of LAMA2-CMD.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7