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Proposal for Chimeric Gene Therapy (v1.3.1) – Curing Trauma, Addiction, and Conditioning – Paper by Kyrtin Atreides

Proposal for Chimeric Gene Therapy (v1.3.1) – Curing Trauma, Addiction, and Conditioning – Paper by Kyrtin Atreides

Kyrtin Atreides


Editor’s Note: The U.S. Transhumanist Party has published this research paper and proposal for a practical gene therapy by member Kyrtin Atreides in order to solicit input from other researchers in the field of gene therapy as well as to provide some ideas for further directions in research and practical applications of genetic engineering. The U.S. Transhumanist Party does not itself conduct research or recommend particular medical procedures, so the publication of this paper should be seen as promoting the exploration of research paths that could one day (hopefully sooner rather than later) materialize into viable treatments for curing diseases and lengthening lifespans. 

~ Gennady Stolyarov II, Chairman, United States Transhumanist Party, April 1, 2018

Introduction:

A wise medical director once told me that 50% of those who go into the field of Psychology need psychological help themselves. I suspect that one day I’ll be able to say the same of genetic engineering.

Epigenetics control our neurochemistry, which dictates base level reactions to stimuli, and everything from a bad meal, job, relationship, or traumatic childhood event, to warzone PTSD, can trigger epigenetic changes. [1] De Bellis, M. D., & A.B., A. Z. (2014), [2] Gudsnuk, K., & Champagne, F. A. (2012), [3] Hardy, T. M., & Tollefsbol, T. O. (2011)

Over time these changes build up, and since human society is often highly unstable due to rapid and lopsided progression, the net result is cumulative damage, similar to aging, because epigenetics attempt to attune you to an environment that doesn’t change in compatible ways. [4] Bowers, E. C., & McCullough, S. D. (2017)

What this means is that in order to roll back the clock the epigenetic equation needs to be recalculated in a local space, a process which occurs with a viral knockout, or insertion of new genetic data, within a region surrounding any given gene. The basic idea is that if you alter the dimensions of the space that the epigenetic equation covers via methylation, you cause it to recalculate the ideal distribution and genetic activation for that region based on current data, rather than the trauma which previously altered it.

By causing this update to take place, the gene expression is recalculated to values which are more closely aligned with current needs and environmental factors. Previously in human history, lives were shorter and epigenetic influences served a healthy role in promoting survival, but the problem with amassing a large pile of trauma-induced epigenetic changes becomes acutely apparent as age increases.  [5] Teschendorff, A. E., West, J., & Beck, S. (2013)

Each change is based on data fixed to the point of trauma, and any alteration to that expression is glacially slow, if it occurs at all. Often times such changes break an element of neurochemistry in the sense that the change can’t naturally reverse itself once it has been made, but it can be easily reversed with minor engineering.

Different genes act like functions in code, separate blocks which can function together, but which also contain sites where new code can be placed without causing harm to the current code. In the same way the human genome also contains 8% integrated viral DNA, which makes for an ideal target for gene knock-out.  [6] (International Human Genome Sequencing Consortium, 2001; Smit, 1999)

Proposal Part 1:

What I propose is two-fold. The first step is the creation of a gene therapy which is practically viable, costing no more than $5 per person in production. The second step is testing the top gene sites active in controlling neurochemistry with both knock-out of viral DNA, and knock-in of dormant placeholder DNA, to cause recalculation to take place.

The first is easily accomplished by understanding the nature of why anything evolves in the first place, for survival. If you create a gene therapy whose survival is guaranteed it loses reason to adapt maliciously, because there is no advantage to be gained. A classic case that demonstrates a virus becoming less lethal over time is HIV, where initially it was a death sentence, but over time not only were treatments developed, the virus became less lethal, because that lethality was acting as a detriment to the purpose of survival, and it evolved in order to live longer. [7] Payne, R., Muenchhoff, M., Mann, J., Roberts, H. E., Matthews, P., Adland, E., … Goulder, P. J. R. (2014)

The myriad of bacteria, archaea, viruses, and eukaryotic microbes in our bodies that outnumber our own cells have come to a balanced state, where our bodies are the ecosystem, and as that 8% viral DNA demonstrates a virus is no different, it favors survival and a stable environment. [8] Eloe-Fadrosh, E. A., & Rasko, D. A. (2013)

I mention this because of a key factor which makes gene therapy completely impractical today, 293T cells. Having to use specialty cells for cloning a virus that isn’t replication-competent, and is often very fragile to begin with, is one monumental waste, which is built on the unfounded fear that a replication-competent virus is in and of itself a threat. As machine learning is applied to the human genome, as well as non-human genomes, the error in that line of reasoning will become increasingly apparent.

What we need is a new gene therapy, engineered for high conversion rates, such as Adeno-Associated-Virus-7 or Lentivirus, and hybridized with a more durable, low-symptom (“clinically silent”), low-transmission-potential virus, such as Epstein-Barr Virus. By making such a virus replication-competent, but also self-inactivating (EBV) and able to integrate itself as a genetic landing site capable of being periodically updated, not only is the problem of practicality and cost solved, but the speed with which new research can be tested is greatly accelerated, and the virus is rendered stable. EBV in particular is already present in roughly 95% of adults, as it has integrated with their genomes. When combined with revised best practices any risk of bad-actor genetic engineering remains a practical impossibility.

By keeping the intermediate stages of the gene therapy in a controlled environment and only releasing the end result beyond that point, the Bio-Safety risk remains functionally unchanged, as the hypothetical “bad actor” would still require the same advanced tools, knowledge, and materials to generate a harmful virus as they already do today. The key difference in Bio-Safety terms is that by allowing the field to advance, the benefits and possible means of defense against that hypothetical would move forward, while undermining the root cause of said hypotheticals. This would be roughly equivalent to creating bulletproof sleepwear before the invention of the firearm.

The end result of utilizing such a gene therapy would be a symbiotic relationship with a genetic update mechanism, where increases to lifespan and survival rates favor both parties, resulting in potential rare mutations that better serve that purpose, like a bird evolving a better beak for catching fish.

Selection of EBV to hybridize with Lentivirus would also allow for the therapy to enter dormant cycles, avoiding immune-system rejection, and reactivating when introduced to engineered updates from additional gene therapy treatments. [9] Houldcroft, C. J., & Kellam, P. (2015)

The replication-competent gene therapy can be created with either AAV-7 or Lentivirus by means of recombination during the manufacturing process. An AAV-2 or AAV-7 variant may be preferable, if not required, for the treatment of HIV-positive humans due to the risk of interaction between any Lentivirus gene therapy and the HIV virus. It is however probable that a Lentivirus/EBV chimeric gene therapy would overwrite wild HIV virus variants rather than being overwritten by them, but rigorous testing is required, which development of this therapy would also make possible. This is partly due to the far greater size, complexity, and long-term stability of EBV compared to Lentivirus. [10] Haifeng Chen. (2015)

On a side note the genetics study that led me to realize this epigenetic mechanic was in play is shown here:

[11] Welle, S., Cardillo, A., Zanche, M., & Tawil, R. (2009)

It was by examining the difference between an adult with gene knock-out applied after maturation versus one born with the modification that the mechanic of Methylation Dimensions / Dimensions of DNA was illuminated. Since this process occurs naturally as a part of viral integration, a mechanic had to evolve that could handle the recalculation. The above study also highlights that gene therapies shouldn’t be administered to individuals prior to adulthood, due to the differences in how they impact an individual prior to biological maturation, unless the need is dire, or unless the difference can be corrected upon maturation.

Another failing point of gene therapies as they exist today is that, due to the lack of replication-competence, viral titers act as a choke-point, where the virus is injected in-mass rather than gradually converting cells, massively increasing the risk of cellular toxicity and immunotoxicity. If a gene therapy was replication-competent, even an extremely low dose could achieve a high level of cellular conversion over a period of time, potentially closing in on Bayes Error, regardless of host mass. In effect, the same dose that yields positive results in a mouse could also work for a human. [12] White, M., Whittaker, R., Gándara, C., & Stoll, E. A. (2017)

Proposal Part 2:

Once the new gene therapy is complete, the ability to repair damage at the epigenetic level becomes practical, speeding up the testing process by an order of magnitude, as well as greatly reducing cost.  For the purpose of initial testing and separation of documented effects, knock-out of viral DNA and placeholder-gene knock-in will be targeted to recalculate small regions surrounding key neurochemistry controlling genes, a few of which I’ve listed below:

HTR6 – Chromosome 1 – (5-Hydroxytryptamine Receptor 6) is a Protein Coding gene.  Diseases associated with HTR6 include Acute Stress Disorder and Amnestic Disorder.

NR4A2 – Chromosome 2 – (Nuclear Receptor Subfamily 4 Group A Member 2) is a Protein Coding gene. Diseases associated with NR4A2 include Arthritis and Late-Onset Parkinson Disease. Among its related pathways are Dopaminergic Neurogenesis and Corticotropin-releasing hormone signaling pathway. GO annotations related to this gene include transcription factor activity, sequence-specific DNA binding, and protein heterodimerization activity. An important paralog of this gene is NR4A3.

HES1 – Chromosome 3 – (Hes Family BHLH Transcription Factor 1) is a Protein Coding gene. Among its related pathways are Signaling by NOTCH1 and NOTCH2 Activation and Transmission of Signal to the Nucleus. GO annotations related to this gene include transcription factor activity, sequence-specific DNA binding, and sequence-specific DNA binding. An important paralog of this gene is HES4. [13] Epigen Global Research Consortium(2015)

DRD5 – Chromosome 4 – (Dopamine Receptor D5) is a Protein Coding gene.  This receptor is expressed in neurons in the limbic regions of the brain. It has a 10-fold higher affinity for dopamine than the D1 subtype.

SLC6A3 – Chromosome 5 – (Solute Carrier Family 6 Member 3) is a Protein Coding gene. Diseases associated with SLC6A3 include Parkinsonism-Dystonia, Infantile and Nicotine Dependence, Protection Against.

DRD1 – Chromosome 5 – (Dopamine Receptor D1) is a Protein Coding gene.  Diseases associated with DRD1 include Cerebral Meningioma and Drug Addiction.

TAAR1 – Chromosome 6 – (Trace Amine Associated Receptor 1) is a Protein Coding gene. Although some trace amines have clearly defined roles as neurotransmitters in invertebrates, the extent to which they function as true neurotransmitters in vertebrates has remained speculative. Trace amines are likely to be involved in a variety of physiological functions that have yet to be fully understood.

DDC – Chromosome 7 – (Dopa Decarboxylase) is a Protein Coding gene. Among its related pathways are Dopamine metabolism and Metabolism.

CRH – Chromosome 8 – CRH (Corticotropin Releasing Hormone, aka CRF) is a Protein Coding gene. Diseases associated with CRH include Crh-Related Related Nocturnal Frontal Lobe Epilepsy, Autosomal Dominant and Autosomal Dominant Nocturnal Frontal Lobe Epilepsy. Among its related pathways are G alpha (s) signalling events and Signaling by GPCR. GO annotations related to this gene include receptor binding and neuropeptide hormone activity. [14] Sandman CA, Curran MM, Davis EP, Glynn LM, Head K, Baram TZ.(2018)

HTR7 – Chromosome 10 – (5-Hydroxytryptamine Receptor 7) is a Protein Coding gene. Diseases associated with HTR7 include Autistic Disorder and Byssinosis.

ETS1 – Chromosome 11 – (ETS Proto-Oncogene 1, Transcription Factor) is a Protein Coding gene. Among its related pathways are Photodynamic therapy-induced NF-kB survival signaling and MAPK-Erk Pathway. GO annotations related to this gene include transcription factor activity, sequence-specific DNA binding and transcription factor binding. An important paralog of this gene is ETS2.

HTR2A – Chromosome 13 – (5-Hydroxytryptamine Receptor 2A) is a Protein Coding gene. Diseases associated with HTR2A include Schizophrenia and Major Depressive Disorder and Accelerated Response to Antidepressant Drug Treatment.

SLC6A4 – Chromosome 17 – (Solute Carrier Family 6 Member 4) is a Protein Coding gene. Diseases associated with SLC6A4 include Obsessive-Compulsive Disorder and Slc6a4-Related Altered Drug Metabolism.

TCF4 – Chromosome 18 – (Transcription Factor 4) is a Protein Coding gene. Among its related pathways are Mesodermal Commitment Pathway and Regulation of Wnt-mediated beta catenin signaling and target gene transcription. GO annotations related to this gene include transcription factor activity, sequence-specific DNA binding and protein heterodimerization activity. An important paralog of this gene is TCF12.

OXT – Chromosome 20 – (Oxytocin/Neurophysin I Prepropeptide) is a Protein Coding gene. This gene encodes a precursor protein that is processed to produce oxytocin and neurophysin I. Oxytocin is a posterior pituitary hormone which is synthesized as an inactive precursor in the hypothalamus along with its carrier protein neurophysin I. Together with neurophysin, it is packaged into neurosecretory vesicles and transported axonally to the nerve endings in the neurohypophysis, where it is either stored or secreted into the bloodstream. The precursor seems to be activated while it is being transported along the axon to the posterior pituitary. This hormone contracts smooth muscle during parturition and lactation. It is also involved in cognition, tolerance, adaptation, and complex sexual and maternal behavior, as well as in the regulation of water excretion and cardiovascular functions.

AVP – Chromosome 20 – (Arginine Vasopressin) is a Protein Coding gene. Diseases associated with AVP include Diabetes Insipidus, Neurohypophyseal and Hereditary Central Diabetes Insipidus. Among its related pathways are G alpha (s) signalling events and HIV Life Cycle. GO annotations related to this gene include protein kinase activity and signal transducer activity. An important paralog of this gene is OXT.

These genes represent only a fraction of the neurochemistry control sites, but they are disproportionately represented in terms of impact due to being frequently targeted by a wide variety of damaging sources focused on addiction, conditioning, reward-behaviors, and various forms of trauma.  By changing the dimensions of a region that methylation, phosphorylation, acetylation, and histone modification have to cover the recalculation is triggered and optimized to the current environment. [15] Tuesta, L. M., & Zhang, Y. (2014), [16] Samonte FGR.(2017)

It is also worth noting that in the case of more extreme imbalances two or more gene targets would either need to be iteratively, or simultaneously, recalculated in order to reach a balanced state. By using one gene therapy, then a second on the parallel site, such as the case with OXT vs. AVP balance, you could iteratively progress towards a balanced state with less extreme gene expression levels, like turning the sides of a Rubik’s Cube. Using multiple versions of the same gene therapy, attaching to different target sites, this process could be activated simultaneously, causing the recalculation to factor in all discovered and targeted regions at once, effectively “training” the epigenetic weights of highly connected regions, instead of working iteratively where half of them are frozen at any given time. Initially this simultaneous trigger could be via standard injection, but it could also be automated a variety of ways, including using links to circadian rhythm conditions and seasonal changes, causing routine recalculation of mental and emotional health critical gene expression. [17] Neumann, ID, Landgraf R.(2012)

Since none of the genes are directly impacted, only recalculating their level of activation, risk is kept to a bare minimum, and the same approach can be repeated to yield different results by varying the conditions present as the gene therapy takes effect.  Ideal circumstances for any given outcome can be established by varying environmental factors until the result is optimized, potentially even personalized, and though this approach would be ideally suited for a laboratory environment, it could also help to establish best-practices for administering the gene therapies once they reached human trials.

Results of epigenetic recalculation could be further utilized for mathematically modeling the potential space of gene activation when coupled with environmental data from the trial facility, increasing prediction accuracy for post-therapy gene expression, as well as the subsequent benefits.

The before-versus-after comparison between fully mapped genomes could also be used in Deep Neural Network terms to generate accurate predictions for post-therapy gene activation levels and the approximate benefits of those changes. A DNN could even be modeled to map causal relationships between epigenetic activation changes in a way that has likely never been done before, allowing for many genes with currently unknown functions to be defined, opening the door to more advanced models that could map the causal and probable space of genetic engineering with far greater accuracy.

In Closing:

How long we remain mired in the Medieval times of genetic engineering is purely up to us, as a collective we can form a safety committee which agrees to create a practical gene therapy that shifts the paradigm away from monopolistic control to one where science can advance, and people can benefit from advances without waiting 20 years for approval.

The best way to win the hearts and minds of people around the world is to give them something to be grateful for, benefiting either themselves or those they love in meaningful ways. I can think of no better start down this path than curing the epigenetic effects of trauma, as virtually everyone has suffered some form of trauma in their lives, and many are needlessly crippled by it today.

Without the scars left on humanity at the epigenetic level the negative-influence house of cards collapses, along with all of the industries who prey upon it, breaking the downward spiral and moving the dial forward, from pointing towards a deeper Dystopia to a brighter future.

Transhumanism is likewise about the freedom to choose who you are, and who you become, which in the field of genetic engineering means that a practical method for genetic updates is as much a prerequisite as the computer was a prerequisite for the Internet. It would by no means remove the threat of archaic legal constructs, but it would greatly reduce their potency, taking us one step closer to being truly Transhuman.

Taking this a step further, the ability to reset the epigenetic level influence of trauma, addiction, and conditioned behaviors is also prerequisite to any major social change, as backlash comes into play when friction of the old meets new paradigms. The act of curing the effects of trauma would in this way also serve to make people more open to new ideas, since the baseline of their neurochemistry shifting would trigger subsequent recalculation going up the chain, all the way to higher order cognitive functions. This could potentially be used to shift neurochemistry into unexplored probability space, allowing for configurations that couldn’t arise naturally.

Without the practical potential there is no room for innovation, and progress stagnates behind monumental pay-gates, but the solution can be engineered today, giving innovators access to build a better tomorrow.

Humanity is but one life form among billions of ever-evolving forms of life that we know of today, and even if only 1 in 10,000 of those lifeforms were evolving in ways compatible with our genetic structure we’d be wasting 99.9999% of the potential evolutionary improvements being made by other species.  Life in the known universe is in a perpetual race to evolve, and to compete in that race in any meaningful way, increasing the survival of the species, it is necessary to take advantage of the advances that other forms of life make, the other 99.9999%+ compute power dedicated to the task of evolving into ever more advanced and resilient beings.  While humanity may not be ready to take this step any time soon, perhaps once the world is cured of trauma this will enter the realm of consideration.

If humanity is to survive, let alone thrive, in the hazards of space, genetic engineering that grants us the resilience of life forms able to survive considerable exposure to radiation, extreme temperatures, increased gravity, and even the vacuum of space, are required for us to move forward. Even survival on Earth is a moving target, and as humanity stands today, vulnerability to any number of cataclysms remains much higher than it could be. Fans of longevity research should favor the generation of a practical gene therapy most of all, because it would only take a few direct gene edits using such a therapy to significantly increase life span, granting talented scientists more years with which they could work towards overcoming challenge after challenge.

Limiting gene therapy treatment to the rarest of diseases is like limiting internet access to the most remote parts of the world, an astronomical waste, and it is time for that to change. From the more directly Transhumanist perspective, this is a step towards being free to choose who you are right down to the genetic level, accessible to everyone, a basic human right that has yet to be written, but before reaching that point humanity needs an epigenetic tabula rasa, a slate clean of trauma, conditioning, and addiction.

Kyrtin Atreides is a researcher and member of the U.S. Transhumanist Party. In his spare time over the past two years, he has conducted research into Psychoacoustics, Quantum Physics, Genetics, Language (Advancement of), Deep Learning / Artificial General Intelligence (AGI), and a variety of other branching domains, and continues to push the limits of what can be created or discovered.

For additional reading on the subject matter mentioned herein, please refer to:

Lentivirus: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2837622/

https://viralzone.expasy.org/264?outline=all_by_species

Adeno-Associated Virus: https://www.wjgnet.com/2220-3184/full/v5/i3/28.htm

https://microbewiki.kenyon.edu/index.php/Epstein-Barr_Virus

Formal Citations:

1. De Bellis, M. D., & A.B., A. Z. (2014). “The Biological Effects of Childhood Trauma.” Child and Adolescent Psychiatric Clinics of North America23(2), 185–222. http://doi.org/10.1016/j.chc.2014.01.002

2. Gudsnuk, K., & Champagne, F. A. (2012). Epigenetic Influence of Stress and the Social Environment. ILAR Journal53(3-4), 279–288. http://doi.org/10.1093/ilar.53.3-4.279

3. Hardy, T. M., & Tollefsbol, T. O. (2011). Epigenetic diet: impact on the epigenome and cancer. Epigenomics3(4), 503–518. http://doi.org/10.2217/epi.11.71

4. Bowers, E. C., & McCullough, S. D. (2017). Linking the Epigenome with Exposure Effects and Susceptibility: The Epigenetic Seed and Soil Model. Toxicological Sciences155(2), 302–314. http://doi.org/10.1093/toxsci/kfw215

5. Teschendorff, A. E., West, J., & Beck, S. (2013). Age-associated epigenetic drift: implications, and a case of epigenetic thrift? Human Molecular Genetics22(R1), R7–R15. http://doi.org/10.1093/hmg/ddt375

6. Pakorn Aiewsakun, Aris Katzourakis(2015) Endogenous viruses: Connecting recent and ancient viral evolution. Virology. 2015 May;479-480:26-37. doi: 10.1016/j.virol.2015.02.011. Epub 2015 Mar 12.

7. Payne, R., Muenchhoff, M., Mann, J., Roberts, H. E., Matthews, P., Adland, E., … Goulder, P. J. R. (2014). Impact of HLA-driven HIV adaptation on virulence in populations of high HIV seroprevalence. Proceedings of the National Academy of Sciences of the United States of America111(50), E5393–E5400. http://doi.org/10.1073/pnas.1413339111

8. Eloe-Fadrosh, E. A., & Rasko, D. A. (2013). The Human Microbiome: From Symbiosis to Pathogenesis. Annual Review of Medicine64, 145–163. http://doi.org/10.1146/annurev-med-010312-133513

9. Houldcroft, C. J., & Kellam, P. (2015). Host genetics of Epstein–Barr virus infection, latency and disease. Reviews in Medical Virology25(2), 71–84. http://doi.org/10.1002/rmv.1816

10. Haifeng Chen. (2015) Adeno-associated virus vectors for human gene therapy. Published by Baishideng Publishing Group Inc. doi: 10.5496/wjmg.v5.i3.28

11. Welle, S., Cardillo, A., Zanche, M., & Tawil, R. (2009). Skeletal muscle gene expression after myostatin knockout in mature mice Address for reprint requests and other correspondence: S. Welle, Univ. of Rochester Medical Center, 601 Elmwood Ave., Box 693, Rochester, NY 14642 (e-mail: stephen_welle@urmc.rochester.edu). Physiological Genomics38(3), 342–350. http://doi.org/10.1152/physiolgenomics.00054.2009

12. White, M., Whittaker, R., Gándara, C., & Stoll, E. A. (2017). A Guide to Approaching Regulatory Considerations for Lentiviral-Mediated Gene Therapies. Human Gene Therapy Methods28(4), 163–176. http://doi.org/10.1089/hgtb.2017.096

13. Lillycrop KA1, Costello PM2, Teh AL3, Murray RJ2, Clarke-Harris R2, Barton SJ4, Garratt ES2, Ngo S5, Sheppard AM5, Wong J3, Dogra S3, Burdge GC2, Cooper C6, Inskip HM4, Gale CR7, Gluckman PD8, Harvey NC4, Chong YS9, Yap F10, Meaney MJ11, Rifkin-Graboi A3, Holbrook JD3; Epigen Global Research Consortium, Godfrey KM12. Int J Epidemiol. 2015 Aug;44(4):1263-76. doi: 10.1093/ije/dyv052.

14. Sandman CA, Curran MM, Davis EP, Glynn LM, Head K, Baram TZ.(2018) Am J Psychiatry. 2018 Mar 2:appiajp201716121433. doi: 10.1176/appi.ajp.2017.16121433.

15. Tuesta, L. M., & Zhang, Y. (2014). Mechanisms of epigenetic memory and addiction. The EMBO Journal33(10), 1091–1103. http://doi.org/10.1002/embj.201488106

16. Samonte FGR.(2017) The Epigenetic of Dopamine Reward in Obesity and Drug Addiction: A Philippine Perspective. J Clin Epigenet. 2017, 3:2. doi: 10.21767/2472-1158.100051

17. Neumann, ID, Landgraf R.(2012) Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci. 2012 Nov;35(11):649-59. doi: 10.1016/j.tins.2012.08.004. Epub 2012 Sep 11.

New FDA Regenerative Medicine Framework is Win-Win for Gene Therapies – Article by Keith Comito and Elena Milova

New FDA Regenerative Medicine Framework is Win-Win for Gene Therapies – Article by Keith Comito and Elena Milova

Elena Milova
Keith Comito


Editor’s Note: In this article, Keith Comito and Elena Milova positively discuss new a FDA regulatory framework on RMAT (regenerative medicine advanced therapies) and on how it benefits the healthy-life-extension community. This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                   ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, March 3, 2018

Back in November 2017, the FDA announced a comprehensive policy framework for the development and oversight of regenerative medicine products, including novel cellular therapies. Both draft guidance documents had 90-day comment periods, and we at LEAF joined forces with the Niskanen Center to submit comments to the FDA to ensure that the voice of the community for healthy life extension was heard. These new regulations could have considerable implications for the therapies and technologies being developed as part of the biomedical gerontology field.

The first draft guidance addresses how the FDA intends to optimize its regulatory requirements for devices used in the recovery, isolation, and delivery of RMATs (regenerative medicine advanced therapies), including combination products.

The second document explains what expedited programs may be available to sponsors of regenerative medicine therapies and describes what therapies may be eligible for RMAT designation.

According to new FDA regulations, a drug is eligible for designation as an RMAT if:

  • The drug is a regenerative medicine therapy, which is defined as a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products, except for those regulated solely under Section 361 of the Public Health Service Act and part 1271 of Title 21, Code of Federal Regulations;
  • The drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and
  • Preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition

We hope that this joint project will support the improvement of US regulations that concern these innovative treatments and will make the overall regulatory landscape more friendly. Below, we cite the most important notes from our resulting paper.

Last week, the Niskanen Center joined with the Life Extension Advocacy Foundation in filing comments to the Food and Drug Administration (FDA), offering our support for the agency’s new regenerative medicine advanced therapy (RMAT) designation draft guidance for industry.

Although there are opportunities for marginal improvements to the guidance, and FDA approval processes more generally, we are happy to see that the agency chose to include gene therapies in its interpretation of what qualifies as a regenerative medicine therapy.

Under section 3033 of the 21st Century Cures Act, the FDA was tasked with developing an accelerated approval process for regenerative advanced therapies. Such therapies would qualify for expedited review and approval so long as the drug (a) met the definition of a regenerative medicine therapy, (b) was “intended to treat, modify, reverse, or cure a serious condition,” and (c) “has the potential to address unmet medical needs” for a serious disease or condition. Unfortunately, the bill’s definition of a regenerative medicine advanced therapy was unclear on whether gene therapies, in particular, would qualify. Luckily, the FDA clarified this point. As the RMAT guidance document notes:

gene therapies, including genetically modified cells, that lead to a durable modification of cells or tissues may meet the definition of a regenerative medicine therapy. Additionally, a combination product (biologic-device, biologic-drug, or biologic-device-drug) can be eligible for RMAT designation when the biological product component provides the greatest contribution to the overall intended therapeutic effects of the combination product.

This is an excellent development and one that portends immense benefits for future gene therapy applications submitted for FDA approval. According to the guidance, the new RMAT designation, unlike other fast-track approval and review processes, “does not require evidence to indicate that the drug may offer a substantial improvement over available therapies.” Liberalizing the threshold standards of evidence for RMAT designation ensures that future gene therapies will encounter fewer unnecessary roadblocks in delivering more effective and innovative treatments for individuals suffering from debilitating diseases.

As we note in our concluding remarks:

Overall, we consider the RMAT guidance to be a stellar improvement over other expedited programs, especially in its qualifying criteria. However, greater clarity is needed in order to capture the benefits of more advanced cell therapies that can help contribute to the healthy aging and well-being of American citizens. As FDA Commissioner Scott Gottlieb recently noted: “The benefits of [gene therapy] science—and the products that become available—are likely to accelerate. How we define the modern framework for safely advancing these opportunities will determine whether we’re able to fully realize the benefits that these new technologies can offer.”

We agree wholeheartedly. Developing a regulatory framework that accommodates safety and innovation will be a key determinant of how quickly the benefits of regenerative medicine, gene therapy, and anti-aging research revolutionize the lives of Americans. This guidance is an important and promising step in the right direction. With the right modifications, it can help usher in a new age of healthcare improvement for individuals from all walks of life.

Read the full comments submitted to the FDA here.

Source: Niskanen Center

About Elena Milova

As a devoted advocate of rejuvenation technologies since 2013, Elena is providing the community with a systemic vision how aging is affecting our society. Her research interests include global and local policies on aging, demographic changes, public perception of the application of rejuvenation technologies to prevent age-related diseases and extend life, and related public concerns. Elena is a co-author of the book “Aging prevention for all” (in Russian, 2015) and the organizer of multiple educational events helping the general public adopt the idea of eventually bringing aging under medical control.

About Keith Comito

Keith Comito is President of LEAF / Lifespan.io and a long-time advocate of longevity research. He is also a computer programmer, mathematician, musician, lover of life and perhaps a man with too many hobbies. He earned a B.S. in Mathematics, B.S. in Computer science, and M.S. in Applied Mathematics at Hofstra University, where his work included analysis of the LMNA protein.

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.

International Team Publishes Roadmap to Enhance Radioresistance for Space Colonization – Press Release by Biogerontology Research Foundation

International Team Publishes Roadmap to Enhance Radioresistance for Space Colonization – Press Release by Biogerontology Research Foundation

Biogerontology Research Foundation


 

IMAGE: These are ways to reduce health risks from space radiation during deep space travels. Multiple approaches from medical selection of radioresistant individuals to gene therapy may be proposed.

Editor’s Note: Below is a press release by the Biogerontology Research Foundation which features a roadmap to enhance radioresistance for space exploration and colonization, published by an international team of scientists from NASA, Health Canada, Canadian Nuclear Laboratories and many other organizations. This press release was originally published here.

~ Dinorah Delfin, Director of Admissions and Public Relations, U.S. Transhumanist Party, February 22, 2018

An international team of researchers from NASA Ames Research Center, Environmental and Radiation Health Sciences Directorate at Health Canada, Oxford University, Canadian Nuclear Laboratories, Belgian Nuclear Research Centre, Insilico Medicine, the Biogerontology Research Center, Boston University, Johns Hopkins University, University of Lethbridge, Ghent University, Center for Healthy Aging, and many others have published a roadmap toward enhancing human radioresistance for space exploration and colonization in the peer-reviewed journal Oncotarget.

“Our recent manuscript provides a comprehensive review of radioresistance for space radiation. Currently there is minimal research being done for radioresistance against HZE irradiation. The importance of these types of studies will be to reduce the associated health risks for long-term space exploration and allow for the development of potential countermeasures against space radiation. In addition, the synergy between understanding aging with radioresistance will allow for further benefits for humans in long-term space missions and allow for reduced health risk. This review sets the stage for the potential research the scientific community can do to allow for safe long term space exploration” said Afshin Beheshti, an author of the paper and a Bioinformatician at NASA Ames Research Center.

The roadmap outlines future research directions toward the goal of enhancing human radioresistance, including upregulation of endogenous repair and radioprotective mechanisms, possible leeways into gene therapy in order to enhance radioresistance via the translation of exogenous and engineered DNA repair and radioprotective mechanisms, the substitution of organic molecules with fortified isoforms, the coordination of regenerative and ablative technologies, and methods of slowing metabolic activity while preserving cognitive function. The paper concludes by presenting the known associations between radioresistance and longevity, and articulating the position that enhancing human radioresistance is likely to extend the healthspan of human spacefarers as well.

“This paper explores the foreseeable means by which human radioresistance could be biomedically enhanced for the purposes of space exploration and colonization. It also aims to elucidate the links between aging, longevity and radioresistance, and the ways in which research into enhancing human radioresistance could synergistically enable human healthspan extension, ultimately highlighting how ongoing research into the very well-funded sphere of aerospace research could galvanize progress in biomedical gerontology, a massively under-funded area of research despite the grave economic burden posed by demographic aging” said Franco Cortese, an author of the paper and Deputy Director of the Biogerontology Research Foundation.

The publication of the paper in Oncotarget this week is timely, given the test launch of the Falcon Heavy, SpaceX’s largest rocket to date, just last week. Interest into space exploration and even colonisation has been mounting for a number of years. Less than one year ago Elon Musk, CEO of SpaceX, unveiled a roadmap toward colonizing Mars, outlining the ambitious goal of placing a million people on Mars within the next 40 to 100 years. If interest in space colonization continues apace, research into methods of enhancing radioresistance to protect against the various forms of space radiation that spacefarers would be subjected to needs to be accelerated accordingly.

“In linking ageing and radioresistance and tying together research into enhancing the radioresistance of astronauts with the extension of healthy longevity, we hope to have shown how aerospace research could be used to leapfrog the massive funding deficit surrounding the clinical translation of healthspan-extending interventions, in order to brave the storm of the oncoming Silver Tsunami and prevent the looming economic crisis posed by demographic aging” said Dmitry Kaminskiy, an author of the paper and Managing Trustee of the Biogerontology Research Foundation.

The roadmap highlights the need to converge and accelerate research in radiobiology, biogerontology and AI to enable spacefarers to address both the healthcare challenges that we are already aware of, as well as those that we are not.

“Sooner or later we’ll have to do it – leave Earth and wander into deep space. Such travel, taking one or more years outside the Earth’s magnetosphere, would take a high toll on astronauts’ health due to exposure to cosmic radiation. So it’s better to start thinking now about how we are going to cope with that challenge. Luckily, current knowledge from such fields as radiobiology, aging research and biotechnology in general, with the wealth of recent advances in gene editing and regenerative medicine, allow for the drafting of conceptual roadmaps to enhance human resistance to cosmic radiation. This is exactly what this work is all about. It was fun and a pleasure to partake in this theoretical project with such a diverse international team. We were just throwing ideas on the table, some being quite ambitious and futuristic, and then examining them carefully for feasibility and assessing their potential. The work laid out several interesting directions and concepts that can eventually pay off. Last but not least, I think it is also very important to attract widespread attention and interest to this topic” said Dmitry Klokov, an author of the paper and Section Head of the Radiobiology & Health section at Canadian Nuclear Laboratories.

Furthermore, given the massive amount of funding allocated to research into facilitating and optimizing space exploration and optimization, the researchers hope to have shown how research into enhancing radioresistance for space exploration could galvanize progress in human healthspan extension, an area of research that is still massively underfunded despite its potential to prevent the massive economic burden posed by the future healthcare costs associated with demographic aging.

“This roadmap sets the stage for enhancing human biology beyond our natural limits in ways that will confer not only longevity and disease resistance but will be essential for future space exploration” said João Pedro de Magalhães, an author of the paper and a Trustee of the Biogerontology Research Foundation.

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The paper, entitled “Vive la radiorésistance!: converging research in radiobiology and biogerontology to enhance human radioresistance for deep space exploration and colonization”, can be viewed on Oncotarget here.

Citation: Franco Cortese, Dmitry Klokov, Andreyan Osipov, Jakub Stefaniak, Alexey Moskalev, Jane Schastnaya, Charles Cantor, Alexander Aliper, Polina Mamoshina, Igor Ushakov, Alex Sapetsky, Quentin Vanhaelen, Irina Alchinova, Mikhail Karganov, Olga Kovalchuk, Ruth Wilkins, Andrey Shtemberg, Marjan Moreels, Sarah Baatout, Evgeny Izumchenko, João Pedro de Magalhães, Artem V. Artemov, Sylvain V. Costes, Afshin Beheshti, Xiao Wen Mao, Michael J. Pecaut, Dmitry Kaminskiy, Ivan V. Ozerov, Morten Scheibye-Knudsen and Alex Zhavoronkov. Vive la radiorésistance!: converging research in radiobiology and biogerontology to enhance human radioresistance for deep space exploration and colonization, Epub ahead of print. Published online 2018 February 09. doi: 10.18632/oncotarget.24461

About the Biogerontology Research Foundation:

The Biogerontology Research Foundation is a UK non-profit research foundation and public policy center seeking to fill a gap within the research community, whereby the current scientific understanding of the ageing process is not yet being sufficiently exploited to produce effective medical interventions. The BGRF funds and conducts research which, building on the body of knowledge about how ageing happens, aims to develop biotechnological interventions to remediate the molecular and cellular deficits which accumulate with age and which underlie the ill-health of old age. Addressing ageing damage at this most fundamental level will provide an important opportunity to produce the effective, lasting treatments for the diseases and disabilities of ageing, required to improve quality of life in the elderly. The BGRF seeks to use the entire scope of modern biotechnology to attack the changes that take place in the course of ageing, and to address not just the symptoms of age-related diseases but also the mechanisms of those diseases.

New Clinical Study May Be the World’s First Cure for Alzheimer’s Disease – Press Release from Libella Gene Therapeutics

New Clinical Study May Be the World’s First Cure for Alzheimer’s Disease – Press Release from Libella Gene Therapeutics

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Libella Gene Therapeutics


ORLANDO, Fla.Jan. 10, 2018 /PRNewswire/ — Libella Gene Therapeutics LLC will conduct an OUS (outside the United States) clinical trial in Cartagena, Colombia, using gene therapy to reverse age-related diseases, starting with Alzheimer’s. Unlike traditional drugs, which tend to be taken for months or years at a time, gene therapy interventions are intended to be one-off treatments that tackle a disease at its source, repairing faulty DNA and allowing the body to fix itself.

Every day 228 Americans die from Alzheimer’s disease, and there is currently no known treatment or cure. Gene therapy offers the ability to permanently correct a disease at its most basic level, the genome, and could offer cures for many conditions that are currently considered incurable. According to Dr. Bill Andrews, the scientist leading the study, “Human telomerase reverse transcriptase (hTERT) is an enzyme whose expression plays a role in cellular aging and is normally repressed in cells, resulting in progressive shortening of telomeres. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer.”

By inducing telomerase, Dr. Andrews and Libella Gene Therapeutics hope to lengthen telomeres in the body’s cells. The clinical trial will treat a limited number of patients using the gene therapy treatment, which has been demonstrated as safe, with minimal adverse reactions in over 186 clinical trials.

Dr. Andrews has been featured in Popular Science, on the “Today” show and in numerous documentaries on the topic of life extension. As one of the principal discoverers of both the RNA and protein components of human telomerase, Dr. Andrews was awarded second place as “National Inventor of the Year” in 1997. He earned a Ph.D. in molecular and population genetics at the University of Georgia in 1981. He has served in multiple senior science and technology roles at leading bioscience corporations. Dr. Andrews is a named inventor on over 50 U.S.-issued patents on telomerase and is the author of numerous scientific research studies published in peer-reviewed scientific journals.

On why the company decided to conduct its clinical research project outside the United States, Libella Gene Therapeutics president Dr. Jeff Mathis said, “Traditional clinical trials in the U.S. can take years and millions — or even billions — of dollars. The research and techniques that have been proven to work are ready now. We believe we have the scientist, the technology, the physicians, and the lab partners that are necessary to get this trial done faster in Colombia.”

The clinical trial is prepping to begin in the first quarter of 2018 and will be conducted at MediHelp Services Clinic in beautiful and tourist-friendly Cartagena, Colombia. The state-of-the-art facility has hosted international public figures including athletes, celebrities and politicians. Dr. Javier Hernandez, MediHelp’s medical director, will oversee the trial.

Colombia’s clinical research regulation is friendly to gene therapy trials, with one of the fastest approval times in Latin America for this kind of research. The trial’s clinical study design; regulatory, operation and logistical support; project management; statistical analysis; and study monitoring services will be provided by LATAM Market Access Inc., a Florida-based clinical research company.

About Libella Gene Therapeutics LLC 
With a mission to reverse aging and cure all age-related diseasesstarting with Alzheimer’sLibella Gene Therapeutics has exclusively licensed the AAV Reverse (hTERT) transcriptase enzyme technology from Sierra Sciences and Dr. Bill Andrews. More information at www.libellagenetherapeutics.com.

About LATAM Market Access Inc.
Dedicated to helping innovative life science companies gather cost-effective clinical data at leading research institutions, the company provides clinical study design; regulatory, operational and logistics support; project management; statistical analysis; and study monitoring services. More information at www.latammarketaccess.com.

 

BGRF and SILS Scientists Analyze Viability of shRNA Therapy for Huntington’s Disease – Press Release by Biogerontology Research Foundation

BGRF and SILS Scientists Analyze Viability of shRNA Therapy for Huntington’s Disease – Press Release by Biogerontology Research Foundation

Biogerontology Research Foundation


Friday, December 1, 2017, London, UK: Researchers from the Biogerontology Research FoundationDepartment of Molecular Neuroscience at the Swammerdam Institute for Life Sciences at the University of Amsterdam, and the Department of Neurobiology, Care Sciences and Society at the Karolinska Institute announce the publication of a paper in Translational Neurodegeneration, a BioMedCentral journal, titled RNAi mechanisms in Huntington’s disease therapy: siRNA versus shRNA.

After many years of development, RNAi therapeutics are nearing the clinic. There are several variants on RNAi therapeutics, such as antisense oligonucleotides (ASOs), short-hairpin RNA (shRNA), small interfering RNA (siRNA), et cetera. The researchers’ paper aimed to answer the question of why RNAi therapeutics for nucleotide repeat disorders (specifically Huntington’s, a devastating genetic neurodegenerative disease), have lost favor in recent years. After a phenomenal amount of excitement, these therapies were hindered by problems like molecular stability, dosing, and transcriptional control of the gene therapeutic construct.

“We compared various RNAi-based therapeutic modalities available for the treatment of Huntington’s Disease and offered mechanistic proposals on how to break through current barriers to clinical development. One key problem has proven to be modulating the expression level of shRNA constructs, which would otherwise be the clear frontrunner among ASOs, siRNAs, and other methods due to duration of expression, dramatically reduced off-target effects, and ease of delivery by adeno-associated viruses that are already approved by the EMA and FDA. We also put forward novel methods of modulating construct expression and avoiding off-target effects” said Franco Cortese, co-author of the paper and Deputy Director of the Biogerontology Research Foundation.

The researchers analyzed available data on the levels of off-target effects associated with siRNA vs shRNA, surveyed emerging strategies to reduce off-target effects in shRNA therapies (such as tough decoy RNAs, or TuDs), and proposed novel methods of controlling shRNA expression, in particular through the use of negative feedback-driven oscillating promoters.

Mechanism of TFEB at the PGC1-a promoter. The PGC1a promoter contains a CLEAR-box that is known to be bound by TFEB, a transcription factor induced during autophagy and lysosomal biogenesis. A construct being the PGC1a promoter CLEAR-box would be induced by TFEB under conditions of intracellular proteotoxicity due to HTT aggregation. By this mechanism, on-demand suppression of HTT could be achieved | Credit: Translational Neuroscience

 

“We proposed two novel feedback mechanisms that 1) activate construct expression stoichiometrically with mutant Huntingtin expression, or 2) only during aggregate-induced autophagy and lysosomal biogenesis. That way, the problem of excessive construct expression may be mitigated. These ideas were inspired by feedback systems used in synthetic biology, and in ‘nonsynthetic,’ naturally occurring biological systems” said Sebastian Aguiar, lead author of the paper.

Readers can read the open-access paper here: https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-017-0101-9.

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About the Biogerontology Research Foundation

The Biogerontology Research Foundation is a UK non-profit research foundation and public policy center seeking to fill a gap within the research community, whereby the current scientific understanding of the ageing process is not yet being sufficiently exploited to produce effective medical interventions. The BGRF funds and conducts research which, building on the body of knowledge about how ageing happens, aims to develop biotechnological interventions to remediate the molecular and cellular deficits which accumulate with age and which underlie the ill-health of old age. Addressing ageing damage at this most fundamental level will provide an important opportunity to produce the effective, lasting treatments for the diseases and disabilities of ageing, required to improve quality of life in the elderly. The BGRF seeks to use the entire scope of modern biotechnology to attack the changes that take place in the course of ageing, and to address not just the symptoms of age-related diseases but also the mechanisms of those diseases.

About the Swammerdam Institute for Life Sciences

The Swammerdam Institute for Life Sciences (SILS) is the largest institute of the Faculty of Science at the University of Amsterdam. The institute comprises biological disciplines including molecular and cell biology, microbiology, plant science, physiology and neurobiology, supported by modern enabling technologies for the life sciences. The research groups of SILS also develop methods in genomics (micro-array, next-gen sequencing, proteomics), bioinformatics and advanced light microscopy technologies. Knowledge from adjacent fields of science, in particular biochemistry, biophysics, medicine, bioinformatics, statistics and information technology make SILS a multidisciplinary research institute with a systems biology approach to the life sciences. SILS’ research objective is to understand the functioning of living organisms, from the most basic aspects up to complex physiological function(s). Biological processes are studied at the level of molecules, cells, cellular networks and organisms. SILS research topics have in common that similar cellular processes and interactions are studied, likewise using similar methodologies and technologies. Therefore SILS scientists often study the same concepts in different biological systems. Within the institute, this leads to exchange of information and extension of research over the borders of different disciplines. Part of SILS research activities are directed to application-oriented research in close collaboration with industry.