Intermittent Hypoxia and Stem Cell Implants Preserve Breathing Capacity in a Rodent Model of Amyotrophic Lateral Sclerosis

Nichols, Nicole L.; Gowing, Genevíève; Satriotomo, Irawan; Nashold, Lisa J.; Dale, Erica A.; Suzuki, Masatoshi; Avalos, Pablo; Mulcrone, Patrick L.; McHugh, Jacalyn; Svendsen, Clive N.; Mitchell, Gordon S.

doi:10.1164/rccm.201206-1072oc

Cited by 96 publications

(142 citation statements)

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“…5-HT 2 receptors activate phospholipase C to produce diacylglycerol and inositol triphosphate (Pandey et al, 1995). Diacylglycerol binds to the regulatory domain (C1) of PKC, activating the catalytic domain to enable phosphorylation of downstream targets (Steinberg, 2008).…”

Section: Spinal Pkc Activity Is Required For Pltfmentioning

confidence: 99%

“…Moreover, the C1B region of PKC may be unable to bind NPC because structural studies demonstrate narrowing of the phorbol ester-binding surface of C1B in PKC versus the relatively similar PKC␦ C1B region, which has 80% sequence homology (Rahman et al, 2013). This difference may explain how NPC, which binds the diacylglycerol binding site of most PKC isoforms (Sullivan et al, 1991), had no effect on pLTF.…”

Section: Spinal Pkc Activity Is Required For Pltfmentioning

confidence: 99%

“…The most frequently studied model of respiratory motor plasticity is pLTF, a prolonged increase in phrenic burst amplitude lasting hours following AIH (Hayashi et al, 1993;Bach and Mitchell, 1996). Studies of pLTF continue to guide therapies with intermittent hypoxia to restore motor function Lovett-Barr et al, 2012;Nichols et al, 2013), but we still have an incomplete understanding of the mechanisms giving rise to this important form of spinal plasticity.…”

Section: Introductionmentioning

confidence: 99%

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Phrenic Long-Term Facilitation Requires PKCθ Activity within Phrenic Motor Neurons

et al. 2015

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Acute intermittent hypoxia (AIH) induces a form of spinal motor plasticity known as phrenic long-term facilitation (pLTF); pLTF is a prolonged increase in phrenic motor output after AIH has ended. In anesthetized rats, we demonstrate that pLTF requires activity of the novel PKC isoform, PKC, and that the relevant PKC is within phrenic motor neurons. Whereas spinal PKC inhibitors block pLTF, inhibitors targeting other PKC isoforms do not. PKC is highly expressed in phrenic motor neurons, and PKC knockdown with intrapleural siRNAs abolishes pLTF. Intrapleural siRNAs targeting PKC, an atypical PKC isoform expressed in phrenic motor neurons that underlies a distinct form of phrenic motor plasticity, does not affect pLTF. Thus, PKC plays a critical role in spinal AIH-induced respiratory motor plasticity, and the relevant PKC is localized within phrenic motor neurons. Intrapleural siRNA delivery has considerable potential as a therapeutic tool to selectively manipulate plasticity in vital respiratory motor neurons.

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Section: Spinal Pkc Activity Is Required For Pltfmentioning

confidence: 99%

Section: Spinal Pkc Activity Is Required For Pltfmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phrenic Long-Term Facilitation Requires PKCθ Activity within Phrenic Motor Neurons

et al. 2015

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“…First, normalization of respiratory volumes to body mass may not be appropriate in degenerative disease models. Mitchell and colleagues have suggested that such an approach may in fact obviate detection of physiologic impairments in a rat amyotrophic lateral sclerosis (ALS) model (52,53). Without clear changes in the size of the lung and chest cavity in diseased animals, but with loss of muscle mass and/or neurological problems, body mass may no longer scale with respiratory volumes in a predictable manner.…”

Section: Commentary Regarding the Plethysmography Datamentioning

confidence: 99%

Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines

ElMallah

Pagliardini

Turner

et al. 2015

Am J Respir Cell Mol Biol

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Pompe disease results from a mutation in the acid a-glucosidase gene leading to lysosomal glycogen accumulation. Respiratory insufficiency is common, and the current U.S. Food and Drug Administration-approved treatment, enzyme replacement, has limited effectiveness. Ampakines are drugs that enhance a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor responses and can increase respiratory motor drive. Recent work indicates that respiratory motor drive can be blunted in Pompe disease, and thus pharmacologic stimulation of breathing may be beneficial. Using a murine Pompe model with the most severe clinical genotype (the Gaa 2/2 mouse), our primary objective was to test the hypothesis that ampakines can stimulate respiratory motor output and increase ventilation. Our second objective was to confirm that neuropathology was present in Pompe mouse medullary respiratory control neurons.The impact of ampakine CX717 on breathing was determined via phrenic and hypoglossal nerve recordings in anesthetized mice and whole-body plethysmography in unanesthetized mice. The medulla was examined using standard histological methods coupled with immunochemical markers of respiratory control neurons. Ampakine CX717 robustly increased phrenic and hypoglossal inspiratory bursting and reduced respiratory cycle variability in anesthetized Pompe mice, and it increased inspiratory tidal volume in unanesthetized Pompe mice. CX717 did not significantly alter these variables in wild-type mice. Medullary respiratory neurons showed extensive histopathology in Pompe mice. Ampakines stimulate respiratory neuromotor output and ventilation in Pompe mice, and therefore they have potential as an adjunctive therapy in Pompe disease.

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“…These research grade hMSCs are similar to the hMSC line already established as a cGMP bank at Waisman Biomanufacturing. hMSC were transduced with lentivirus encoding GDNF used previously by our group for growth factor production in human stem cells [18]; [19]; [20]; [21]; [12]; [22]; [23]; [24] and showed over 90% infection efficiency in total cells. A clinical grade lentivirus has already been produced by the Svendsen laboratory for their current preclinical work targeting stem cells to the spinal cord of ALS patients and is available for the production of hMSC-GDNF cells at Waisman Biomanufacturing.…”

Section: Objective 3 (12 Months): Complete Dosing Studies For Msc-gdnmentioning

confidence: 99%

Muscle-Derived GDNF: A Gene Therapeutic Approach for Preserving Motor Neuron Function in ALS

Svendsen¹,

Gowing²

2015

Self Cite

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERCedars-Sinai Medical Center 8700 Beverly Blvd. AHSP8450, Los Angeles, CA, 90048 +9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S)U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES14. ABSTRACT: Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons leading to skeletal muscle atrophy, paralysis, and the death of patients within 2 to 5 years of disease onset. Currently, ALS cannot be prevented and disease progression can be only minimally delayed. Many previous reports have shown that glial cell linederived neurotrophic factor (GDNF) ameliorates certain aspects of the disease in a number of different animal models of ALS. Despite many encouraging results, a strategy aimed at delivering GDNF has yet to be used in a clinical trial for ALS. Recent research and phase I/II clinical trial successes using adeno-associated virus (AAV) as a therapeutic tool have led to a renewed interest in a gene therapy approach for various disorders of the nervous system. To date, no clinical trial for ALS has yet exploited a gene therapeutic strategy, which prompted us to investigate this approach for ALS. Here, we have chosen to use an AAV based gene therapy approach as a straightforward strategy to promote GDNF production in muscles. Hypothesis: Intramuscular AAV5-GDNF injection will ameliorate motor neuron function in the SOD1G93A rat model of ALS. Objectives: To perform crucial and extensive pre-clinical studies to enable an investigational new drug (IND) application with the Food and Drug Administration (FDA) for the approval to move the use of intramuscular GDNF delivery by AAV5 into humans affected by ALS. Findings: Using a combination of DOD, ALS Association and institutional funding we have investigated the potential of intramuscular AAV1, AAV5, AAV2/6 and AAV9 encoding GDNF as a therapeutic approach to ALS. In all cases intramuscularly administered AAV encoding GDNF did not have an overt beneficial effect on motor neuron function.

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Intermittent Hypoxia and Stem Cell Implants Preserve Breathing Capacity in a Rodent Model of Amyotrophic Lateral Sclerosis

Abstract: AIH-induced respiratory plasticity and stem cell therapy have complementary translational potential to treat breathing deficits in patients with ALS.

Cited by 96 publications

References 51 publications

Phrenic Long-Term Facilitation Requires PKCθ Activity within Phrenic Motor Neurons

Phrenic Long-Term Facilitation Requires PKCθ Activity within Phrenic Motor Neurons

Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines

Muscle-Derived GDNF: A Gene Therapeutic Approach for Preserving Motor Neuron Function in ALS

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