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Benitec Biopharma Ltd good mice results
http://www.proactiveinvestors.com.au/companies/news/67395/benitec-biopharma-ltd-has-hepatitis-b-success-with-treatment-67395.html
Benitec Biopharma Ltd (ASX:BLT; NASDAQ:BNTC) should gain a boost today as its Hepatitis B therapy has been seen to reduce the virus (HBV) by 98.5% in a mice study.
The in vivo study assessed the activity of BB-HB-331 treatment in the PhoenixBio (PXB) mouse model and demonstrated robust and durable suppression of HBV in vivo following a single administration.
Benitec's ddRNAi technology is a combination of gene silencing using RNA interference coupled with the long term therapeutic potential of gene therapy.
Once infected with HBV, mice were treated with a one time systemic injection of BB-HB-331. Weekly assessment of serum antigen levels, HBV viral proteins and extracellular HBV DNA were conducted for the duration of the 56 day study.
The key findings in this study were that a single BB-HB-331 treatment reduced serum HBV DNA by 1.83 logs, equivalent to 98.5% elimination of circulating HBV.
The in vivo experiment validates the BB-‐HB-331 in vitro findings previously observed in human hepatocytes isolated from the PXB mouse model which was announced on 7 December 2015.
Benitec Biopharma Ltd (ASX:BLT; NASDAQ:BNTC) should gain a boost today as its Hepatitis B therapy has been seen to reduce the virus (HBV) by 98.5% in a mice study.
The in vivo study assessed the activity of BB-HB-331 treatment in the PhoenixBio (PXB) mouse model and demonstrated robust and durable suppression of HBV in vivo following a single administration.
Benitec's ddRNAi technology is a combination of gene silencing using RNA interference coupled with the long term therapeutic potential of gene therapy.
Once infected with HBV, mice were treated with a one time systemic injection of BB-HB-331. Weekly assessment of serum antigen levels, HBV viral proteins and extracellular HBV DNA were conducted for the duration of the 56 day study.
The key findings in this study were that a single BB-HB-331 treatment reduced serum HBV DNA by 1.83 logs, equivalent to 98.5% elimination of circulating HBV.
The in vivo experiment validates the BB-‐HB-331 in vitro findings previously observed in human hepatocytes isolated from the PXB mouse model which was announced on 7 December 2015.
It appears they are using adenovirus associated vector 8 that is strongly hepatotropic as vehicle to introduce the permanent production of the interfering hairpin RNA.
while this virus is known not to produce obvious disease, it can mildly integrate into the host genome and also produce a few new proteins that can cause at least mild tcell activation with their epitopes. Furthermore a strong bcell response is typical, resulting in circulating neutralizing antibodies against the vector virus.
thus to eliminate or reduce the hbv infection, a new presumably harmless chronic viral liver infection is produced.
The final efficacy against hbv also remains to be seen, a 90% transcription reduction, eg might still not be sufficient to achieve the hbsag seroconversion desired.
But then you have a new guest in the liver, with unclear long term effects.
The use of this technology might be warranted against diseases with strong pathologies for which no good alternative therapy exists. For hepatitis b and C we have to wait and see.
while this virus is known not to produce obvious disease, it can mildly integrate into the host genome and also produce a few new proteins that can cause at least mild tcell activation with their epitopes. Furthermore a strong bcell response is typical, resulting in circulating neutralizing antibodies against the vector virus.
thus to eliminate or reduce the hbv infection, a new presumably harmless chronic viral liver infection is produced.
The final efficacy against hbv also remains to be seen, a 90% transcription reduction, eg might still not be sufficient to achieve the hbsag seroconversion desired.
But then you have a new guest in the liver, with unclear long term effects.
The use of this technology might be warranted against diseases with strong pathologies for which no good alternative therapy exists. For hepatitis b and C we have to wait and see.
As Benitec frequently stated, there is no turning back from the treatment:
"yet the genetic change is long-lasting, because the shRNA continues to be expressed for long periods, potentially up to years from the integrated DNA construct (Sci Trans Med 2010)."
I think it would require a lengthy period of observation, maybe be long after the disease is cured, that the introduced DNA is safe.
"yet the genetic change is long-lasting, because the shRNA continues to be expressed for long periods, potentially up to years from the integrated DNA construct (Sci Trans Med 2010)."
I think it would require a lengthy period of observation, maybe be long after the disease is cured, that the introduced DNA is safe.
The approach is quite fascinating, if several target sequences could be used it might even be possible to overcome the adaptive power. I do not know how they intend to get the plasmid into the human liver cells.
The e ag related mutations are not relevant to the adaptive mutations in this context. It is the same problem all interfering RNA have to block a dynamic genome like hbv from functioning.
The e ag related mutations are not relevant to the adaptive mutations in this context. It is the same problem all interfering RNA have to block a dynamic genome like hbv from functioning.
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I found this wikipedia article to be quite informative in understanding how the technique with ddRNAi works.
The issue of delivery is said to be simplified by "clinically approved and well-characterised gene therapy vectors developed for the purpose".
And, yes, there is also the possiblity of targeting several sites of the viral mRNA by using the so-called multi-cassette constructs.
https://en.wikipedia.org/wiki/DNA-directed_RNA_interference#Delivery
The issue of delivery is said to be simplified by "clinically approved and well-characterised gene therapy vectors developed for the purpose".
And, yes, there is also the possiblity of targeting several sites of the viral mRNA by using the so-called multi-cassette constructs.
https://en.wikipedia.org/wiki/DNA-directed_RNA_interference#Delivery
Two major problems remain with this approach.
First the plasmid has to be successfully inserted into the liver cells.
Second, the recognition region of the interfering RNA made from the short hairpin RNA is fairly short. If even a single nucleotide mutation is present, or generated through mutation, the binding will be too weak to work.
this means, that the system is quite vulnerable to mutational adaption of the HBV virus to this transcription efficacy reducing machinery.
First the plasmid has to be successfully inserted into the liver cells.
Second, the recognition region of the interfering RNA made from the short hairpin RNA is fairly short. If even a single nucleotide mutation is present, or generated through mutation, the binding will be too weak to work.
this means, that the system is quite vulnerable to mutational adaption of the HBV virus to this transcription efficacy reducing machinery.
2 Comments
So in practice does it mean it may work better/only for wild type with hbe+ than mutated hbe- ones ?
And is ddRNAi bad idea for hbv or you think just Benitec's approach is wrong ?
Hi Sorte, thanks for the news: 98.5% elimination of circulating hbv after a single treatment is indeed amazing.
Here is a video that shows how their techinque of ddRNAi works.
https://www.youtube.com/watch?v=UuicPthdT70
Here is a video that shows how their techinque of ddRNAi works.
https://www.youtube.com/watch?v=UuicPthdT70
2 Comments
It's amazing, but too late for us, new generation is already vaccinated, so I don't know their profit. To win billions they should be already on market
Remember there are 350 million hbv carriers around the world; and upto this point we do not have any cure. Besides, their technology is being developed not only for hbv; but also for other diseases like hiv, cancers,etc.
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