Preclinical siRNA Targeting TMPRSS6 is a Potential Disease-Modifying Treatment for Polycythemia Vera.
« We look forward to initiating IND-enabling studies this year with the aim of delivering a transformative treatment option for this patient community with profound unmet need »
Good stuff. I think this is the or one of the gene based agents that target hepcidin discussed in a prior post. In that manner similar to Rusfertide that's in phase 3. But seems it gets there at a deeper level.
But they make this statement:
"PV is a rare hematologic disease with no disease-modifying treatments.."
From what I can see this new agent is not disease modifying as they claim to be the 1st of. It controls HCT, which is very useful. But it does not affect the lower level mutation at Jak2 for example.
Most of us need to control other things along with HCT so this could remain an adjunct to current therapies.
In contrast IFN and Rux can for many be disease modifying if using the modern definition of allele reductions and marrow effects.
Hi EPguy,
What makes you think it won’t affect the jak2 allele burden ?
The siRNA does seem to be a powerful new method, I guess part of the general revolution in using RNA for therapeutics, ie mRNA vaxes.
Regarding what this version is for, this part seems to explain well. It targets hepcidin which we have seen is all about RBC and thus HCT control. Further it says "low off target activity". Usually a good thing but here it also points no action beyond increasing hepcidin.
"This (the new siRNA) results in increased hepcidin,..., thereby reducing red blood cell production. This has the potential to maintain hematocrit within the normal range and reduce the risk of complications in individuals living with PV. TMPRSS6 siRNA has demonstrated low off-target activity"
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This is the same effect via a different path for Rusfertide:
"rusfertide (PTG-300), (is)a potent hepcidin mimetic(imitator) .." So Rusf makes fake extra hepcidin while the new siRNA makes more of the real thing, both leading to RBC control.
"ashpublications.org/blood/a...
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Rusf is not being promoted as a fix-all, while the new siRNA is. But I can't can't see the global difference except that the siRNA seems a more pure approach to hepcidin modulation.
In contrast, inhibiting Jak2 (via IFN, Rux) seems to me a lower level deeper effect while hepcidin levels are a higher level effect of the mutation.
In my case I'm hoping for some of Rux's off target activity to also help with my autoimmune.
You wrote: »Rusf is not being promoted as a fix-all, while the new siRNA is. But I can't can't see the global difference except that the siRNA seems a more pure approach to hepcidin modulation ».
I’m not about Rusfertide, but siRNA might have some advantages over ruxolitinib, such as:
- **More selective**: siRNA can target the specific mutations or variants of JAK2 that are present in different patients or subclones of polycythemia vera, while ruxolitinib inhibits both normal and abnormal JAK1 and JAK2, which may cause unwanted side effects or resistance¹.
- **More durable**: siRNA can potentially induce long-term or irreversible silencing of the target genes, while ruxolitinib requires continuous administration to maintain its effect².
- **More versatile**: siRNA can target other genes that are implicated in polycythemia vera, such as TMPRSS6 or hepcidin, which regulate iron metabolism and affect anemia and inflammation³. Ruxolitinib has no effect on these genes.
However, siRNA also faces many challenges and limitations, such as delivery, specificity, regulation, safety, and efficacy. Therefore, more research is needed to compare the effectiveness of siRNA and ruxolitinib for polycythemia vera.
(1) The Next Generation of JAK Inhibitors: an Update on Fedratinib .... link.springer.com/article/1....
(2) New Concepts of Treatment for Patients with Myelofibrosis. link.springer.com/article/1....
(3) The Next Generation of JAK Inhibitors: an Update on Fedratinib .... link.springer.com/content/p....
You wrote: « In contrast IFN and Rux can for many be disease modifying if using the modern definition of allele reductions and marrow effects ».
This what ChatGPT has to say about this topic: « Both siRNA and rusfertide can potentially reduce the JAK2 allele burden in patients with polycythemia vera, but the evidence is limited and inconsistent.
siRNA is a type of gene therapy that can target and silence the JAK2 gene, which is mutated in about 98% of patients with polycythemia vera¹². By inhibiting the expression of JAK2, siRNA can reduce the activation of downstream signaling pathways that promote the growth and survival of abnormal blood cells. This can potentially lower the JAK2 allele burden, which is the percentage of mutated JAK2 copies in the total JAK2 copies. However, the clinical efficacy and safety of siRNA for polycythemia vera are still under investigation, and there are only a few studies that have tested siRNA in patients with polycythemia vera. One study reported that siRNA targeting JAK2 reduced the JAK2 allele burden by 50% in cell lines and by 30% in CD34+ cells from patients¹. Another study reported that siRNA targeting TMPRSS6, a negative regulator of hepcidin expression, reduced the JAK2 allele burden by 20% in cell lines and by 10% in CD34+ cells from patients². However, these studies used different siRNA molecules, delivery methods, and outcome measures, and they did not evaluate the long-term effects or clinical benefits of siRNA therapy.
Rusfertide is a synthetic peptide that mimics the natural hormone hepcidin, which regulates iron metabolism and affects anemia and inflammation³. Rusfertide binds to the iron transporter ferroportin, causing its internalization and degradation, and reducing the plasma iron levels. This can potentially lower the JAK2 allele burden by inducing iron deficiency, which has been shown to suppress the proliferation of JAK2-mutated cells⁴. However, the clinical efficacy and safety of rusfertide for polycythemia vera are also still under investigation, and there are only a few studies that have tested rusfertide in patients with polycythemia vera. One study reported that rusfertide reduced the JAK2 allele burden by 10% in patients with polycythemia vera after 12 weeks of treatment⁵. Another study reported that rusfertide reduced the JAK2 allele burden by 8% in patients with polycythemia vera after 24 weeks of treatment. However, these studies used different doses, durations, and outcome measures of rusfertide therapy, and they did not evaluate the long-term effects or clinical benefits of rusfertide therapy.
Therefore, both siRNA and rusfertide can potentially reduce the JAK2 allele burden in patients with polycythemia vera, but the evidence is limited and inconsistent. More research is needed to compare the effectiveness of siRNA and rusfertide for polycythemia vera »
(1) Selective reduction of JAK2 V617F -dependent cell growth by siRNA/shRNA .... ashpublications.org/blood/a....
(2) JAK2 V617F Mutation Allele Burden (MAB) and Its Correlation with .... ashpublications.org/blood/a....
(3) Clinical features and outcomes of JAK2 V617F-positive .... bloodresearch.or.kr/journal....
(4) undefined. doi.org/10.1182/blood-2008-....
(5) undefined. doi.org/10.1182/blood.V130.....
Agree, siRNA should be great for various other defined targets. It is surprising that it has not yielded more magic so far.
For now it seems the only current progress re MPNs is the hepcidin path. Hepcidin is recently found to be useful for RBC control and it seems once knowing this there are various ways to take advantage. (Rusf, SiRNA...) This will be useful for example when IFN cannot get HCT low enough or for a PV pt who is abnormal only for HCT.
The title of the 1st link (4th is the same) "Selective reduction of JAK2 V617F -dependent cell growth by siRNA/shRNA" is exciting. But I see its date is 2009 and it's in vitro. When I search this most links are about this age. Usually absence of new results, and clustering around a certain old time, means it did not yield actionable results for clinical study. Also could be just the researchers lost the funding lottery. But by now some money should have come up with all that Cancer designation attention.
We know that Jak2 allele is esp tricky being hard to identify in vivo since it has min unique surface features. But maybe CALR will be a great near term candidate for SiRNA as it does have such features.
One pattern seems to be SiRNA is used a lot for identifying genes in research.
Agree on this one "...while ruxolitinib inhibits both normal and abnormal JAK1 and JAK2"
For pure MPN a more targeted Jak-i should be better. In my case and others with autoimmune issues, this wider action is likely a feature rather than a bug, my MPN doc said this too. Jak-is are used for some autoimmunes. It's part of my hope for some control of my Sjogren's.
Regarding siRNA and according to the web search results, exosomes have been used as vectors for siRNA delivery for about 11 years only, and rarely on MPN. So, I suppose we’ll know more about this approach once the IND-enabling studies mentioned on the top of this thread will be launched.
“IND-enabling studies are studies that are conducted to evaluate the potential toxicity risks of a new drug before it can be tested in humans. They are required by the FDA and other regulatory authorities to ensure the safety and efficacy of the drug. IND-enabling studies include various types of assessments, such as pharmacology, pharmacokinetics, and toxicology. These assessments help to define the pharmacological and toxicological properties of the drug, such as its effects on different organs and systems, its absorption, distribution, metabolism, and excretion, and its dose and exposure dependencies. IND-enabling studies also help to estimate the safe starting doses and dose ranges for clinical trials, and to identify the key parameters for monitoring the drug's effects in humans. ¹²
(1) IND-Enabling Studies | Charles River. criver.com/products-service....
(2) Key IND-Enabling Studies Required for IND Approval - Allucent. allucent.com/resources/blog....
(3) IND-Enabling Studies Definition: 122 Samples | Law Insider. lawinsider.com/dictionary/i....
siRNA stands for **small interfering RNA**. It is a type of RNA molecule that can interfere with the expression of specific genes by binding to their complementary messenger RNA (mRNA) and preventing them from being translated into proteins. ¹²
siRNA is part of the natural process of RNA interference (RNAi), which regulates gene expression in many organisms. Scientists can also use synthetic siRNA to study gene function or develop new treatments for diseases by silencing harmful or overactive genes. ¹³
siRNA has a well-defined structure that consists of a short (usually 20 to 24 base pairs) double-stranded RNA with phosphorylated 5' ends and hydroxylated 3' ends with two overhanging nucleotides. The enzyme Dicer produces siRNA from long double-stranded RNA or small hairpin RNA.
The mechanism of siRNA-mediated gene silencing involves the following steps:
- The siRNA is recognized and incorporated into a protein complex called RISC (RNA-induced silencing complex) in the cytoplasm of the cell.
- The RISC complex becomes activated by unwinding the siRNA and discarding the sense strand (the strand that matches the target mRNA).
- The activated RISC complex binds to the target mRNA by complementary base pairing between the antisense strand of the siRNA and the mRNA.
- The RISC complex cleaves the target mRNA at the site of binding, resulting in its degradation and preventing its translation into protein.
siRNA is a powerful tool for biomedical research and drug development, as it can potentially target any gene of interest and modulate its expression. However, there are also some challenges and limitations associated with siRNA, such as:
- Delivering siRNA efficiently and specifically to the desired cells and tissues.
- Avoiding off-target effects and immune responses caused by siRNA.
- Achieving long-term and stable gene silencing with siRNA. ²³
Several clinical trials are underway to test the safety and efficacy of siRNA-based therapies for various diseases, such as cancer, viral infections, genetic disorders, and cardiovascular diseases. ³⁴
(1) Small interfering RNA - Wikipedia. en.wikipedia.org/wiki/Small....
(3) What is SiRNA? - News-Medical.net. news-medical.net/life-scien....
NICE Final Guidance on Ruxolitinib for the treatment of Polycythaemia Vera
Besremi - NHS
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