Therapeutic perspectives

A.I.G.S.S. Association



Therapeutic perspectives

Prion diseases are incurable and rapidly fatal neurodegenerative diseases. Very little has been done in the past 30 years. However, something is finally changing. We now expose two drugs for PRNP positive but asymptomatic patients.
Our hope is that they will soon be subjected to further studies and administered in "science and consciousness". In Europe for over 10 years a drug has been administered the active substance is doxycycline, an antibiotic.

Unfortunately, it was a failure, although it has been text tested on patients for many years. Regarding the treatment in question, we wish to make known to those who follow us, the opinion of the greatest researcher currently active in the United States, ERIC MINIKEL.

However, times have changed and although science has long times there is something new, we start from potential drugs for patients who are positive for DNA testing but asymptomatic:

As we have seen, elevated cholesterol levels are a risk factor for those who are positive but asymptomatic.
At the same time, for at least 15 years, TRIALs have been carried out on mice with statins. In 2008, Yaron Haviv of the University of Jerusalem demonstrated that a particular statin, SIMVASTATIN, delays the progression of prion disease and increases in vivo survival, regardless of the pathogenic conversion of PrP (c) to PrP (Sc).
Induced Neuroprotection Independently from PrP (Sc) Accumulation in a Mouse Model for Prion Disease Treated with Simvastatin.

It was given to sick patients in the United States. This, however, did not prove decisive and no TRIAL was started to see if life expectancy increased.
Nothing was given to positive but asymptomatic patients. At that time all efforts were focused on the mix of chlorpromazine and quinacrine. More or less the same conclusion was also reached by Prof. Maurizio Pocchiari of the Istituto Superiore di Sanità (Rome) in 2009 with another type of statin, PRAVASTATIN.
Oral pravastatin prolongs survival time of scrapie.

However, in those years in Italy efforts were focused on doxycycline and it was never tested.
Today that both experiments (both the American and the Italian one) have failed, we believe there are the conditions to start a TRIAL. In order to potential a possible TRIAL we think it is useful to add an artophagous substance that has given good results on Parkinson's disease and prion diseases, TREHALOSE.
Autophagy induction by trehalose counteracts cellular prion infection.

Furthermore, according to a study carried out at the Institute of Neuropathology in Düsseldorf, Germany, it seems that there is another substance which could give further benefit to positive but asymptomatic patients: VITAMIN E.

We are confident that in 2023 we will start this TRIAL on mice and subsequently in humans.

The Ionis Pharmaceutical company has already developed drugs for the treatment of rare diseases based on antisense oligonucleotides (antisense oligonucleotide means a short fragment of DNA, which contains the complementary nucleotide sequence of the coding (sense) DNA strand or messenger RNA (mRNA). Therefore, the antisense, thanks to its "mirroring" with respect to the sense DNA, appears to it or to the mRNA, canceling its biological activity).

The company is working to find an effective therapy for prion diseases and hopes to be able to begin a phase 1 clinical trial at the end of 2022 (it will be a trial in the US). RNA therapies: what are they and what are they for? The therapies that target RNA, "RNA targeted therapies" in scientific jargon, are mostly strategies based on short molecules of RNA or DNA that act by modulating the expression of messenger RNA (m-RNA) by means of mechanism of "RNA interference" or regulation of "splicing" (a process of maturation of the mRNA). They are very innovative therapies but do not fall within the technical definition of Advanced Therapy Medicinal Product (ATMP), so they are not advanced therapies. However, they remain among the most relevant technologies in the biotechnology field. Messenger RNA is the molecule responsible for carrying the instructions contained in the genome to ensure that they are transformed into the final functional product: proteins. Being able to modulate m-RNA in a precise and effective way therefore allows you to regulate the expression of the product of a gene without changing the original genetic code. Thus, differentiating from gene therapy and genomic editing which aim to correct the genetic defect by acting directly on the DNA. It is a very good prospect, which two young American scientists, husband and wife Eric Minikel and Sonia Vallabh are pursuing. The Ionis Pharmaceutical company is betting a lot on this therapy, financing it and supporting the staff in Boston.
Antisense oligonucleotides extend survival of prion-infected mice

Now let's take a break and try to understand how the aforementioned ASO therapy should work:

Porphyrins are substances that are found within our body (but not in the brain). As early as 2015, a study in the field of prion diseases began at the Mario Negri Institute, under the guidance of Prof. Roberto Chiesa of the Mario Negri Institute in Milan. In particular, a particular porphyrin has been identified which has a dual action against the prion; it is thought to be an extremely effective drug. The problem is that porphyrin is a large molecule and has a hard time crossing the blood-brain barrier (the barrier that separates blood from the brain).

It is not a simple problem, but enormous progress has been made using nanoparticles, i.e. microscopic vehicles that have signals on their surface that direct them to the brain. Finally, they managed to load the porphyrin onto these microscopic vehicles and they are about to verify if they can transport it to the brain and if, once it reaches this organ, the porphyrin does what it is supposed to do, that is, eliminate the prion. Now other strategies are being pursued. One of these consists in clarifying at the atomic level how our porphyrin works, in order to design other drugs with the same mechanism of action but which reach the brain without the need to use nanoparticles.

This experiment, which began in mouse models in 2015, ended successfully in 2019. Studies have only recently resumed due to the pandemic. Let us now read what Prof. Roberto Chiesa said.

“A novel application of a tetra cationic porphyrin capable of reducing PrP(C) and inhibiting PrP (Sc) replication: characterization of the mechanism of action and preclinical studies in mouse models of genetic prion diseases”.

Prion encephalopathies are degenerative diseases of the central nervous system for which there is no effective therapy. Three forms are known in humans: Creutzfeldt- Jakob disease, characterized primarily by dementia and motor system disorders, fatal familial insomnia, characterized by intractable insomnia, motor system impairment, and dementia, and Gerstmann disease. -Sträussler-Scheinker, which manifests itself mainly with a progressive inability to coordinate movements. These are very rare diseases, which generally arise in adulthood and whose prognosis is poor.

In animals, the most common forms of these diseases are mad cow disease (bovine spongiform encephalopathy) and sheep scrapie. These pathologies are all due to the conformational change of the cellular prion protein (PrPC) into an altered form, called PrPSc. This altered form is then able to induce the pathological conversion of other PrPC and to propagate in the brain with a chain reaction, causing neuron death. These diseases can arise spontaneously, be acquired through infection (in this case PrPSc is the infectious agent, called a prion) or inherited genetically (due to mutations in the PrPC gene).

In case of mutation, the structure of PrPC is altered, and this favors the transformation of the protein into the pathological form. There are two therapeutic strategies that could be adopted: to reduce the total levels of normal PrPC protein in the brain, thus eliminating the substrate for the formation of PrPSc, or to develop drugs capable of inhibiting the conversion. In our laboratory we have identified a new molecule, called Zn (II)-BnPyP, which possesses both of these capabilities. The aim of this research project will be to understand the mechanism of action of this new molecule and evaluate its ability to prevent or cure the disease in mouse animal models, in order to obtain an advance in knowledge that will lead to the development of an effective therapy for these pathologies”.

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