The n-of-1 patient is that one person with a unique genetic mutation that causes an ultra-rare disease, designated as a disease with less than 30 patients in the whole world. The advent of affordable genomic sequencing has identified millions of n-of-1 patients, which is becoming a large and growing population with desperate needs.
Though a great progress is made in identifying n-of-1 patients, and ruling the genetic causes of their diseases; usually, drugs that work in patients with the common mutations, often do not work for these unique patients.
n-Lorem is a foundation created by Dr. Stanley Crooke, the founder, chairman and chief executive officer of Ionis Pharmaceuticals, a global leader in RNA-targeted therapy. This foundation was created to provide individualized treatments for patients with ultra-rare diseases using the technology developed at Ionis Pharmaceuticals.
The mission of n-Lorem is to use the versatility and specificity of antisense technology to kindly offer experimental antisense oligonucleotides (ASO) medicines to treat the n-of-1 patient.
Antisense oligonucleotides (ASOs) are short, synthetic, single-stranded DNA-mimics that can alter the RNA, and consequently protein expression and function. Because they can manipulate the intermediate step between gene and protein translation – at the pre-mRNA level – ASOs can reduce, or restore, or modify protein expression by different mechanisms.
Very simply: DNA gets converted into mRNA. ASOs function in between the two. As such, if the DNA gene has a mutation and codes a dysfunctional mRNA, and consequentially a dysfunctional protein that causes a disease, an ASO can change that. The ASO has the correct complementary code to produce the precise mRNA, and automatically, the precise protein needed to perform the right function. By intervening in the step before protein gets translated, it makes sure that nothing goes wrong and that the mutated gene doesn’t go any further, preventing disease from happening.
Anyone can apply to n-Lorem for a potential treatment. The proposals are approved and prioritized based on certain criteria, such as the severity of the disease, feasibility of developing an ASO treatment for the genetic cause of the disease, degree of potential benefit vs. potential risks, practicality of treatment, availability of physician and institution to treat patient, and other intricacies of the condition.
The unique patient needs to work with a physician that makes the connection to n-Lorem, who will then make an informed decision about whether a patient is appropriate to receive an experimental ASO treatment through a Commission.
It’s outstanding that the FDA reaction to n-Lorem has been very supportive; and, in fact, initial guidance has been put in place in January 2021 to reach more patients in need.
Once regulatory permission has been given, an investigator-led clinical trial is initiated and the patient can receive their custom experimental ASO treatment at no personal cost and will all clinical support.
This cost-free individualized therapy is possible for Ionis Pharmaceuticals because of the inherent efficiency and versatility of the ASO technology. The knowledge of modern ASOs mechanisms and specific possible effectiveness in selected organs, with different possible routes of application, together with integrated safety databases, allows a dive for the treatment of unique patients.
It’s honourable to use science to help the n-of-1 patient and their families.
It’s funny that this pandemic can prove all anti-evolutionists wrong.
Nothing like seeing Charles Darwin natural selection right in front of your eyes at the speed of light. Just look at the SARS-CoV-2 viral evolution…
In his book “On the origin of species” written in 1859, Charles Darwin defined natural selection as the “principle by which each slight variation of a trait, if useful, is preserved”. What does this mean (?), it means the individuals best adapted to their environments are more likely to survive and reproduce.
What we are seeing now, is that the mutations of SARS-CoV-2 that better promote spreading, are the ones that are becoming more common among the population, even when derived in different locations. The virus is changing and evolving to spread more rapidly, because natural selection will optimize the level of virulence that maximizes pathogen fitness – expressed as the basic reproductive number (R0)1,2.
On average, comparative data from previous studies tell us that, low-virulence infections have a greater chance of successfully establishing transmission cycles in humans than virus with higher mortality3. As such, as before, the virus actually just wants to spread and not kill.
But, since the environment also affects transmissibility, there are more factors on the equation “when will this madness end” than we would have wished for.
For example, in the evolutionary trade-off between virulence and transmissibility, because intra-host virus replication is needed to allow inter-host transmission, it is almost impossible for natural selection to optimize all traits simultaneously1 and give us some peace.
For example, in the case of the Myxoma virus (MYXV) in rabbits, this evolutionary trade-off leads to an ‘intermediate’ virulence being more advantageous to the virus than a higher virulence1,4. This happens because the rabbit host dies before inter-host transmission, in the case of higher virulence; and, with lower virulence the virus goes absolutely nowhere, because it does not increase virus transmission rates. A similar trade-off model has been proposed to explain the evolution of HIV virulence1,5.
Unfortunately, experimental studies in some viruses have shown that high virulence can promote certain advantages, as in the case of malaria, where a higher virulence was shown to provide the Plasmodium parasites with a competitive advantage within hosts1,6. Or, in the case of the rabbit haemorrhagic disease virus (RHDV), where there is evidence that virulence has increased through time, probably because virus transmission often occurs through flies that feed on animal carcasses, making host death selectively favourable1,7.
Let’s thank the Gods that SARS-CoV-2 is NOT transmissible through flies.
So, current evolutionary theory tells us that it is possible to anticipate the direction of virulence evolution, if the key relationship between virulence and transmissibility, and hence viral fitness, is understood1. Crucial to this is the analysis of the intersection between genomics and evolutionary studies, what is called phylogenomics.
This field of science provides a way to understand virulence evolution, and creates a number of hypotheses that can be tested using appropriate experimental cell assays and bioinformatic tools8,9.
The collaboration of public health and research teams worldwide has now allowed the publication of 620,338 SARS-CoV-2 genomes in GISAID (http://www.gisaid.org/) (as of February 25, 2020)9. At the same time, a dynamic nomenclature system for SARS-CoV-2 has been described to facilitate real-time epidemiology revealing links between global outbreaks that share similar viral genomes10. At the root of the phylogeny are two lineages, A and B; where, A is likely ancestral, as it shares two distinguishing variants with the closest known bat viruses. Further linage designations link new variants to geographically distinct populations, B.1 in the Italian outbreak, then other parts of Europe and the world; and, B.1.1 being the major European lineage which was spread throughout the world. However, many of the major lineages are now present in most countries, and recapitulate the global diversity of SARS-CoV-2, indicating that most local epidemics were seeded by a large number of independent introductions of the virus.
The current evolutionary tree of SARS-CoV-2 shows multiple introductions of different variants across the globe, with introductions from distant locations seeding local epidemics, where infections sometimes went unrecognized for several weeks and allowed wider spread11. The tree topology actually indicates that SARS-CoV-2 viruses have not diverged significantly since the beginning of the pandemic11. These results show that, so far, SARS-CoV-2 has evolved through a non-deterministic, noisy process; and, that random genetic drift has played the dominant role in disseminating unique mutations throughout the world11.
There remains an urgent need for a SARS-CoV-2 vaccine as a primary countermeasure to contain and mitigate the spread; and, the virus’s surface S (Spike) protein continues to be an attractive vaccine target,because it plays a key role in mediating virus entry into the cells, and is known to be immunogenic.
Of course, the virus was only recently identified in the human population with a short time frame relative to the adaptive processes that can take years to occur.
But, the most recent findings show us that the SARS-CoV-2 viruses that are currently circulating, constitute a homogeneous viral population, to which the current vaccines available will be sufficient to mitigate the spread.
Soon, SARS-CoV-2 will become just another viral acquaintance during the winter, like a common cold
1 Geoghegan, J. L. & Holmes, E. C. The phylogenomics of evolving virus virulence. Nature Reviews Genetics19, 756-769, doi:10.1038/s41576-018-0055-5 (2018).
2 Bull, J. J. & Lauring, A. S. Theory and empiricism in virulence evolution. PLoS Pathog10, e1004387, doi:10.1371/journal.ppat.1004387 (2014).
3 Geoghegan, J. L., Senior, A. M., Di Giallonardo, F. & Holmes, E. C. Virological factors that increase the transmissibility of emerging human viruses. Proc Natl Acad Sci U S A113, 4170-4175, doi:10.1073/pnas.1521582113 (2016).
4 Kerr, P. J. et al. Next step in the ongoing arms race between myxoma virus and wild rabbits in Australia is a novel disease phenotype. Proceedings of the National Academy of Sciences114, 9397-9402, doi:10.1073/pnas.1710336114 (2017).
5 Fraser, C., Hollingsworth, T. D., Chapman, R., de Wolf, F. & Hanage, W. P. Variation in HIV-1 set-point viral load: epidemiological analysis and an evolutionary hypothesis. Proc Natl Acad Sci U S A104, 17441-17446, doi:10.1073/pnas.0708559104 (2007).
6 de Roode, J. C. et al. Virulence and competitive ability in genetically diverse malaria infections. Proc Natl Acad Sci U S A102, 7624-7628, doi:10.1073/pnas.0500078102 (2005).
7 Di Giallonardo, F. & Holmes, E. C. Viral biocontrol: grand experiments in disease emergence and evolution. Trends Microbiol23, 83-90, doi:10.1016/j.tim.2014.10.004 (2015).
8 Stern, A. et al. The Evolutionary Pathway to Virulence of an RNA Virus. Cell169, 35-46.e19, doi:10.1016/j.cell.2017.03.013 (2017).
9 Sjaarda, C. P. et al. Phylogenomics reveals viral sources, transmission, and potential superinfection in early-stage COVID-19 patients in Ontario, Canada. Scientific Reports11, 3697, doi:10.1038/s41598-021-83355-1 (2021).
10 da Silva Filipe, A. et al. Genomic epidemiology reveals multiple introductions of SARS-CoV-2 from mainland Europe into Scotland. Nat Microbiol6, 112-122, doi:10.1038/s41564-020-00838-z (2021).
11 Dearlove, B. et al. A SARS-CoV-2 vaccine candidate would likely match all currently circulating strains. bioRxiv, 2020.2004.2027.064774, doi:10.1101/2020.04.27.064774 (2020).