Sylentis

Design, modelling
and AI

Nanotechnology and drug delivery

Therapy
Development

Production
and escaling

Sylentis, coordinator of the OLIGOFASTX project, is a PharmaMar Group company and one of the pioneers in the development of drugs based on RNA interference (RNAi) technology. Sylentis seeks to build a solid and sustainable business in the development of new therapies based on RNA interference technology, especially in the area of ophthalmology, with two products currently in clinical development.

The company has a proprietary software platform, SirFinder^TM, with powerful RNAi drug design capabilities based on the use of artificial intelligence. Thanks to this platform, it is possible to design active molecules based on oligonucleotides considering a wide range of parameters that ensure a better drug development life cycle, always seeking innovative drugs that improve the quality of life of patients.

Sylentis has also been approved by the Spanish Agency for Medicines and Health Products (AEMPS) as a pharmaceutical laboratory manufacturing investigational medicinal products and has the industrial capacity to manufacture oligonucleotides under both GMP and non-GMP quality.

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TECNOLOGIES

INTERFERENCE RNA
COMPUTATIONAL DESIGN OF OLIGONUCLEOTIDES USING AI

A significant number of diseases and their symptoms are due to a malfunction or excessive production of certain proteins in the patients’ cells. Therefore, trying to reduce the production of these proteins may help to treat a disease.

Proteins are long chemical chains composed of a sequence of structural units called amino acids that serve many important functions in the body. They are vital for most of the work performed by cells and are necessary to maintain the structure, function and regulation of the body’s tissues and organs. Proteins have to be built in the right way for the whole gear of our body to work perfectly.

All the information needed to make any protein in the cell is inside the nucleus of the cell stored in the genes. These in turn are made up of segments of DNA that contain the specific code that carries the instructions that tell a cell how to produce a specific protein. Since DNA is a very large double-stranded molecule and contains a lot of information, it cannot leave the nucleus; for this, the cell uses an intermediate single-stranded molecule, messenger RNA, which is a partial copy of DNA and transports the information of interest out of the nucleus, enabling the synthesis of proteins thanks to ribosomes. While DNA contains the genetic information, it is RNA that allows this information to be understood by cells, serving as a guideline for protein synthesis. RNA is sized to pass through tiny pores in the nucleus into the cytoplasm, where ribosomes are located. Ribosomes are responsible for creating proteins. They must read the RNA, pick up amino acids and link them together to build a chain according to the previously indicated code of the RNA. As this chain grows, it bends and folds, sticks to itself, and gives rise to a protein that performs the actions inside the cell.

RNA-based interfering RNA (RNAi) drugs act at the level of the mRNA that carries the information of pathogenic or highly expressed proteins, initiating a process of mRNA destruction. Therefore, by reducing the pathological mRNA, the amount of pathogenic proteins produced is reduced accordingly. This allows the cells to return to their original functionality, and therefore the patient to a situation of normality. This process is called gene silencing.

Among the most important compounds that enable gene silencing are small interfering RNAs (siRNAs). siRNAs are small oligonucleotides with a double-stranded structure and a composition similar to that of DNA or RNA. Both DNA and RNA are composed of a combination of different letters T, C, G, A, (DNA) and U, C, G, A, (RNA). The combination of these allows the creation of different patterns that give rise to different instructions that are subsequently interpreted and translated by the ribosomes, giving rise to very different proteins. The particular combination of these letters is in turn related to the specificity and efficiency of function of the siRNAs. siRNAs are designed to be highly specific drugs and avoid potential unwanted effects. Thanks to the AI algorithms used during the design of siRNAs, risks associated with any drug, such as toxicological risks, are avoided from the beginning of their development.

Within the consortium, the company specializing in the design and development of these molecules, Sylentis, uses an advanced and powerful software platform, called SirFinderTM. From the design phase, a wide range of properties are controlled to substantially increase the possibilities of these molecules to be functional, not only in the in vitro phases of development, but also in the following stages of drug development, while presenting adequate chemical and pharmacological characteristics to facilitate their manufacture and commercialisation in case they reach the market.

The genetic information for the development and functioning of all living organisms is contained in their DNA molecules. These molecules store and transport information, in a structured form, with the orders and rules that mark the functioning of the cellular machinery, and that we can understand today. Similar to any data storage medium, this information is recorded in the form of a code in the DNA.

DNA consists of two long chains joined together in the form of a double helix with a chemical backbone composed of sequences of four repeating building blocks, called bases, whose names are Adenine, Guanine, Cytosine and Thymine. We can assimilate the appearance of each of these bases in the DNA sequence to a letter in the genetic code, abbreviated as A, G, C and T. And we can take these four letters as those that make up the words of the cellular language.

DNA is a very stable and large molecule. This is an advantage for preserving the information contained, but does not make it functional for communicating it to the rest of the cell since the DNA is confined to the cell nucleus. To transmit the information contained in DNA, cells make a copy of this information, already fragmented, to another analogous molecule with slight chemical modifications, the messenger RNA (mRNA). Thymine in mRNA (T) is replaced by a very similar molecule, the Uracil (U). So its letters become A, G, C and U. Smaller and single-stranded, the messenger RNA is able to navigate through the cell to specific organs where the instructions contained in the transmitted information are executed: the ribosomes. These instructions are none other than those necessary for the creation of proteins and the ribosomes are able to interpret them and manufacture these proteins.

Proteins, like DNA, are long chains composed of repeated chemical building blocks called amino acids (in this case there are 20). Within DNA and RNA there are combinations of 3 bases grouped together that inform the ribosome of the specific amino acid to be added to the chain of a protein, equivalent to a word.

For example, if the genetic code read has the sequence UGC, the ribosome will add one unit of the amino acid cysteine to the protein, but if a CGA group is read, an arginine will be added. Other base groups will indicate when the protein sequence begins and ends.

The fact that we understand this code of information transmission in living beings, together with the advanced knowledge of the physico-chemistry of these molecules, makes it a process that can be analyzed with computer tools to search for applications. One of them is to create small molecules with structures similar to DNA and RNA, the so-called oligonucleotides, which with this same cellular language are able to interfere or give instructions to the cells in a controlled way so that they behave in a certain way. Despite being a complex task, nowadays, the use of information technologies, the application of advanced algorithms and the irruption of artificial intelligence offer incredibly effective tools for the design of these molecules, seeking from the outset the design of safer and more effective drugs.

Within the OLIGOFASTX consortium, Sylentis contributes its expertise in the application of these technologies by providing the project with its SIRFINDERTM platform. This platform is entirely developed by the company and includes more than 30 algorithms for the accelerated design of oligonucleotide-based drugs including a large number of predictive parameters for the optimization of drug efficiency during its development and after its eventual approval, such as its possible toxicity, considerations of product properties in preclinical trials or factors that may affect its manufacture.

RARE DISEASES

Retinitis pigmentosa or retinitis pigmentosa (RP) comprises a group of eye diseases that involve damage to the retina. The retina is a specialized tissue on the inner surface of the eye, where images are projected and with the capacity to convert light signals into nerve signals, being its fundamental function of the sense of vision. In retinitis pigmentosa patients, this tissue degrades and even disappears in many patients. Some forms of retinitis pigmentosa may be associated with deafness, obesity, kidney disease and other general health problems, including metabolic and central nervous system disorders. Sometimes it is also associated with chromosomal abnormalities.

It is estimated that 1 in every 3.000-4.000 people in the world suffers from retinitis pigmentosa and it is the leading cause of total blindness. With a world population currently estimated at over 7.74 billion people, it can be estimated that approximately 1.94 to 2.58 million people worldwide suffer from one of these disorders. It is therefore a rare disease, but affects a significant number of people in the population. The disease is estimated to affect 2 to 2.6 million worldwide, with 15.000 cases in Spain alone.

It is a disease that is generally inherited through one or both parents, although, on rare occasions, it can evolve spontaneously from DNA miscoding during cell division. 50% of cases have a family history. However, severe visual impairment does not affect everyone equally, even within the same family. Several specific genes involved in this disease have been identified, but it is not clear why mutations in one gene alter photoreceptors and other retinal layers.

Retinitis pigmentosa manifests itself in different ways causing progressive vision loss. Among the various symptoms described, some of the most relevant are night vision problems or reduced peripheral vision (lateral, upper or lower). As the patient’s vision worsens they may experience ‘tunnel vision’. In some people, retinitis pigmentosa can also lead to disturbances in colour perception. There is currently no cure for retinitis pigmentosa.

Leber’s congenital amaurosis (LCA) is an eye disease that primarily affects the retina, the inner eye tissue on which images are projected and where light signals are converted into electrical impulses reaching the brain and generating vision. Its prevalence is estimated at 1 to 9 cases per 100.000 population and accounts for 5% of all retinal dystrophies and 20% of paediatric blindness. It is therefore a rare but serious, genetically based eye disease that begins to show signs as early as the first year of life.

This disease causes severe visual impairment in children from the first months of life and can be recognised by the persistence of nystagmus (continuous pendular movements of both eyes) from the third month of life, intense photophobia and enophthalmos (sunken eyes). Vision loss in children with LCA occurs when the photoreceptor cells of the retina (rods and cones) stop functioning. Cones (allow daytime vision and colour vision) and rods (allow vision at night or in dimly lit places).

LCA is characterized by severely reduced visual acuity (≤ 20/400) or blindness during the first year of life. Depending on the genetic cause, slow pupillary response, wandering eye movements, photophobia, high hyperopia, nystagmus, convergent strabismus or keratoconus may be present. Franceschetti’s oculo-digital sign, consisting of squeezing, pressing and rubbing the eyes, is characteristic of the disease and allows the diagnosis to be established. Leber congenital amaurosis may also be associated with mutations in genes linked to other syndromes presenting with neurodevelopmental delay, intellectual disability, apraxia (eye movement difficulty) and renal dysfunction.

Älstrom Syndrome (ALMS) is a rare genetic multisystem disorder. Its estimated prevalence is 1 case per 1.000.000 inhabitants in Europe and North America, being much higher in certain populations with a high degree of consanguinity or geographically isolated.

Älstrom Syndrome is characterized by dystrophy of the cones (cells that allow daytime vision and color vision) and rods (cells that allow night vision or vision in dimly lit places) in the retina, The syndrome is also associated with hearing loss, hypertriglyceridemia and obesity, hyperinsulinemia, type 2 diabetes mellitus, dilated cardiomyopathy (DCM), multiorgan fibrosis, hypogonadism/hyperandrogenism, chronic respiratory disease, and progressive renal and hepatic dysfunction.

The syndrome is also associated with hearing loss, hypertriglyceridemia and obesity, insulin resistance and hyperinsulinemia, type 2 diabetes mellitus, dilated cardiomyopathy (DCM), multiorgan fibrosis, hypogonadism/hyperandrogenism, chronic respiratory disease, and progressive renal and hepatic dysfunction.

Cone and rod retinal dystrophy usually has a strong genetic factor and develops within a few weeks after birth, although the form and age of onset of the first symptoms are highly variable among patients. Symptoms include nystagmus (involuntary eye movement) and photodysphoria (high sensitivity to light).

From an ophthalmic perspective, it is a serious eye disease since it progressively causes total blindness usually in adolescence. However, the symptoms, in many cases systemic, go much further, as most patients develop progressive bilateral neurosensory loss of varying intensity, multiorgan fibrosis, obesity, hyperinsulinemia and risk of heart failure. There is no curative treatment, so the therapeutic objective is based on improving symptoms. As it is a process that affects many organs, it usually involves different specialists who must work in a coordinated manner, including the pediatrician, family physician, ophthalmologist, endocrinologist, otolaryngologist and cardiologist.