Gene-modified leucoconcentrate for personalized ex vivo gene therapy in a mini pig model of moderate spinal cord injury

The regeneration of nerve tissue after spinal cord injury is a complex and poorly understood process. Medication and surgery are not very effective treatments for patients with spinal cord injuries. Gene therapy is a popular approach for the treatment of such patients. The delivery of therapeutic genes is carried out in a variety of ways, such as direct injection of therapeutic vectors at the site of injury, retrograde delivery of vectors, and ex vivo therapy using various cells. Recombinant adenoviruses are often used as vectors for gene transfer. This review discusses the advantages, limitations and prospects of adenovectors in spinal cord injury therapy.

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Neurotrophic factors, cellular bridges and gene therapy for spinal cord injury

The Journal of Physiology ◽

10.1111/j.1469-7793.2001.0083b.x ◽

2001 ◽

Vol 533 (1) ◽

pp. 83-89 ◽

Cited By ~ 165

Author(s):

Leonard L. Jones ◽

Martin Oudega ◽

Mary Bartlett Bunge ◽

Mark H. Tuszynski

Keyword(s):

Spinal Cord ◽

Gene Therapy ◽

Spinal Cord Injury ◽

Neurotrophic Factors ◽

Cord Injury

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Planet of the AAVs: The Spinal Cord Injury Episode

Biomedicines ◽

10.3390/biomedicines9060613 ◽

2021 ◽

Vol 9 (6) ◽

pp. 613

Author(s):

Katerina Stepankova ◽

Pavla Jendelova ◽

Lucia Machova Urdzikova

Keyword(s):

Spinal Cord ◽

Gene Therapy ◽

Spinal Cord Injury ◽

Cell Types ◽

Specific Cell ◽

Adeno Associated Virus ◽

Adequate Treatment ◽

Cord Injury ◽

The Central Nervous System ◽

Transgene Delivery

The spinal cord injury (SCI) is a medical and life-disrupting condition with devastating consequences for the physical, social, and professional welfare of patients, and there is no adequate treatment for it. At the same time, gene therapy has been studied as a promising approach for the treatment of neurological and neurodegenerative disorders by delivering remedial genes to the central nervous system (CNS), of which the spinal cord is a part. For gene therapy, multiple vectors have been introduced, including integrating lentiviral vectors and non-integrating adeno-associated virus (AAV) vectors. AAV vectors are a promising system for transgene delivery into the CNS due to their safety profile as well as long-term gene expression. Gene therapy mediated by AAV vectors shows potential for treating SCI by delivering certain genetic information to specific cell types. This review has focused on a potential treatment of SCI by gene therapy using AAV vectors.

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An Ex Vivo Laser-induced Spinal Cord Injury Model to Assess Mechanisms of Axonal Degeneration in Real-time

Journal of Visualized Experiments ◽

10.3791/52173 ◽

2014 ◽

Cited By ~ 3

Author(s):

Starlyn L. M. Okada ◽

Nicole S. Stivers ◽

Peter K. Stys ◽

David P. Stirling

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Real Time ◽

Axonal Degeneration ◽

Ex Vivo ◽

Spinal Cord Injury Model ◽

Injury Model ◽

Cord Injury

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Cell viability in three ex vivo rat models of spinal cord injury

Journal of Anatomy ◽

10.1111/joa.12909 ◽

2018 ◽

Vol 234 (2) ◽

pp. 244-251 ◽

Cited By ~ 2

Author(s):

Azim Patar ◽

Peter Dockery ◽

Linda Howard ◽

Siobhan S. McMahon

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Cell Viability ◽

Ex Vivo ◽

Rat Models ◽

Cord Injury

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Behavioral, Histological, and Ex Vivo Magnetic Resonance Imaging Assessment of Graded Contusion Spinal Cord Injury in Mice

Journal of Neurotrauma ◽

10.1089/neu.2006.0204 ◽

2007 ◽

Vol 24 (4) ◽

pp. 674-689 ◽

Cited By ~ 46

Author(s):

Rebecca A. Nishi ◽

Hongli Liu ◽

Yong Chu ◽

Mark Hamamura ◽

Min-Ying Su ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Spinal Cord ◽

Spinal Cord Injury ◽

Magnetic Resonance ◽

Ex Vivo ◽

Resonance Imaging ◽

Cord Injury ◽

Magnetic Resonance Imaging Assessment

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Epidural Stimulation Combined with Triple Gene Therapy for Spinal Cord Injury Treatment

International Journal of Molecular Sciences ◽

10.3390/ijms21238896 ◽

2020 ◽

Vol 21 (23) ◽

pp. 8896

Author(s):

Rustem Islamov ◽

Farid Bashirov ◽

Filip Fadeev ◽

Roman Shevchenko ◽

Andrei Izmailov ◽

...

Keyword(s):

Spinal Cord ◽

Gene Therapy ◽

Spinal Cord Injury ◽

Combined Treatment ◽

Small Sample ◽

Functional Restoration ◽

Synaptic Proteins ◽

Large Animal ◽

Cord Injury ◽

Spinal Contusion

The translation of new therapies for spinal cord injury to clinical trials can be facilitated with large animal models close in morpho-physiological scale to humans. Here, we report functional restoration and morphological reorganization after spinal contusion in pigs, following a combined treatment of locomotor training facilitated with epidural electrical stimulation (EES) and cell-mediated triple gene therapy with umbilical cord blood mononuclear cells overexpressing recombinant vascular endothelial growth factor, glial-derived neurotrophic factor, and neural cell adhesion molecule. Preliminary results obtained on a small sample of pigs 2 months after spinal contusion revealed the difference in post-traumatic spinal cord outcomes in control and treated animals. In treated pigs, motor performance was enabled by EES and the corresponding morpho-functional changes in hind limb skeletal muscles were accompanied by the reorganization of the glial cell, the reaction of stress cell, and synaptic proteins. Our data demonstrate effects of combined EES-facilitated motor training and cell-mediated triple gene therapy after spinal contusion in large animals, informing a background for further animal studies and clinical translation.

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Molecular and functional characterization of detrusor PDGFRα positive cells in spinal cord injury-induced detrusor overactivity

Scientific Reports ◽

10.1038/s41598-021-95781-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ken Lee ◽

Sang O Park ◽

Pil-Cho Choi ◽

Seung-Bum Ryoo ◽

Haeyeong Lee ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Detrusor Overactivity ◽

Ex Vivo ◽

Functional Characterization ◽

Interstitial Cells ◽

Sk Channels ◽

Loss Of Function ◽

Cord Injury

AbstractVolume accommodation occurs via a novel mechanism involving interstitial cells in detrusor muscles. The interstitial cells in the bladder are PDGFRα+, and they restrain the excitability of smooth muscle at low levels and prevents the development of transient contractions (TCs). A common clinical manifestation of spinal cord injury (SCI)-induced bladder dysfunction is detrusor overactivity (DO). Although a myogenic origin of DO after SCI has been suggested, a mechanism for development of SCI-induced DO has not been determined. In this study we hypothesized that SCI-induced DO is related to loss of function in the regulatory mechanism provided by PDGFRα+ cells. Our results showed that transcriptional expression of Pdgfra and Kcnn3 was decreased after SCI. Proteins encoded by these genes also decreased after SCI, and a reduction in PDGFRα+ cell density was also documented. Loss of PDGFRα+ cells was due to apoptosis. TCs in ex vivo bladders during filling increased dramatically after SCI, and this was related to the loss of regulation provided by SK channels, as we observed decreased sensitivity to apamin. These findings show that damage to the mechanism restraining muscle contraction during bladder filling that is provided by PDGFRα+ cells is causative in the development of DO after SCI.

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