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Page 18 of 35 Scherman. Rare Dis Orphan Drugs J 2023;2:12 https://dx.doi.org/10.20517/rdodj.2023.01

allowed to achieve reasonable distribution through the brain and spinal cord, the latter being an absolute
requisite for SMA.

Acutely conceived clinical development allowed us to prove the clinical benefit of intrathecal Nusinersen in
Type I SMA in only a few years. The results obtained on patients were so spectacular that FDA approval was
obtained within about 3 months, which represents one of the fastest delays ever observed. Recent clinical
data show that the earlier the treatment is given after birth, the best are the clinical results. This opened the
way to systematic SMA newborn screening in various countries’ legislation, which was not the case before.
More details on the clinical advances and ongoing development of Nusinersen have been published
elsewhere [5,7,8] .

[100]
Multiple other candidate ASOs are being tested as splice modifiers, such as an LNA/DNA mixmer .
Remarkably, quite a short time after the revolutionary Nusinersen commercialization, two other approaches
led to approved drugs against SMA. Zolgensma is a self-complementary AAV-9 vector able to cross the
[101]
blood-brain barrier carrying the SMN1 cDNA sequence, which showed positive results by systemic IV
administration and has been FDA- and EMA-approved. Ridisplam is an orally administered splicing
[102]
modifier of SMN2 which increases the level of functional SMN2 protein. The Ridisplam large domain of
application covers all types of SMA, and it has been approved in the USA, Japan, and Europe as a treatment
that does not necessitate hospital intervention.

RNase H-dependent ASO inotersen for the treatment of hereditary transthyretin amyloidosis
Hereditary transthyretin amyloidosis (hATTR) is a gain-of-function genetic rare disease. It represents a
paramount example of clinical success for RNA drugs inducing mRNA degradation because both ASO and
siRNA drugs have reached clinical use. This disease represents the first indication of a clinically approved
siRNA. Moreover, two siRNA drugs with different delivery principles have been approved for hATTR in a
brief period of time, and more are on the way.

The transthyretin protein (TTR) is secreted by the liver, choroid plexus, and retinal pigment epithelium. Its
important function is to transport the thyroid hormone thyroxine (T4) and retinol to the liver. TTR is a 55
kDa homotetramer, which is formed by the first association of dimers, followed by dimer-dimer binding.
Hereditary transthyretin amyloidosis is a group of several dominant negative diseases related to variants in
the TTR gene. More than 140 different TTR variants have been identified. In these rare hereditary diseases,
mutant TTR misfolding leads to the formation of amyloid aggregates which accumulate in various tissues
and cause various pathologies: hereditary transthyretin amyloidosis (hATTR), familial amyloid
polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC) [103-105] . Cardiomyopathy results from
myocardial infiltration of abnormal amyloid protein. Moreover, wild-type transthyretin amyloidosis
(wtATTR) has been observed, which occurs mainly at a late age and is caused by the aggregation of normal
transthyretin . It affects older age patients carrying the wild-type TTR gene. In addition to
[106]
polyneuropathy and cardiomyopathy, other transthyretin amyloidosis symptoms involve nephropathy and
ocular pathology.

Before the introduction of RNA drugs, hATTR treatment involved liver transplantation and, more recently,
the small molecule drugs Diflunisal and Tafamidis, which stabilize TTR in a non-aggregating form. In
recent years, however, a very efficient treatment for hATTR with polyneuropathy has been obtained
through RNA drugs decreasing liver TTR mRNA. Either RNases H-dependent ASOs such as Inotersen
(Tegsedi) or Ago-dependent siRNA Patisiran (Onpattro) and Vutrisiran have successfully reached the
market.