Human Gene Therapy Products Incorporating Human Genome Editing

U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research, January 2024

As of January 2024, the Human Gene Therapy Products Incorporating Human Genome Editing: Guidance for Industry can be found here.

The HHS, FDA and CBER decided they needed to update guidance for industry on the subject matter of human gene therapy products incorporating human genome editing. I can’t imagine why.

This guidance represents the current ‘thinking’ of the FDA. I highlight some of the phrases that caught my attention in this document and did some translations and made some comments.

Viral vectors may support sustained expression of GE component transgenes, and nanoparticles may allow the temporal delivery of GE components as DNA, RNA, or proteins.

This sentence means that lipid nanoparticles can be used to deliver nucleotides in the form of RNA or DNA.

When administered in vivo in the form of DNA, RNA and/or protein via nanoparticles, the GE components are considered the active pharmaceutical ingredients or drug substances.

This sentence means that when you introduce the genetic material to a human being using lipid nanoparticles, the genome editing materials are active. I can think of at least one component discovered in the Pfizer products that this definition applies to: the SV40 promoter.

Additional testing, such as that for process residuals, should be included, depending on the manufacturing process. Descriptions of the analytical procedures utilized for GE component testing, including the sensitivity (e.g., limit of detection/quantitation) and specificity of the procedures, should be included in the IND.

This sentence means that subsequent testing for genetic material, like DNA that shouldn’t be there, should be done and that the detection methods should be included and necessarily, sufficient, to determine potential problems that may arise in vivo with regards to ‘off-target editing, unintended consequences of on-target editing, and the unknown long term effects of on- and off-target editing’.

For example, we recommend that potency assays for a genome edited CD34+ hematopoietic stem/progenitor cell product measure both the stem/progenitor cell activity and the biologically relevant outcome of the GE.

Agreed. Are we doing this in the context of the COVID modified mRNA injectable products?

Toxicities may be related to the human GE product, delivery method, and/or modification of the genomic structure. The safety assessment should include identification and characterization of on and off-target editing, chromosomal abnormalities, and their biological consequences.

Agreed. Are we doing this in the context of the COVID modified mRNA injectable products?

Assessment of bio-distribution should be conducted to characterize the distribution, persistence, and clearance of the GE product, any expressed GE components in vivo, editing activity in target and non-target tissues, and the potential for inadvertent germline modification. These evaluations may be conducted independently or in conjunction with POC and/or safety studies.

Agreed. Did we do this in the context of the COVID modified mRNA injectable products? No. We did not. Furthermore, the bio-distribution pharmacokinetic data is still being white-washed.

Assessment of genomic integrity, including chromosomal abnormalities, insertions or deletions, and potential oncogenicity or insertional mutagenesis.

Yes. This should be done considering that foreign DNA has been reproducibly found in the Pfizer and Moderna vials, and this is regardless of the amounts. The amounts are pretty much moot due to the fact that the detection methods and limits are not standardized to this particular administration technique - ie: the lipid nanoparticle human intramuscular delivery system.

[The] first-in-human trials involving such products generally should enroll only subjects for whom no other treatment options are available or justified.

Agreed. Since DNA was found in the vials only after billions of people were injected with potentially contaminated/adulterated products, it is absolutely necessary to determine whether this DNA has integrated into both germline and/or somatic cells because if this has occurred, then the above had been violated. It is also true that no informed consent could have been made and that ex post-facto law applies.

Assessment of Product-Related Adverse Events

A thorough safety monitoring strategy, with a well-defined toxicity grading system, and a toxicity management plan is crucial for clinical trials evaluating human GE products.

I think we all know where I stand on this. The modified mRNA product-related adverse events are by no means typical and a public inquiry in every country and on every continent is required to address the millions injured by these liability-free products.

Prior to enrolling subjects in a clinical study evaluating a human GE product, they should be asked to provide voluntary, informed consent to long term follow-up (LTFU). As discussed, the long-term safety and therapeutic effects of intended on-target editing, as well as off-target editing and unintended editing at the on-target loci may be unknown at the time of GE product administration.

Agreed. It has been known since the onset of the administration of these products that the long-term safety profile is unknown. This was an obvious observation made based on the fact that there were no long-term studies done due to imposed ‘emergencies acts’ and ‘operation warp speed’.

Therefore, we recommend that sponsors conduct LTFU for up to 15 years after product administration, as outlined in FDA’s Long Term Follow-Up After Administration Contains Non-binding Recommendations 15 of Human Gene Therapy; Guidance for Industry (Ref. 10)

15 years. Agreed. This sounds like a good time-frame to assess long-term potential problems.

Additionally, accelerated approval may be an appropriate pathway for approval of a human GE product intended to treat a serious or life-threatening disease or condition, where there is a lack of available alternative treatments.

Interestingly, in the case of the COVID era, there were many alternative treatments including steroids, IVM and quinine derivatives, not to mention natural immunity. Acceleration of the COVID injections should NOT have occurred.

Here is where it gets even more disturbing to me.

For clinical investigations involving children, associated with greater than minimal risk, a reviewing Institutional Review Board must find, among other things, that these risks are justified by the anticipated direct clinical benefit to the children (21 CFR 50.52).

Sure. We do not want to impose risk on our kids. Since COVID-19 was never a risk to our kids, they should never have been considered for experimental injections - regardless of whether or not they qualify as potential genetic alteration products. Period. Hands off the kids. Now these as-yet experimental products are getting on the childhood vaccination schedule in the United States.

Read on.

Therefore, it is important to enroll at least an initial cohort of adult subjects, whenever feasible, to obtain preliminary data on safety and feasibility, bioactivity, and preliminary efficacy to support enrollment of children. If enrollment of children is justified based on the benefit-risk assessment, then an effort should be made to enroll adolescents prior to enrollment of younger children and infants, as appropriate for the specific disease of interest. See the draft guidance entitled “Ethical Considerations for Clinical Investigations of Medical Products Involving Children; Draft Guidance for Industry, Sponsors, and IRBs,” September 2022 (Ref. 13) for additional recommendations on including pediatric subjects in cell and gene therapy trials.

The sentence means: 1. inject adults, 2. then teenagers, 3. then young children, in this order. Sounds familiar doesn’t it?

— End of document quotes —

I have been looking into this specific subject matter for years and every time I read a document even remotely connected to it, or the relevant involved entities, my alarm bells go off. I must ask the question: what if the FDA, HHS and CDC knew that the modified mRNA products were potentially ‘products incorporating genome editing (GE) of human somatic cells’? What about germline cells?

The fact of the matter is that we DO NOT KNOW. Nobody does. Because nobody checked/is checking.

There are many excellent scientists publishing data every day with concerning results pertaining to the unexamined effects of the modified mRNA injections, and some of this data pertains to human genome modification. Since HHS, FDA, CDC, HC and the EMA know about SV40 in particular (they always had the power to know), then why are they all dismissing the potential dangers/risks? Is it because admitting even a potential risk will create a panic? Will it forever damage their upcoming program? If the plan is to use the lipid nanoparticle nucleotide delivery platform to ‘cure diseases’ like cancer, then come hell or high water, this program needs protecting! I mean, just think of all of those poor investors who would go under if their program went under.

This whole thing makes me sick to my stomach because it is so obvious that people are being sacrificed for profit. For programs. For the ‘greater good’. What does that even bloody mean? What greater good? If our genomes are being modified - even at the somatic cell level - then finding out and preventing this sounds to me like serving a greater good. Does it not to you? I reiterate what I said to Jan Jekielek in our recent interview, I believe that this entire COVID thing was the segue required to test a prototype. The prototype is the platform.

Compliance also needed to be tested. Boy, did they get it. Some people still think there’s nothing wrong in the world. In Canada, it is going far beyond compliance testing - people are being treated, and tried, like criminals for simply talking. For simply reporting on what the actual criminals are doing. For simply disagreeing with grandmaster rainbow hairboy plus.

My advice is to talk your faces off to anybody and everybody about this subject matter and to demand answers to questions from your MPs. Do FOIAs, write letters and read as much as you can while we still can. Use social media while you still can to post scientific papers and information. Use video platforms that don’t discriminate and censor to disseminate educational videos.

The censorship campaign is roaring ahead. Fight it while you can. Read about CRISPR/cas.¹

Keep your books. Write everything down. Keep fighting.

1. CRISPR-Cas9 was adapted from a naturally occurring genome editing system that bacteria use as an immune defense.