Pls when would the treatment for functional cure be available ?
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@Scientists in the house, is this of great significance to ongoing search for cure? If yes, how significant? The Rockefeller University » New tool to study hepatitis B could open the door to a cure @availlant @ThomasTu and others
Hi @CNN,
The system was developed by a very well-known group, and our group is directly working with Bill Schneider to use this model for our own work.
This is a really interesting tool that makes it easier for us to study hepatitis B. One of the major advantages is that it is relatively easy for scientists to test drugs against a “quasi-species” of HBV, rather than just a clone (that is, not just a single sequence of HBV, but a “cloud” of variants that may respond differently to any given drug). This is really important for cure, as quasispecies can be a source of resistance to treatments.
Hope this helps,
Thomas
2 Likes
Just seen this.
http://www.cubanews.acn.cu/science/21115-hebernasvac-cuban-scientists-achievement-against-hepatitis-b
Dear @beinghealthy,
Thanks for raising this. Nasvac has been discussed elsewhere in the forum:
Cheers,
Thomas
what is the current update on TherVacB as we are near end of 2023, I know the deadline is dec 2024, but how does it look so far if any knows?
Hi @john.tavis, a cure for HepB in less than 10 years in the clinical world would be like a dream come😊 . I pray they succeed soon .
However in some part of west Africa mostly Ghana, Nigeria, Sierra Leone etc, people has been cured through herbs. They usually take it for a month and they will lose the HBsag and it will never relapse.
So I think whilst we are waiting for the clinical cure, let’s look on the other side. Combining both herbal and clinical therapy to attain atleast a functional cure is our only hope now.
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The trial was meant to start in 2022, it now says 2024 just another carrot on a stick so far
Dear @Agibaby,
Work to cure HBV is progressing. From an HBV+ person’s perspective, I am am sure it is maddeningly slow, but HBV is a very difficult problem and some very smart people are working on it as hard as they can. There is no way to predict the rate of scientific/medical advances, and HBV clinical trials are slow due to the nature of the disease, so the “10 year” estimate is just that – an estimate. The current generation of clinical trials are producing functional cure rates of up to ~30%, at least in people with low HBs levels, so significant progress is being made.
As to the herbal medicines: Such medications have been used by people since the dawn of time. Some of them are effective, but most have only modest effects or no effects at all. That is not to say that they are not worth pursuing–Far from it! A good example is the drug tamoxifen (widely used for breast cancer) that was first isolated from tree bark. Another example is penicillin (made by a fungus) that may explain why some cultures put spider webs on wounds (the web would catch the fungus spores, some of which could be beneficial). However, there is a huge variation in efficacy for most of such herbal treatments even when they are effective due to lack of standardization on how they are produced, stored, and used. Most fail when subjected to controlled clinical trials.
I cannot comment on the particular treatments you refer to, but I would be skeptical about claims of high efficacy. If they were that effective, word would have spread among the HBV+ community and infection and disease rates would not be so high in W Africa. I hope the scientists who study such “natural products” in search of cures for HBV know of these treatments and take a look at them. Natural product drug discovery is a major branch of the drug discovery field, but unfortunately it is extremely complex because the effective agents in herbal treatments are often combinations of very complex biological molecules. That makes identifying, improving, and standardizing them enough to convert them to drugs extremely hard and time consuming.
Finally, a word of caution. About 1/3 to 1/2 of the supplements sold int the USA don’t have anywhere near the level of the advertised active ingredient, and a large fraction have none at all! These products are unregulated and untested for safety issues. So even if some of them work, there is a risk of harm as they’ve not been examined carefully.
I hope this helps.
John.
3 Likes
Is anyone but me worried that the pharmaceutical industry may stand in the way of finding a cure for hepatitis B? They surely have more money to make by people taking medication every day indefinitely than they’d make if hep b patients were all cured.
Dear @Barry,
Your concern is valid in that pharmaceutical companies stand to make more money from a drug that people have to take forever than from a drug which can provide a cure with a finite course of therapy. However, it is important to understand that we already have this situation well developed in HBV with drugs that directly target viral replication like ETV, TDF and TAF. The first two have already become much more cheaply available as generic medications as the patents protecting these medications have already expired. This makes it very unattractive for companies to develop new medications which cannot improve on the performance already achieved by these medications.
Importantly, these three medications, while effective at halting the progression of liver disease and controlling viral replication, have not done a good job at controlling the death rates from HBV infection. In fact the most recent data show that global death rates from HBV are unfortunately increasing. This is due in part to guidelines restricting the introduction of these medications earlier on in the disease and ageing of the patient population but also because of an important deficiency in these medications: they cannot remove the infection from the liver.
As such, there is a real drive in the industry to develop new medications, most of which are focused on targeting restoration of immune control of the virus (by targeting HBsAg) so that therapy is no longer required. With this scenario achieved (we call this functional cure) only a very tiny but dormant trace of viral infection is present and is persistently dormant in the absence of therapy. These new therapies by definition will all have to be finite in nature and have the promise of better long term outcomes for patients without the need for therapy.
Best regards.
5 Likes
Hello,
I’m totally ignorant about it… but I just came across this article and wanted to ask @ThomasTu and @john.tavis what do you think? could this be used in HBVDNA?
New algorithm finds lots of gene-editing
enzymes in environmental DNA**
CRISPR—Clustered Regularly Interspaced Short Palindromic
Repeats—is the microbial world’s answer to adaptive immunity.
Bacteria don’t generate antibodies when they are invaded by a
pathogen and then hold those antibodies in abeyance in case
they encounter that same pathogen again, the way we do.
Instead, they incorporate some of the pathogen’s DNA into their
own genome and link it to an enzyme that can use it to
recognize that pathogenic DNA sequence and cut it to pieces if
the pathogen ever turns up again.The enzyme that does the
cutting is called Cas, for CRISPR associated. Although the
CRISPR-Cas system evolved as a bacterial defense mechanism,
it has been harnessed and adapted by researchers as a
powerful tool for genetic manipulation in laboratory studies. It
also has demonstrated agricultural uses, and the first CRISPR-
based therapy was just approved in the UK to treat sickle-cell
disease and transfusion-dependent beta-thalassemia.
Now, researchers have developed a new way to search
genomes for CRISPR-Cas-like systems. And they’ve found thatwe may have a lot of additional tools to work with.Modifying
DNA
To date, six types of CRISPR-Cas systems have been identified in
various microbes. Although they differ in detail, they all have the
same appeal: They deliver proteins to a given sequence of
genetic material with a degree of specificity that has heretofore
been technically difficult, expensive, and time-consuming to
achieve. Any DNA sequence of interest can be programmed
into the system and targeted.
The native systems found in microbes usually bring a nuclease—
a DNA-cleaving enzyme—to the sequence, to chop up the
genetic material of a pathogen. This ability to cut any chosen
DNA sequence can be used for gene editing; in tandem with
other enzymes and/or DNA sequences, it can be used to insert
or delete additional short sequences, correcting mutant genes.
Some CRISPR-Cas systems cleave specific RNA molecules
instead of DNA. These can be used to eliminate pathogenic
RNA, like the genomes of some viruses, the way they are
eliminated in their native bacteria. This can also be used to
rescue defects in RNA processing.
But there are lots of additional ways to modify nucleic acids that
might be useful. And it’s an open question as to whether
enzymes that perform additional modifications have evolved.
So, some researchers decided to search for them.Researchers at MIT developed a new tool to detect variable
CRISPR arrays and applied it to 8.8 tera (1012)-base pairs of
prokaryotic genomic information. Many of the systems they
found are rare and only appeared in the dataset in the past 10
years, highlighting how important it is to continue adding
environmental samples that were previously hard to attain into
these data repositories.The new tool was required because
databases of protein and nucleic acid sequences are expanding
at a ridiculous rate, so the techniques for analyzing all of that
data need to keep up. Some algorithms that are used to analyze
them try to compare every sequence to every other one, which
is obviously untenable when dealing with billions of genes.
Others rely on clustering, but these find only genes that are
highly similar so they can’t really shed light on the evolutionary
relationships between distantly related proteins. But fast locality-
sensitive hashtag-based clustering (“flash clust”) works by
binning billions of proteins into fewer, larger clusters of
sequences that differ slightly to identify new, rare relatives.
The search using FLSHclust successfully pulled out 188 new
CRISPR-Cas systems.
Lots of CRISPyness
A few themes emerged from the work. One is that some of the
newly identified CRISPR systems use Cas enzymes with never-
before-seen domains, or appear to be fusions with knowngenes. The scientists further characterized some of these and
found one to be more specific than the CRISPR enzymes
currently in use, and another that cuts RNA that they propose is
structurally distinct enough to comprise an entirely new seventh
type of CRISPR-Cas system.
A corollary of this theme is the linkage of enzymes with different
functionalities, not just nucleases (enzymes that cut DNA and
RNA), with CRISPR arrays. Scientists have harnessed CRISPR’s
remarkable gene-targeting ability by linking it to other kinds of
enzymes and molecules, like fluorescent dyes. But evolution
obviously got there first.
As one example, FLSHclust identified something called a
transposase associated with two different types of CRISPR
systems. A transposase is an enzyme that helps a particular
stretch of DNA jump to another part of the genome. CRISPR
RNA-guided transposition has been seen before, but this is
another example of it. A whole host of proteins with varying
functions, like proteins with transmembrane domains and
signaling molecules, were found linked to CRISPR arrays,
highlighting the mix-n-match nature of the evolution of these
systems. They even found a protein expressed by a virus that
binds to CRISPR arrays and renders them inactive—essentially,
the virus inactivates the CRISPR system that evolved to protect
against viruses.Not only did the researchers find novel proteins
associated with CRISPR arrays, but they also found otherregularly interspaced repeat arrays that were not associated
with any cas enzymes—similar to CRISPR but not CRISPR. They’re
not sure what the functionality of these RNA guided systems
might be but speculate that they are involved in defense just like
CRISPR is.
The authors set out to find “a catalog of RNA-guided proteins
that expand our understanding of the biology and evolution of
these systems and provide a starting point for the development
of new biotechnologies." It seems they achieved their goal:
“The results of this work reveal unprecedented organizational
and functional flexibility and modularity of CRISPR systems,”
they write. They go on to conclude: “This represents only a small
fraction of the discovered systems, but it illuminates the
vastness and untapped potential of Earth’s biodiversity, and the
remaining candidates will serve as a resource for future
exploration.” New algorithm finds lots of gene-editing
enzymes in environmental DNA
CRISPR—Clustered Regularly Interspaced Short Palindromic
Repeats—is the microbial world’s answer to adaptive immunity.
Bacteria don’t generate antibodies when they are invaded by a
pathogen and then hold those antibodies in abeyance in case
they encounter that same pathogen again, the way we do.
Instead, they incorporate some of the pathogen’s DNA into their
own genome and link it to an enzyme that can use it to
recognize that pathogenic DNA sequence and cut it to pieces if
the pathogen ever turns up again.The enzyme that does the
cutting is called Cas, for CRISPR associated. Although the
CRISPR-Cas system evolved as a bacterial defense mechanism,
it has been harnessed and adapted by researchers as a
powerful tool for genetic manipulation in laboratory studies. It
also has demonstrated agricultural uses, and the first CRISPR-
based therapy was just approved in the UK to treat sickle-cell
disease and transfusion-dependent beta-thalassemia.
Now, researchers have developed a new way to search
genomes for CRISPR-Cas-like systems. And they’ve found thatwe may have a lot of additional tools to work with.Modifying
DNA
To date, six types of CRISPR-Cas systems have been identified in
various microbes. Although they differ in detail, they all have the
same appeal: They deliver proteins to a given sequence of
genetic material with a degree of specificity that has heretofore
been technically difficult, expensive, and time-consuming to
achieve. Any DNA sequence of interest can be programmed
into the system and targeted.
The native systems found in microbes usually bring a nuclease—
a DNA-cleaving enzyme—to the sequence, to chop up the
genetic material of a pathogen. This ability to cut any chosen
DNA sequence can be used for gene editing; in tandem with
other enzymes and/or DNA sequences, it can be used to insert
or delete additional short sequences, correcting mutant genes.
Some CRISPR-Cas systems cleave specific RNA molecules
instead of DNA. These can be used to eliminate pathogenic
RNA, like the genomes of some viruses, the way they are
eliminated in their native bacteria. This can also be used to
rescue defects in RNA processing.
But there are lots of additional ways to modify nucleic acids that
might be useful. And it’s an open question as to whether
enzymes that perform additional modifications have evolved.
So, some researchers decided to search for them.Researchers at MIT developed a new tool to detect variable
CRISPR arrays and applied it to 8.8 tera (1012)-base pairs of
prokaryotic genomic information. Many of the systems they
found are rare and only appeared in the dataset in the past 10
years, highlighting how important it is to continue adding
environmental samples that were previously hard to attain into
these data repositories.The new tool was required because
databases of protein and nucleic acid sequences are expanding
at a ridiculous rate, so the techniques for analyzing all of that
data need to keep up. Some algorithms that are used to analyze
them try to compare every sequence to every other one, which
is obviously untenable when dealing with billions of genes.
Others rely on clustering, but these find only genes that are
highly similar so they can’t really shed light on the evolutionary
relationships between distantly related proteins. But fast locality-
sensitive hashtag-based clustering (“flash clust”) works by
binning billions of proteins into fewer, larger clusters of
sequences that differ slightly to identify new, rare relatives.
The search using FLSHclust successfully pulled out 188 new
CRISPR-Cas systems.
Lots of CRISPyness
A few themes emerged from the work. One is that some of the
newly identified CRISPR systems use Cas enzymes with never-
before-seen domains, or appear to be fusions with knowngenes. The scientists further characterized some of these and
found one to be more specific than the CRISPR enzymes
currently in use, and another that cuts RNA that they propose is
structurally distinct enough to comprise an entirely new seventh
type of CRISPR-Cas system.
A corollary of this theme is the linkage of enzymes with different
functionalities, not just nucleases (enzymes that cut DNA and
RNA), with CRISPR arrays. Scientists have harnessed CRISPR’s
remarkable gene-targeting ability by linking it to other kinds of
enzymes and molecules, like fluorescent dyes. But evolution
obviously got there first.
As one example, FLSHclust identified something called a
transposase associated with two different types of CRISPR
systems. A transposase is an enzyme that helps a particular
stretch of DNA jump to another part of the genome. CRISPR
RNA-guided transposition has been seen before, but this is
another example of it. A whole host of proteins with varying
functions, like proteins with transmembrane domains and
signaling molecules, were found linked to CRISPR arrays,
highlighting the mix-n-match nature of the evolution of these
systems. They even found a protein expressed by a virus that
binds to CRISPR arrays and renders them inactive—essentially,
the virus inactivates the CRISPR system that evolved to protect
against viruses.Not only did the researchers find novel proteins
associated with CRISPR arrays, but they also found otherregularly interspaced repeat arrays that were not associated
with any cas enzymes—similar to CRISPR but not CRISPR. They’re
not sure what the functionality of these RNA guided systems
might be but speculate that they are involved in defense just like
CRISPR is.
The authors set out to find “a catalog of RNA-guided proteins
that expand our understanding of the biology and evolution of
these systems and provide a starting point for the development
of new biotechnologies." It seems they achieved their goal:
“The results of this work reveal unprecedented organizational
and functional flexibility and modularity of CRISPR systems,”
they write. They go on to conclude: “This represents only a small
fraction of the discovered systems, but it illuminates the
vastness and untapped potential of Earth’s biodiversity, and the
remaining candidates will serve as a resource for future
exploration.”
Hi @Gregory,
Yes, CRISPR has been used in many instances to try to target HBV and get rid of the virus DNA in the liver. In general, this has not been highly effective because there is just so much virus in the liver and this can target at most 90% of the virus. If there’s even one copy left over, then there is a chance that the virus infection just restarts itself. One of the issues has been getting the CRISPR into all the infected liver cells. Another issue is that you’re essentially breaking the DNA genomes, which can lead to all sorts of things happening (like precancerous mutations)
This may be a way to reduce the amount of virus in the liver in the far future, but in its current form, it may be at best an additional adjunct to a combination therapy.
Thomas
Hi @Gregory,
Thomas covered the applicability of this to HBV very well, so I’ll just commenton the biology of these gene editing mechanisms. They are part of the bacterial “immune systems” to protect the cells against invading DNA (transposons on plasmids acquired by conjugation, bacterial viruses). They were discovered only relatively recently, and I think that they are biologically exceptionally cool! Note that it is statistically certain that a huge diversity of such mechanisms exist, most of which are unknown adn some which are not CRISPR-related, in bacteria. The amount we don’t know about bacterial metabolism, genetics, and self-defense mechanisms vastly exceeds what we do know. There will undoubtedly be more discoveries of similar massive “coolness”, some of which will have medical implications.
John.
2 Likes
In addition to John’s comment, the search for new enzymes like this may still discover new molecular tools to target HBV in completely novel ways. So I don’t mean to be a dampener on this work, but what we have at the moment has not be terribly promising.
Thomas
Hello Dr. @ThomasTu @availlant @john.tavis
I just came across this article dated 1/11/2024 and was wondering if you have heard of it ( it’s from San Raffaelle hospital in Milan) the scientists involved are Dr. Matteo Iannacone and Dr. Luca Guidotti. I understand its a preclinical model but it sounds promising.
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For the first time in the world, an immunotherapy capable of combating chronic hepatitis B has been tested on preclinical models
01/11/2024
Immunotherapy could also prove to be an effective solution for the treatment of chronic hepatitis B, which afflicts over 300 million people worldwide and is among the primary risk factors for liver cirrhosis and liver cancer. In fact, it seems that interleukin-2 (Il2) is able to reactivate the immune system of the HBV virus infection, which normally becomes chronic precisely because the body’s defenses are unable to eradicate the virus, which continues to survive and reproduce. inside the liver cells.
The first tests in the world on the molecule were conducted on preclinical models by a group of researchers from the Irccs San Raffaele hospital in Milan and the Vita-Salute San Raffaele university, in collaboration with the American start-up Asher Biotherapeutics. The results are published in Science Translational Medicine.
Existing therapies
The hepatitis B virus – they recall from San Raffaele – is transmitted by contact with infected blood, sexually or from mother to child during childbirth. Unlike what happens when an adult contracts the virus, over 90% of children infected at birth develop the chronic form of hepatitis B. Today there is a preventive vaccine against the infection, but patients who have already contracted it do not have it can benefit.
The turning point
For them, a possible turning point comes from the study coordinated by Matteo Iannacone, director of the Division of Immunology, Transplants and Infectious Diseases of the Irccs San Raffaele hospital, who returned to Italy after a long experience in the United States thanks to the Career Development Award of the Armenise-Harvard Foundation . Iannacone’s research, in synergy with the unit directed by Luca Guidotti, deputy scientific director of San Raffaele, has contributed in recent years to developing some of the antivirals commonly used to treat hepatitis B in its chronic form.
Previous research
Already in 2019, with some data published in Nature, through a molecular analysis carried out thanks to intravital microscopy techniques, scholars had demonstrated that T lymphocytes are unable to eradicate Hbv infection and are dysfunctional since their activation. The characterization of dysfunctional T lymphocytes had also allowed the San Raffaele researchers to identify the most suitable and effective molecules for reawakening these cells.
The role of IL2
One is interleukin-2, a messenger molecule of the immune system, which acts as a sort of immunotherapy and has already been successfully tested both in cultured cells obtained from patient samples and in animal models. However, Il-2, when administered systemically, produces serious side effects, increasing the permeability of blood vessels and causing severe edema. This happens because the molecule not only acts on T lymphocytes, but also on Natural killer cells that induce toxicity, as well as on regulatory cells that inhibit the immune response. The new study bypasses these obstacles.
“cis-targeting”
The results just published in the journal Science Translational Medicine add a piece to those published in 2019. Thanks to the collaboration with the company Asher Biotherapeutics which produces interleukin-2, the researchers managed to experiment with this molecule, developing an approach called " cis-targeting”. That is, interleukin-2, conjugated with a specific antibody, is able to target only T lymphocytes, activating them correctly against the disease.
Open road to immunotherapy
“We have seen in mouse models of the disease that, by administering this type of immunotherapy, the T lymphocytes expand in number and increase their function, i.e. they release cytokines capable of inhibiting viral replication and eliminate the infected cells, effectively killing the virus ”, comments Iannacone.
The results have therefore demonstrated, in preclinical models of hepatitis B and in the blood of healthy people, the safety, low toxicity and therapeutic efficacy of this innovative approach. “In addition to antiviral approaches, it is possible to finally think about an immunotherapy strategy. The next step is to test this approach on humans, in combination with antivirals,” concludes the researcher.
The research was supported by the European Research Council (ERC), the Airc Foundation for cancer research, the Ministry of Health and the Ministry of University and Research.
Source: aboutpharma.com
1 Like
Yes, we are familiar with this work. It is quite promising.
Luca has been a colleague and friend for over 25 years. He is a truly outstanding scientist and is one of the leading immunologists in the world studying HBV. The HBV research community voted to award him the annual Distinguished Award in Hepatitis B Research in 2023 in recognition of his outstanding achievements.
2 Likes