Ivermectin & CRISPR Treats Genetic Disease

In this episode, we are going to talk about a new breakthrough in CRISPR technology and Ivermectin.

CRPSIR Injected Into Bloodstream treats a Genetic Disease for the First Time

Ever since we started to talk about CRISPR-Cas9, they have been pushing the boundaries of genome modifications. Just in May researchers were using CRISPR to fix cholesterol in monkeys. 

Just last year, researchers used CRISPR to turn on a fetal form of hemoglobin to correct sickle cell disease or related disease in several people. The treatment required removing a patient’s diseased blood stem cells, modifying them with CRISPR in a dish, and then infusing them back into the body.

The new major breakthrough in gene modification, researchers at University College London (UCL) injected CRISPR into the blood of six people with a genetic condition between the ages 46 and 64. Three of those people showed positive results, creating the opportunity to further trials using this approach. 

The genetic condition is known as transthyretin amyloidosis (TRR). Amyloidosis is a protein misfolding disorder. In this disease, proteins change shape (misfold), then bind together and form amyloid fibrils which deposit in organs. They frequently occur in the peripheral nervous system, which results in a loss of sensation in the extremities (peripheral neuropathy). The autonomic nervous system, which controls involuntary body functions such as blood pressure, heart rate, and digestion, may also be affected by amyloidosis.

These amyloid fibrils usually deposit in:

  • The wrist is called the carpal tunnel. This can cause carpal tunnel syndrome, which causes your hand and arm to become numb and tingle.
  • The spinal canal, which can cause narrowing of the spinal column (spinal stenosis).
  • The heart, which can cause heart failure and/or an irregular heart rhythm called atrial fibrillation.
  • Carpal tunnel syndrome and spinal stenosis can develop several years before heart failure.

Most CRISPR-related treatments involve treatment of the cells in-vitro, injecting into the target organ. This study was different because it required a mode of transport of the whole editing assembly inside the cells. Researchers at Regeneron Pharmaceuticals used messenger RNAs (mRNAs), which carry instructions for making proteins. Since the host cell can use the mRNAs to make its own proteins, researchers simply needed to send enough information to enable CRISPR editing inside the cell.

They injected two messenger RNAs (mRNAs), one identified the mutation on the TTR gene and one made the Cas protein that can cut the DNA at the directed site. It also made it easier for the researchers, since the liver is the site of origin for the disease. 

The mRNAs were encased in lipid particles, which were taken up by the liver cells, allowing the mRNAs entry inside the cell. Once there, the cellular machinery made the necessary Cas protein, which cut the mutation site recognized by the other mRNA. The in-house DNA repair mechanism kicks in and repairs the cut site but this time, leaves the gene out, thereby stopping the production of misfolded protein. 

After 28 days, three men given the higher of two doses of the treatment had an 80% to 96% drop in TTR levels, better than the average of 81% with Patisiran, the current treatment for TTR. This new RNA silences TRR’s production temporarily meaning it must be injected on a regular basis. 

Patisiran (ONPATTRO) costs $13,022 per vial. The annual cost is between $451,430 and $677,145 per patient depending on the weight of the patient.

Jennifer Dounda who last year shared a Nobel prize for developing the gene editor CRISPR says “a critical first step in being able to inactivate, repair, or replace any gene that causes disease, anywhere in the body.”

https://my.clevelandclinic.org/health/diseases/17855-amyloidosis-attr

https://www.ncbi.nlm.nih.gov/books/NBK549697/#:~:text=Patisiran%20is%20supplied%20in%20single,cost%20of%20%2413%2C022.02%20per%20vial.&text=The%20annual%20cost%20is%20between,kg

Ivermectin in the Fight against COVID 19

Ivermectin is being talked about in greater numbers. Research is coming out this antiparasitic drug might be used for covid 19 in prophylaxis and even in possible treatment. It seems that ivermectin interferes with COVID 2 possible ways.

  1. Reports from in vitro studies suggest that ivermectin acts by inhibiting the host importin alpha/beta-1 nuclear transport proteins, which are part of a key intracellular transport process that viruses hijack to enhance infection by suppressing the host’s antiviral response.
  2. Ivermectin docking may interfere with the attachment of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein to the human cell membrane. 

https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ivermectin/

Interesting facts: 

  • Between 1995 and 2010 the program using donated ivermectin to prevent river blindness is estimated to have prevented seven million years of disability whilst costing US$257 million.
  • Costs about 7 dollars per pill and generics are available. 

What is the research showing

  1. Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen
    1. Examined the antiviral properties of Ivermectin
    2. Ivermectin proposes many potential effects to treat a range of diseases, with its antimicrobial, antiviral, and anti-cancer properties as a wonder drug.
      1. In this comprehensive systematic review, the antiviral effects of ivermectin are summarized including in vitro and in vivo studies over the past 50 years. Several studies reported antiviral effects of ivermectin on RNA viruses
        1. There are some studies showing antiviral effects of ivermectin against DNA viruses
      2. Ivermectin plays a role in several biological mechanisms, therefore it could serve as a potential candidate in the treatment of a wide range of viruses including COVID-19 as well as other types of positive-sense single-stranded RNA viruses.
      3. https://pubmed.ncbi.nlm.nih.gov/32533071/
  2. Ivermectin, a US Food and Drug Administration-approved anti-parasitic agent, was found to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in vitro.
    1. The trial included 72 hospitalized patients in Dhaka, Bangladesh, who were assigned to one of three groups: 
      1. oral ivermectin alone (12 mg once daily for 5 days.
      2. oral ivermectin in combination with doxycycline (12 mg ivermectin single dose and 200 mg doxycycline on day 1, followed by 100 mg every 12 h for the next 4 days)
      3. A placebo control group. 
    2. Results: 
      1. Clinical symptoms of fever, cough, and sore throat were comparable among the three groups. 
      2. Virological clearance was earlier in the 5-day ivermectin treatment arm when compared to the placebo group (9.7 days vs 12.7 days; p = 0.02), but this was not the case for the ivermectin + doxycycline arm (11.5 days; p = 0.27). 
      3. There were no severe adverse drug events recorded in the study. A 5-day course of ivermectin was found to be safe and effective in treating adult patients with mild COVID-19.
      4. https://pubmed.ncbi.nlm.nih.gov/33278625/
  3. Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19
    1. A large majority of randomized and observational controlled trials of ivermectin are reporting repeated, large magnitude improvements in clinical outcomes. Numerous prophylaxis trials demonstrate that regular ivermectin use leads to large reductions in transmission.
    2. Results:
      1. Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID-19 have found large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance. 
      2. Results from numerous controlled prophylaxis trials report significantly reduced risks of contracting COVID-19 with the regular use of ivermectin. 
      3. The many examples of ivermectin distribution campaigns leading to rapid population-wide decreases in morbidity and mortality indicate that an oral agent effective in all phases of COVID-19 has been identified.
      4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088823/

 

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