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Page 28 of 35 Scherman. Rare Dis Orphan Drugs J 2023;2:12 https://dx.doi.org/10.20517/rdodj.2023.01

[174]
treatment, which points to the value of early diagnosis . In most cases, the proof of concept was obtained
using shRNA delivered by an AAV vector because this is easily obtained at the laboratory level and because
several AAV serotypes display suitable organ penetration and accessibility [100,175] . An AAV shRNA proof of
concept then opens the way to the search for synthetic genetic RNA drugs.

Genetic pharmacology with synthetic RNA drugs, which is sometimes presented as belonging to the
broader gene therapy field, has made remarkable progress after 20 years of relentless and intensive efforts to
improve RNA drug performances. Two to three logs enhancement of their potency has led to recent
extraordinary successes, such as being able to silence a pathological gene by a twice, or even once-a-year
subcutaneous administration of a small amount of compound, which represents a historical performance
never reached before by a chemical compound.

The chemical RNA drugs technology platform, whose chemistry is still continuously improving, is very
versatile and can be applied to a large variety of therapeutic applications once the first proof of concept has
been obtained, including for targeting previously non-druggable proteins. Of particular value for rare
diseases is the possibility to tackle dominant negative gain-of-function genetic diseases, among them those
linked to triplet expansion. Trinucleotide repeat diseases lead to either toxic RNA or toxic protein product,
and they represent a widening class of rare diseases that is not restricted to the ones illustrated or mentioned
in the present review: Type 1 myotonic dystrophy, centronuclear myopathy, Huntington chorea, and
spinocerebellar ataxia [141-145] , but also cover other expanding disease families [176,177] .

The mRNA vaccine technology can be rapidly adapted to any new pathogen by administering pathogen-
specific mRNA sequences through a unique delivery technology platform and could thus be rapidly applied
to the COVID-19 pandemic spread. Similarly, RNA drug improvements are of general and extendable
value, such as modifications in the phosphodiester linkage, sugars, and nucleic bases. However, it must be
stressed that the number and respective position of the linkage, ribose, and base modifications need a tailor-
made optimization that might be optimized for specific antisense sequences [68,145] .

Tri-GalNac targeting has now demonstrated its extraordinary efficacy in delivering RNA drugs to the liver,
and the majority of actual clinical trials concerning RNA drugs make a profit from this technology, not only
for rare metabolic or neuromuscular disorders such as TTR, or blood disorders such as hemophilia but also
for diseases concerning a much larger share of the population, such as hypercholesterolemia by targeting the
[178]
PCSK9 gene , hypertension, diabetes or chronic hepatitis.
In parallel to this extension of RNA drugs application to highly prevalent diseases, the technology shows the
potential to treat an increasing number of severely debilitating or life-threatening ultrarare diseases, which
can affect worldly only 1 or a very limited number of patients. They are now referred to as “N-of-1”
treatments. How this ultrarare diseases population could benefit from antisense RNA drugs is now raising
increasing interest from scientists, GMP producers, and regulatory authorities . Since there might be little
[179]
or no commercial value for these unmet medical needs, patient advocacy groups, charities, and foundations
[180]
are at the frontline of this challenge .

In 2018, the ASO Milasen was developed to treat a single 6-year-old patient with neuronal ceroid
lipofuscinosis 7, a neurodegenerative lysosomal storage disorder originating from excessive accumulation of
pigment lipofuscin in the body's tissues. The clinical trial result was published in 2019 . Remarkably, the
[181]
molecular diagnosis of this fatal condition led to the rational design, testing, and manufacture of the splice-
modulating antisense ASO tailored to this unique patient. Proof-of-concept experiments in cell lines from