57th Session of the International Seminars on Planetary Emergencies
9-14 August 2025
Session 2: Biomedical discoveries, preventive/therapeutic strategies and
the risks Chairman: Franco Maria Buonaguro (Chairman, Medicine and Biotechnology PMP)
Speakers:
Massimo Ciccozzi, Sofie Nyström, Emanuele Buratti, Felice Iasevoli, Neal S. Young, Sam
Mbulaiteye, Ishwar Gilada, Per Hammarström
Franco Maria Buonaguro
Introduction – Presentation Slides FMB
Biomedical discoveries in the preventive and therapeutic fields
have been significant and frequent over the
past 50 years. Have they been risk-free? The latest COVID experience is the
most recent we have all witnessed. Although the COVID pandemic
appears to be over, with the exception
of some still unresolved
questions related to long COVID,
the two main
aspects that continue
to intrigue the scientific community are:
(a) the potential role of laboratory manipulations as a source of a highly
pathogenic SARS-CoV-2, and (b) the amyloidogenic role of the virus's
spike protein and even the recombinant spike protein expressed by the recently developed mRNA vaccine. Furin
plays a role
in both. Furin
is the first
human proprotein convertase (PC), identified in 19861.
It is widely distributed in all human
tissues and involved
in various metabolic and pathological processes, including the maturation of over 150 proproteins, particularly virtually all hormones and neuropeptides2,3. Furin is
also exploited by viruses to increase transmission efficiency and viral
tropism4,5. In addition to the COVID pandemic and strategies to contain it,
this session reported and discussed new developments in neurodegenerative and neurocognitive diseases, as well as rheumatological
diseases and rare cancers such
as Burkitt's lymphoma. We must improve
our preparedness for
potential new epidemics, as
highlighted by Ishwar Gilada, but we must also contain the risks associated
with our technologies, as warned
by Per Hammarström.
Massimo Ciccozzi
In the last years
several studies have been performed on the evolutionary processes of the SARS-CoV_2, have identified and characterized the
unique presence of the PRRA Furin Cleavage Site (FCS), which is absent in other
known Sarbecorvirus (lineage B beta Coronaviruses) 5-8. Although it is possible
a rare recombination event between the SARS-CoV-2 and other human Coronaviruses prevalent in the rino-pharyngeal tract, which often carry such FCS (in particular the two human Alphacoronavirus, NL63 and 229E),
a laboratory engineered manipulation has been suggested
to increase the pathogenicity, by a gain of function strategy, in order to
establish an in vivo model based on humanized mice. Dr Ciccozzi presentation
has been focused on the key dilemma of a natural zoonotic
evolution from mammalians with an ACE2 receptor homologous to the humans or a laboratory engineered
recombinant virus. The key issue is the presence of the PRRA Furin Cleavage
site (FCS), not present in the SARS-CoV_1 (the Urbani strain of 2003) and not
present in other Sarbecorvirus strains. Several Sarbecorvirus (lineage B beta
Coronaviruses) have proteolytic cleavage sites at the S1/S2 boundaries and the
S2 NH2 terminal sensitive to other proteases, i.e. the TMPRSS2, which is
however not highly diffuse as for the Furin in human tissues8. Furin cleavage sites
are in the genera AlphaCoronavirus and
Gammacoronavirus
as well as in other subgenera of the Betacoronavirus such as Merbecovirw; and
Embecovirus, with peculiarities which suggest a different evolutionary process.
Finally, it should be mentioned that Furin cleavage
is critical to many viral diseases, including
HIV, Ebola, and influenza H5 and H79. Furin is a
ubiquitously expressed protease in human body, with a wider distribution range
than the major protease responsible for cleaving spike, TMPRSS2. Therefore,
coronaviruses with spike containing furin cleavage
site may have advantage in spreading8. In conclusion, for all such reasons, although at the moment there is not a
final prove of human manipulation, all such anomalies strongly favor a human
role. The obvious final question, if the active role of humans were
demonstrated, would be whether it was simply
a laboratory error or a conceptual error in failing
to evaluate all the potential risks of a gain-of-function
activity. To resolve this question, the project approved and funded by the NIH
would need to be analyzed in detail to verify whether this strategy was already
a goal of the project and had in fact also been approved by the U.S. funding agency.
Sofie Nyström
Amyloidogenic peptides Presentation Slides
Prof
Nyström focused on proteins, as the working horses of life and essential for
all life forms. The function of a protein is dependent on its unique
three-dimensional shape, the native fold. However, proteins can also undergo a
shape-shifting misfolding process and sometimes this leads to the formation of
amyloid protein structures. An amyloid is s threadlike structure that is
composed of many protein molecules held together by intermolecular
interactions. These amyloid fibrils are notorious for their ability to recruit
more of neighbouring proteins into the amyloid state and for causing a
multitude of disease in humans. Neurodegenerative diseases such as Alzheimer’s
disease and Parkinsons disease are examples of such amyloid dependent diseases.
Although the mechanism of amyloid formation is similar between several amyloid
diseases, they are coupled to the misfolding, and amyloid formation of distinct
proteins and the symptoms of the disease are different.
Both in the case of Alzheimer’s disease
and Parkinson’s disease
there are known
genetic mutations in the
culprit protein, rendering a protein that is more prone to misfold into the
aberrant amyloid state. Such mutations account for
5-15% of all cases of Alzheimer’s and Parkinson’s disease. The direct cause
of the rest, the overwhelming majority of all
disease cases is not known, although several risk factors have been identified. Both
viruses10 and bacteria11 are known to contain amyloid-forming proteins that in many cases play a functional role for the
microbe. Epidemiologic studies
provide an insight
to virus infections as a driving force for neurodegenerative
disease12,13 and it was recently established that vaccination against Herpes
Zoster gives some protection also against dementia14,15. Bacterial amyloids have been shown to provoke amyloid formation of the Alzheimer’s disease
associated protein Aβ Parkinson’s disease
associated protein
α-synuclein16,17.
Experiments conducted on virus derived
proteins in the test
tube, from both SARS-CoV-2, Influenza A and Herpes Simplex
demonstrate their potential to form amyloid structures. Furthermore, adding
such preformed amyloids of virus proteins to human proteins involved in
Alzheimer´s and Parkinsons disease
results in acceleration of the disease associated misfolding of the human
proteins18 and Nyström et al unpublished. Epidemiologic evidence and laboratory experiments in concert lead to the conclusion that it is worth
to follow the trail of viral and bacterial infections to find the root cause
and potentially a strategic point for combating
neurodegenerative disease that are devastating many lives world-wide.
Emanuele Buratti
TPD-43 misfolding and SLA Presentation Slides Buratti
The
SISMIC-TDP43 project focuses on the TAR-DNA binding protein (TDP-43), an
amyloidogenic protein implicated in the pathogenesis of Amyotrophic lateral
sclerosis (ALS). TDP-43 is a 414 amino acid nuclear protein, and its misfolding
and accumulation in the cytoplasm are recognized hallmarks of ALS and
FrontoTemporal Lobar Degeneration (FTLD). ALS is characterized by the progressive loss of motor
neurons, while FTLD involves
the deterioration of frontal and temporal lobes, causing behavioral changes and language impairment. Current therapeutic
strategies have failed to effectively and specifically target the structural
transitions of TDP-43, often relying on non-specific approaches like increasing
clearance or preventing phosphorylation. To address this problem, the
SISMIC-TDP43 project, which stands for Structure based Identification of Small Molecules Interacting with and Counteracting TDP-43
aggregation, aims to bridge this therapeutic gap. Its objective
is to discover, synthesize, and validate small molecules designed
to bind to TDP-43. The molecules adopt a dual
approach: either stabilizing physiological TDP-43 dimers
or preventing and reversing pathological aggregates, thereby
restoring protein function. Small molecules are preferred due to
their chemical versatility, tractable pharmacology, and potential for brain penetration. The project employs five interconnected aims to
systematically identify and validate candidate therapeutics and diagnostic imaging tools. These aims include:
Proteochemometrics (Aim 1) that consists
in mapping the full TDP-43 CTD
pocketome
to detect approximately 23,700 potential sites
and facilitate drug
repurposing by comparing them with pockets in the Protein
Data Bank (PDB);
Virtual Screening (Aim
2) that utilizes an AI-driven Large
Scale Virtual Screening Pipeline
to explore chemical
space. This massive
effort involves identifying binding sites using the
InDeep neural network
and docking libraries, including the EnamineREAL database containing up to 36 billion compounds;
Peptidomimetics (Aim 3) for the design and synthesis of peptide analogues to
interfere with the aggregation process;
and In Vitro Assays (Aim 4) to characterize the binding affinity
and aggregation interference efficacy
using advanced biophysical methods, such as ThT fluorescence and electron
microscopy (EM). Finally,
the project will
include interactions with
the Biology (Aim
5) to validate efficacy in cellular models
against aggregation, clearance, nuclear localization, and splicing regulation, leading to the selection of both candidate therapeutics and PET tracers. To this date, preliminary results
have led to the
identification of four candidate molecules. All four molecules
demonstrated a positive
effect by reducing TDP-43 aggregation, a result
confirmed through both
ThT fluorescence monitoring and supporting electron microscopy images.
In conclusion, this data has contributed to defining the TDP-43 CTD pocketome and yielded first-generation small
molecules that inhibit or reverse TDP-43 aggregation, alongside initial
candidate diagnostic tracers
necessary for monitoring ALS.
Felice Iasevoli
Misfolding in neurodevelopmental and
neurodegenerative disorders Presentation Slides Iasevoli
Felice Iasevoli’s presentation focused on the
association of the reduction of Furin activity with neurodegenerative (i.e.
Alzheimer’s Disease) and neurocognitive (i.e.
Schizophrenia) diseases. If increase of proteins and peptides with
amyloidogenic properties have been shown to play a major role in older-age neurodegenerative disorder, including Parkinson and Alzheimer’s
Disease, neurodevelopmental disorders, in particular
autism spectrum of disorders (ASD) and Schizophrenia (SCZ) have been associated
with the reduction of Furin expression and the consequent reduction of Brain-derived neurotrophic factor (BDNF), relevant for the dendritic prunic involved in the maturation of neuronal connections19. FURIN is a prototypical member
of the proprotein convertase (PCSK) family,
a group of subtilisin-like serine proteases responsible for converting a wide range
of inactive precursors into their biologically active forms. This enzymatic activation represents a key post-translational regulatory step across
numerous physiological
systems. FURIN’s substrates include more than 150 precursor proteins, encompassing hormonal
peptides, growth
factors, receptors, and neuropeptides20,21. Among the best characterized are
proinsulin, cleaved to insulin22; pro-ACTH and pro-vasopressin, converted into
their active neuropeptide forms23,24; and various substrates implicated in
neuroendocrine communication and homeostatic regulation. Within the central
nervous system, FURIN plays an equally pivotal
role. It is highly expressed in neurons and glial cells, where it controls axon guidance, neuronal
migration, and synaptic maturation. Among its most relevant neurobiological
functions is the cleavage of proBDNF into mature BDNF, a process essential for
maintaining appropriate levels of synaptic pruning, dendritic arborization,
and network plasticity20. Proper maturation of BDNF is indispensable for experience-dependent
refinement of cortical and subcortical circuits, particularly during
adolescence and early adulthood—a developmental window crucial for the
establishment of cognitive and affective functions. Defective FURIN activity
disrupts this delicate equilibrium. Reduced conversion of proBDNF leads to an
excess of its unprocessed form, which preferentially binds to p75NTR receptors,
triggering apoptotic and anti-synaptogenic pathways. This shift from trophic to
atrophic signaling is thought to underlie altered synaptic density, impaired
excitatory–inhibitory balance, and dysfunctional network connectivity, all of
which are recognized hallmarks of schizophrenia, autism spectrum disorders
(ASD), and other neurodevelopmental syndromes.
Recent genomic and transcriptomic studies
have confirmed the presence of both common
and rare variants in the FURIN gene that modulate
expression and enzymatic efficiency. One key regulatory element
is the rs4702 SNP within the 3′-UTR region,
which affects the binding of microRNA miR-338-3p25. The G allele
of this variant weakens miRNA binding, reducing FURIN translation and
subsequently diminishing the availability of mature
BDNF. The result
is a cascade of neurobiological effects involving impaired synaptic signaling, dendritic simplification, and cortical
dysconnectivity. Furthermore, converging evidence from post- mortem and
animal studies supports
a dimensional view
of psychiatric nosology, where FURIN dysregulation contributes to a shared
molecular vulnerability that spans from autism to schizophrenia. The gradient
of FURIN activity may influence not only the degree of cortical pruning but
also the timing of critical neurodevelopmental
events, thereby determining the specific clinical
phenotype along this continuum.
Beyond its molecular
and developmental roles, FURIN’s pharmacological relevance is gaining
increasing attention. A number of FURIN inhibitors are currently being
explored as antiviral and anticancer agents, exploiting its role in processing viral
glycoproteins and tumor-associated growth
factors26. However, given FURIN’s pleiotropic functions in the brain, systemic
inhibition might pose neuropsychiatric risks—particularly in individuals with preexisting genetic
or epigenetic vulnerability leading to reduced
FURIN functionality. In such
subjects, further suppression of FURIN activity
could theoretically precipitate acute neurocognitive
disturbances, behavioral disinhibition, or even neuroinflammatory sequelae. This consideration emphasizes the need for careful safety evaluation and translational research,
integrating molecular pharmacology with neurodevelopmental and neuropsychiatric expertise.
Overall, FURIN represents a biological and pharmacological intersection point between infectious disease, oncology, endocrine regulation, neurotrophic
signaling, and brain architecture integrity, relevant to both
neurodevelopmental and neurodegenerative diseases. Its balanced activity
ensures the proper maturation of neuropeptides and growth factors,
sustaining the dynamic
equilibrium between synaptic
formation and elimination that
underpins higher-order cognition. Dysregulation of this system—whether
genetically, epigenetically, or pharmacologically induced—may constitute one of
the core mechanisms linking neurodevelopmental and neurodegenerative disorders.
Neal S. Young
Neal S. Young described the new VEXAS syndrome caused
by somatic mutations in the UBA1 gene, which is
located on the X chromosome. The initial description, from NIH with Young
contributing, was published on NEJM in 202027 and many publications have followed28-30. The mutations in the UBA1, located on the X chromosome, are acquired (non-hereditary) and occur
during a person's lifetime specifically in the hematopoietic stem and its progenitor cells.
The most common mutation is at the methionine 41 (Met41)
position, with specific
variants like Met41Thr, Met41Val, and Met41Leu being most frequent. This mutation
affects the E1 enzyme's function, leading to systemic inflammation and features
of autoinflammatory diseases.
The
name VEXAS is an acronym deriving from the core features of disease: V:
Vacuoles are often identified in the bone marrow stem cells of patients
presenting with VEXAS; E: The E1 ubiquitin conjugating enzyme encoded by the UBA1 gene is mutated in patients; X: The mutated
UBA1 gene is recessive and located on the
X-chromosome and thus the disease is almost exclusively found in individuals
with a single X chromosome and thus said to be X-linked; A: Patients with VEXAS
present with a wide array of autoinflammatory conditions; S: The mutations which cause VEXAS
are somatic: they are acquired
throughout life, not inherited,
and are not passed on to offspring. The frequency of the mutation is not rare with 1 case in 13 591 unrelated
individuals (95% CI, 1:7775-1:23 758): 1 in 4269 men >50 years (95% CI,
1:2319-1:7859) and 1 in 26 238 women older than 50 years (95% CI, 1:7196-1:147
669); macrocytosis of red blood cells and anemia appear to be early signs; the
disease is not uncommon among older, usually Caucasian men (31).
The treatment is still not defined and standardized but
includes high doses
of corticosteroids, Ruxolitinib (and other jak inhibitors), Tocilizumab (anti-IL6R), Azacytidine. Hematopoietic stem cell transplant is curative but carries risks of morbitidy
and mortality.
Moreover, Young described several non -oncological conditions characterized by somatic mutations, such as endometriosis (32,33), and possibly brain
diseases including autism (34)
and schizophrenia (35,36). This discovery
opens a totally new field not only benign and malignant cancers
are associated to genetic changes,
but also inflammatory conditions (including rheumatological auto-immune disease) associated to genetic changes which could generate protein’s changes, perhaps able
to induce an immune response
against a modified
self and by other still uncertain mechanisms.
Sam
Mbulaiteye in his presentation recapitulate the information on the EBV role in
human diseases and in particular in Burkitt Lymphoma, a very peculiar cancer in
sub-Saharan young children, characterized by jaws involvement. Sam, in 2010
established and since then coordinated a very unique study in 3 sub-Saharan
countries (Kenya, Uganda and Tanzania) funded by NIH: the EMBLEM project, an Epidemiology
of Burkitt Lymphoma in East African Children and Minors study to assess the
relationship between coendemic Malaria and the pediatric
Endemic Burkitt lymphoma
(eBL) in sub-Saharan Africa37. Previous cross-sectional studies of limited geographic areas have not found a convincing
association. The scientists involved in the project used spatially detailed
data from the EMBLEM study to assess this relationship. EMBLEM is a
case-control study of eBL from 2010 through 2016 in six regions of Kenya, Uganda,
and Tanzania. To measure the intensity
of exposure to the malaria parasite, Plasmodium falciparum, among children in
these regions, we used high- resolution spatial data from the Malaria Atlas
Project to estimate the annual number of P. falciparum infections from 2000
through 2016 for each of 49 districts within the study region. Cumulative P.
falciparum exposure, calculated as the sum of annual infections by birth
cohort, varied widely, with a median of 47 estimated infections per child by
age 10, ranging from 4 to 315 infections. eBL incidence increased 39% for each
100 additional lifetime P. falciparum infections (95% CI: 6.10 to 81.04%) with
the risk peaking among children aged 5 to 11 and declining thereafter.
Alternative models using estimated annual P. falciparum infections 0 to 10 y
before eBL onset were inconclusive, suggesting that eBL risk is a function of cumulative rather than
recent cross-sectional exposure. Their findings provide population-level
evidence that eBL is a phenotype related to heavy lifetime exposure to P.
falciparum malaria and support emphasizing the link between malaria
and eBL (38). Moreover,
the EMBLEM studies
on one of the largest
sample collections allowed several molecular studies, including Next
generation sequencing, with the identification and characterization of EBV Variants (39 and genetic susceptibility to recurrent or chronic infection
by Epstein-Barr virus or Plasmodium falciparum (40).
EBV
Variants: Epstein-Barr virus (EBV) infection, a ubiquitous infection,
contributes to the etiology of both Burkitt Lymphoma (BL) and nasopharyngeal carcinoma, yet their global distributions vary geographically with no overlap. Genomic variation in EBV
is suspected to play a role in the geographical patterns of these EBV-
associated cancers, but relatively few EBV samples from BL have been
comprehensively studied. We sought to compare phylogenetic patterns of EBV
genomes obtained from BL samples in Africa and from tumor and non-tumor samples
from elsewhere. We concluded that EBV obtained from BL in Africa is genetically
separate from EBV in Asia.
Through comprehensive analysis
of nucleotide variations in EBV's LMP-1 gene, we describe 12 LMP-1 patterns, two of which (B and G) were found mostly
in Asia. Four LMP-1 patterns
(A, AB, D, and F) accounted for 92% of EBVs sequenced from BL in Africa. Our results identified extensive diversity
of EBV, but BL in Africa was associated with a limited number of variants
identified, which were different from those identified in Asia. Further
research is needed to optimize the use of PCR and sequencing to study LMP-1
diversity for classification of EBV variants and for use in epidemiologic
studies to characterize geographic and/or phenotypic associations of EBV
variants with EBV-associated malignancies, including eBL (41).
Genetic
susceptibility to recurrent or chronic infections: Burkitt lymphoma (BL) is
responsible for many childhood cancers in sub-Saharan Africa, where it is
linked to recurrent or chronic infection by Epstein-Barr virus or Plasmodium
falciparum. However, whether human leukocyte antigen (HLA) polymorphisms, which
regulate immune response, are associated with BL has not been well
investigated, which limits our understanding
of BL etiology. Here we investigate this association among 4,645 children
aged 0-15 years,
800 with BL, enrolled
in Uganda, Tanzania,
Kenya, and Malawi.
HLA alleles are imputed with accuracy >90%
for HLA class I and 85-89% for class II alleles. BL risk is elevated with
HLA-DQA1*04:01 (adjusted odds
ratio [OR] = 1.61, 95% confidence interval [CI] = 1.32-1.97, P = 3.71
× 10-6), with
rs2040406(G) in HLA-DQA1
region (OR =
1.43, 95% CI = 1.26-1.63, P = 4.62 × 10-8), and with amino acid Gln at position
53 versus other variants in HLA-DQA1 (OR = 1.36, P = 2.06 × 10-6). The associations with HLA-DQA1*04:01 (OR = 1.29, P = 0.03) and rs2040406(G) (OR = 1.68,
P = 0.019) persist in mutually adjusted
models. The higher risk rs2040406(G) variant for BL is associated with decreased HLA-DQB1
expression in eQTLs in EBV transformed lymphocytes. Our results support the
role of HLA variation in the etiology of BL and suggest that a promising area
of research might be understanding the link between
HLA variation and EBV control (40).
Ishwar
Gilada in his presentation discussed the need for new strategies to combat
viral outbreaks and future pandemics, as traditional tools like vaccines and
antiviral drugs are not enough on their own. It emphasizes exploring
innovative, scalable, and globally inclusive strategies.
•
Preventive Strategies: To better prevent
and manage future pandemics, we must explore
alternative and complementary strategies that are innovative, scalable,
and globally inclusive (replicability, adaptability and
accessibility). These include developing universal vaccines, using genetic
engineering to build resistance, employing AI and genomics for viral bio-surveillance, enhancing the microbiome, utilizing antiviral surfaces and air filtration, and adopting a "One Globe-One Health" framework that connects human, animal, and environmental health.
•
Curative / Therapeutic Strategies: Advances in this
area include broad-spectrum antivirals, RNA-based
therapies, engineered immune cells, and
repurposing natura*l compounds offer new hope.
•
Systemic
and Infrastructure Strategies: Multi-faceted strategies can help focus on building
a more resilient public health
system through decentralized manufacturing platforms, digital
health and early warning systems, and global coordination via a pandemic
treaty.
In
conclusion, the lessons from past pandemics underscore the urgent need for
global preparedness, proactive strategies, and collective action.
Emerging threats like HPV, HBV, and AMR highlight the necessity
of alternative approaches alongside conventional methods. Embracing innovations
such as universal vaccines, broad-spectrum antivirals, RNA-based therapies,
nanotechnology, and AI can revolutionize our pandemic response. Central to
success are robust systems for pathogen tracking, genome sequencing, and global
knowledge sharing. Ensuring health security requires integrated disaster
management and a unified “One World–One Hope” vision, grounded in environmental
respect and preventive action.
Per Hammarström
Per
Hammarström’s talk conveyed both enthusiasm and concern regarding the rapid
development of biopharmaceutical drugs, also known as biologics. Biologic drugs
are at the forefront of modern medicine, enabling the treatment of previously
intractable diseases. Biopharmaceuticals encompass synthetic, semisynthetic,
and recombinant peptide and protein drugs, as well as
oligonucleotide-based agents, including
modified messenger RNAs
(mRNA), small interfering RNAs (siRNA), and
antisense oligonucleotides
(ASOs) (42).
According
to Pharmaceutical Research and Manufacturers of America (PhRMA)
(https://phrma.org/), more than 7,000 biopharmaceutical products are currently
in clinical development worldwide, with over 1,000 having reached
Phase 3 trials.
Additionally, more than 100 non-COVID-19 monoclonal antibody (mAb)-based products are in late-stage clinical development. The global biopharmaceuticals market was valued at USD 616.94 billion in 2024 and is
projected to grow from USD 666.41 billion in 2025 to USD 1,183.87 billion by 2032
(https://www.fortunebusinessinsights.com/biopharmaceuticals-market-106928). However,
the rapidly expanding and increasingly accessible biopharmaceutical landscape
also presents risks. Proteins are labile molecules, and amyloidosis refers to a
group of conditions in which proteins misfold and assemble into stable
fibrillar structures with a strong tendency to grow and replicate by recruiting
additional proteins into the misfolded form, which can have very detrimental
effects in the organs where it occurs.
Dr. Hammarström demonstrated that the essential diabetes drug insulin
is highly amyloidogenic - a property that has been known
for a long time43. More
recently, the highly
successful glucagon-like peptide-1 (GLP-1) agonists, such as semaglutide (Wegovy®, Ozempic®), which are now widely used for both diabetes and weight
loss, have been shown to be highly
amyloidogenic. Similar properties have been observed
in other peptide drugs, such as enfuvirtide
(Fuzeon®) used against HIV44. The potential long-term effects of localized
iatrogenic amyloidosis resulting from such treatments remain unknown. Even
more concerning is the emergence of mRNA-based biologics, which use the human
body as a platform to express novel
- and in many cases,
exotic - proteins. This was exemplified by the mRNA COVID-19 vaccines, which instruct cells to produce
the SARS-CoV-2 spike protein. The spike protein itself has been shown to be
highly amyloidogenic under immune-reactive conditions45 (Nyström and
Hammarström 2022). Because the mRNA is delivered via lipid nanoparticles that
can distribute systemically, there is potential for expression in a wide range of cells and organs, raising
concerns about the possibility of systemic amyloidosis in susceptible
individuals. The long-term risks of adverse events, such as amyloidosis, are
not yet sufficiently considered in the rapidly evolving
field of biologic
drug development.
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