AAV for pain: steps towards clinical translation

Beutler, Andreas S.; Reinhardt, Matthias

doi:10.1038/gt.2009.23

Cited by 44 publications

(31 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, DRG transduction could have potential benefit in models of chronic pain (Federici and Boulis, 2007;Storek et al, 2008;Beutler and Reinhardt, 2009). Xu et al have achieved strong GFP expression with AAV vector in DRG, dorsal roots, and peripheral axons (Xu et al, 2003a).…”

Section: Discussionmentioning

confidence: 99%

Efficient Retrograde Transport of Adeno-Associated Virus Type 8 to Spinal Cord and Dorsal Root Ganglion After Vector Delivery in Muscle

et al. 2010

View full text Add to dashboard Cite

The peripheral nervous system (PNS), including peripheral nerves and dorsal root ganglion (DRG), is involved in numerous neurological disorders, such as peripheral neuropathies (diabetic neuropathy, chronic pain, etc.) and demyelination diseases (multiple sclerosis, congenital muscular dystrophy, Charcot-Marie-Tooth disease, etc.). Effective clinical interventions for those diseases are very limited. Gene therapy represents a novel therapeutic strategy for the PNS diseases, especially with simply and minimally invasive delivery methods. Previously, we have shown that adeno-associated virus type 8 (AAV8) can efficiently transduce muscles body wide by a simple intraperitoneal injection in neonatal mice. In this study, we investigated the capacity of AAV8 in transducing PNS in neonatal mice by intraperitoneal injection and also in adult mice by intramuscular injection. Efficient and longterm gene transfer was found in the white matter of the spinal cord, DRG neurons, and peripheral nerves in both groups, treated either as neonates or as adults, particularly neonates. In the adult mice injected with AAV8 in tibialis anterior and gastrocnemius muscles in one of the hind legs, more neurons were transduced in the lower part of the spinal cord than in the upper part; the DRG neurons were transduced more on the vector-injected side than in the contralateral uninjected side. Few cells in the gray matter of the spinal cord were transduced regardless of the delivery methods and age of the mice. These results support the mechanism of vector retrograde transport and suggest that AAV8 crosses blood-nerve barrier poorly. Our finding should have important implications in gene therapy for peripheral neurological disorders.

show abstract

Section: Discussionmentioning

confidence: 99%

Efficient Retrograde Transport of Adeno-Associated Virus Type 8 to Spinal Cord and Dorsal Root Ganglion After Vector Delivery in Muscle

et al. 2010

View full text Add to dashboard Cite

show abstract

“…For example, recombinant adeno-associated virus (rAAV) was used as mediators for delivery miRNA134 in mice resulting in almost 100% transduction efficiency (Christensen et al, 2010). rAAV can target non-dividing cells and show transgene expression in a long term with relatively non-pathogenic and considered safe nature (Beutler and Reinhardt, 2009). Clinical trials of rAAV gene therapy in PD also showed that they were well tolerated in the human CNS and expressed persistence of transgenes in a long-term (Kaplitt et al, 2007; Marks et al, 2008).…”

Section: Vector Systems To Deliver Mirnasmentioning

confidence: 99%

Getting miRNA Therapeutics into the Target Cells for Neurodegenerative Diseases: A Mini-Review

Wen

2016

Front. Mol. Neurosci.

View full text Add to dashboard Cite

miRNAs play important roles in modulating gene expression in varying cellular processes and disease pathogenesis, including neurodegenerative diseases. Several miRNAs are expressed in the brain, control brain development and are identified as important biomarkers in the pathogenesis of motor—and neuro-cognitive diseases such as Alzheimer’s (AD), Huntington’s and Parkinson’s diseases (PD) and amyotrophic lateral sclerosis. These remarkable miRNAs could be used as diagnostic markers and therapeutic targeting potential for many stressful and untreatable progressive neurodegenerative diseases. To modulate these miRNA activities, there are currently two strategies involved; first one is to therapeutically restore the suppressed miRNA level by miRNA mimics (agonist), and the other one is to inhibit miRNA function by using anti-miR (antagonist) to repress overactive miRNA function. However, RNAi-based therapeutics often faces in vivo instability because naked nucleic acids are subject to enzyme degradation before reaching the target sites. Therefore, an effective, safe and stable bio-responsive delivery system is necessary to protect the nucleic acids from serum degradation and assist their entrance to the cells. Since neuronal cells are non-regenerating, to design engineered miRNAs to be delivered to the central nervous system (CNS) for long term gene expression and knockdown is representing an enormous challenge for scientists. This article provides an insight summary on some of the innovative strategies employed to deliver miRNA into target cells. These viral and non-viral carrier systems hold promise in RNA therapy delivery for neurodegenerative diseases.

show abstract

“…Furthermore these data act as an independent proof of principle that inhibiting GCH1 in patients may well be an effective anti-neuropathic. It remains to be seen if this particular delivery system will be effective in humans, but if clinical trials for other conditions are successful [164, 165] chronic neuropathic pain would certainly be a first line target for such viral constructs [166]. …”

Section: Other Evidence Of Gch1 Link To Painmentioning

confidence: 99%

GCH1, BH4 and Pain

Latrémolière¹,

Costigan

2011

CPB

View full text Add to dashboard Cite

Understanding and consequently treating neuropathic pain effectively is a challenge for modern medicine, as unlike inflammation, which can be controlled relatively well, chronic pain due to nerve injury is refractory to most current therapeutics. Here we define a target pathway for a new class of analgesics, tetrahydrobiopterin (BH4) synthesis and metabolism. BH4 is an essential co-factor in the synthesis of serotonin, dopamine, epinephrine, norepinephrine and nitric oxide and as a result, its availability influences many systems, including neurons. Following peripheral nerve damage, levels of BH4 are dramatically increased in sensory neurons, consequently this has a profound effect on the physiology of these cells, causing increased activity and pain hypersensitivity. These changes are principally due to the upregulation of the rate limiting enzyme for BH4 synthesis GTP Cyclohydrolase 1 (GCH1). A GCH1 pain-protective haplotype which decreases pain levels in a variety of settings, by reducing the levels of endogenous activation of this enzyme, has been characterized in humans. Here we define the control of BH4 homeostasis and discuss the consequences of large perturbations within this system, both negatively via genetic mutations and after pathological increases in the production of this cofactor that result in chronic pain. We explain the nature of the GCH1 reduced-function haplotype and set out the potential for a ‘BH4 blocking’ drug as a novel analgesic.

show abstract

AAV for pain: steps towards clinical translation

Cited by 44 publications

References 58 publications

Efficient Retrograde Transport of Adeno-Associated Virus Type 8 to Spinal Cord and Dorsal Root Ganglion After Vector Delivery in Muscle

Efficient Retrograde Transport of Adeno-Associated Virus Type 8 to Spinal Cord and Dorsal Root Ganglion After Vector Delivery in Muscle

Getting miRNA Therapeutics into the Target Cells for Neurodegenerative Diseases: A Mini-Review

GCH1, BH4 and Pain

Contact Info

Product

Resources

About