Somatic Gene Therapy: Methods for the Present and Future

O’Malley, Bert W.; Ledley, Fred D.

doi:10.1001/archotol.1993.01880220044007

Cited by 15 publications

(6 citation statements)

References 27 publications

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“…This would provide a mechanism for single administration of a vector to achieve limited long term, steady levels of gene product using common routes of delivery. 26,27 To overcome the problems concerning RLN reinnervation failure, we have demonstrated the potential of gene therapy. Insulin-like growth factor (IGF)-I gene transfer to denervated thyroarytenoid (TA) muscle has been shown to prevent muscle atrophy while improving motor endplate morphology in a rat laryngeal paralysis model, 28,29 and adenoviral vector-mediated GDNF gene transfer prevents motor neuron loss in the nucleus ambiguus in a rat vagal nerve avulsion model.…”

Section: Introductionmentioning

confidence: 99%

Adenoviral GDNF gene transfer enhances neurofunctional recovery after recurrent laryngeal nerve injury

et al. 2005

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Section: Introductionmentioning

confidence: 99%

Adenoviral GDNF gene transfer enhances neurofunctional recovery after recurrent laryngeal nerve injury

et al. 2005

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“…9,10 Gene therapy provides a mechanism whereby infrequent administration achieves long-term steady-state levels of the gene product using common routes of delivery. 11,12…”

mentioning

confidence: 99%

Human Insulinlike Growth Factor 1 Gene Transfer Into Paralyzed Rat Larynx

Shiotani

O’Malley

Coleman³

et al. 1999

Arch Otolaryngol Head Neck Surg

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Applied to laryngeal paralysis, hIGF1 gene therapy provides an opportunity to augment surgical treatment modalities by the prevention or reversal of muscle atrophy, and enhancement of nerve sprouting and muscle reinnervation. Although the percentage of denervated muscles demonstrating hIGF1 expression was increased following multiple injections, no difference was observed in the biological response compared with that in the single-injection treatment groups. Further investigation will be conducted to assess long-term benefits and physiological responses and to define the limitations of this potentially valuable therapeutic strategy.

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“…18 Given the short half-life of GDNF in vivo and rapid diffusion into adjacent tissues, hydrogel delivery allows GDNF to remain at the injury site during hydrogel degradation, whereas even high doses administered by bolus injection are quickly cleared or metabolized. 48 For example, while the burst release of $3 mg of GDNF from a hydrogel over the 1st day provides continuous dosing, a 5 mg bolus injection provides twice the dosage within minutes. Furthermore, bolus injection poses the risk of toxic side effects such as focal cell loss, pia thickening, Schwann cell hyperplasia, and ingrowth of sympathetic fibers resulting from a high dose of local delivery.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, bolus injection poses the risk of toxic side effects such as focal cell loss, pia thickening, Schwann cell hyperplasia, and ingrowth of sympathetic fibers resulting from a high dose of local delivery. 38,48,49 Repeated administration of lower doses could replicate mechanical allodynia produced by the sustained delivery of a hydrogel or minipump. While repeated injections would more clearly define temporal profiles in vivo, the hydrogel delivery provides simplified treatment with alterable release kinetics eliminating multiple treatments or implantation of minipumps.…”

Section: Discussionmentioning

confidence: 99%

Controlled release of GDNF reduces nerve root‐mediated behavioral hypersensitivity

Hubbard

Martínez

Burdick

et al. 2008

Journal Orthopaedic Research

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Nerve root compression produces persistent behavioral sensitivity in models of painful neck injury. This study utilized degradable poly(ethylene glycol) hydrogels to deliver glial cell line-derived neurotrophic factor (GDNF) to an injured nerve root. Hydrogels delivered $98% of encapsulated GDNF over 7 days in an in vitro release assay without the presence of neurons and produced enhanced outgrowth of processes in cortical neural cell primary cultures. The efficacy of a GDNF hydrogel placed on the root immediately after injury was assessed in a rat pain model of C7 dorsal root compression. Control groups included painful injury followed by: (1) vehicle hydrogel treatment (no GDNF), (2) a bolus injection of GDNF, or (3) no treatment. After injury, mechanical allodynia (n ¼ 6/group) was significantly decreased with GDNF delivered by the hydrogel compared to the three injury control groups (p < 0.03). The bolus GDNF treatment did not reduce allodynia at any time point. The GDNF receptor (GFRa-1) decreased in small, nociceptive neurons of the affected dorsal root ganglion, suggesting a decrease in receptor expression following injury. GDNF receptor immunoreactivity was significantly greater in these neurons following GDNF hydrogel treatment relative to GDNF bolus treated and untreated rats (p < 0.05). These data suggest efficacy for degradable hydrogel delivery of GDNF and support this treatment approach for nerve root-mediated pain. Keywords: radiculopathy; neurotrophic factor; GDNF; hydrogel; allodynia Chronic neck pain affects as many as 71% of adults at some point during their lives. 1,2 Painful cervical spine injuries can result from nonphysiologic loading of the neck as occurs in recreational accidents and contact sports, 3,4 when nerve roots can be compressed. 5 Nerve root compression induces persistent behavioral hypersensitivity in rat models of radiculopathy, in which painful responses are elicited in the affected dermatome by stimulation that does not normally provoke pain (mechanical allodynia). [6][7][8][9] Further, hypersensitivity to a stimulus has been used as a sensitive clinical indicator of pain. 10 Compression of primary afferent neurons also produces increased neuronal excitability, ectopic axonal firing, Wallerian degeneration, endoneurial edema, inflammatory responses, and decreased spinal substance P. 7,8,[11][12][13][14][15][16] Current treatments for neuropathic pain include opioids, nonsteroidal anti-inflammatories, antagonists to ion channels, neuropeptides, cytokines, and trophic factors to promote cell survival and regeneration. [17][18][19][20][21][22][23] Neurotrophic factors can prevent secondary neuronal degeneration and reduce spontaneous firing. In particular, glial cell line-derived neurotrophic factor (GDNF) has analgesic effects and modulates nociceptive signaling by altering sodium channel subtype expression and reducing aberrant A-fiber sprouting into the cord. 18,19,[24][25][26] However, in neuropathic pain models, GDNF is decreased after injury which may initiate ...

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Somatic Gene Therapy: Methods for the Present and Future

Cited by 15 publications

References 27 publications

Adenoviral GDNF gene transfer enhances neurofunctional recovery after recurrent laryngeal nerve injury

Adenoviral GDNF gene transfer enhances neurofunctional recovery after recurrent laryngeal nerve injury

Human Insulinlike Growth Factor 1 Gene Transfer Into Paralyzed Rat Larynx

Controlled release of GDNF reduces nerve root‐mediated behavioral hypersensitivity

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