Widespread suppression of huntingtin with convection-enhanced delivery of siRNA

Practical Considerations of Convection Enhanced Delivery for Novel Therapies Treating Spinal Cord Injury Related Neuropathic Pain

“…A single administration into the adult striatum of an siRNA targeting Htt can silence mutant Htt, attenuate neuronal pathology, and delay the abnormal behavioral phenotype observed in a rapid-onset, viral transgenic mouse model. In a non-human primate brain model, the silencing Htt obtained after sufficient distribution of siRNA that target Htt and high levels of Htt suppression and, thus, could lead to therapeutic benefit [57].…”

First use of creatine hydrochloride in premanifest Huntington disease

“…Intense research is being conducted into the genetic aspects of the disease with a view to modifying or correcting the genetic mutation, either by gene silencing/interference, replacement of the expanded CAG repeat or by use of molecular chaperones to alter downstream effects [50][51][52][53][54][55] . Whilst these strategies are promising, and are moving closer to clinical trials 53,56 , they currently represent strategies for the future. Thus, there is an urgent need to identify alternate treatments capable of impacting on disease progression with a clear intent to improve quality of life whilst the search for a cure continues.…”

Recent Advances in RNA Interference Therapeutics for CNS Diseases

“…Thus, it is important to understand what kind of dose may be appropriate and how long the RNAi efficacy is retained in the human brain. A number of studies have focused on determining an appropriate dose of RNAi that is efficacious and safe in the primate brain using viral and nonviral methods [81,82,168,169]. Nonviral delivery systems used cannulas implanted in the brain or convection enhanced delivery systems that use flow pressure to increase the volume of distribution.…”

“…For long-term effects, repeated dosing would be required. For AAVs, directed delivery can be done, or, if the targeted structure is larger, convection enhanced delivery is effective [168]. Various methods are used to inform investigators about the distribution of the drug after delivery.…”

“…Various methods are used to inform investigators about the distribution of the drug after delivery. To detect siRNAs after delivery, Stiles et al [168] used radiolalebeled siRNAs, which allowed comparison of the volume of brain for which there was target suppression, as a function of dose and spread. For viral vectors, a common strategy to determine the distribution of transduced cells takes advantage of reporter genes, such as eGFP [80,82].…”