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General Description:

Voretigene neparvovec, identified by CAS number 1646819-03-5, is a notable compound with significant therapeutic applications. Voretigene Neparvovec-rzyl (VN-rzyl) is an adeno-associated virus vector-based gene therapy. An adeno-associated virus is a small virus that infects humans and other primates. It is not pathogenic and it causes a very mild immune response. This type of virus is vastly used as vectors for gene therapy because they can infect dividing and quiescent cell integrating just the carried genes into the host genome without fully integrating into the genome. An advantage of this adeno-associated virus is the high predictability, unlike retrovirus, as they associate with a specific region of the human cellular genome localized in the chromosome 19. When used in genetic therapy, this virus is modified for the elimination of its negligible integrative capacity by the removal of *rep* and *cap* and the insertion of the desired gene with its promoter between the inverted terminal repeats. VN-rzyl was developed by Spark Therapeutics Inc. and FDA approved on December 19, 2017.

Indications:

This drug is primarily indicated for: VN-rzyl is indicated for the treatment of children and adult patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. The administration of VN-rzyl is conditioned to the physician determination of the presence of viable retinal cells. The RPE65 represents the LCA2 form of the Leber's congenital amaurosis (LCA). LCA is a group of inherited conditionts that involves retinal degeneration and severe vision loss in early childhood leading to total blindness by 30-40 years old. The LCA2 form is associated with a mutation that interferes with the isomerohydrolase activity of the retinal pigment epithelium. The isomerohydrolase activity transforms the trans-retinyl esters to 11-cis-retinal which is the natural ligand and chromophore of the opsins of rod and cones photoreceptors. In the presence of RPE65 mutations, the opsins cannot capture light or transduce it into electrical responses to initiate vision. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Absorption:

The absorption characteristics of Voretigene neparvovec are crucial for its therapeutic efficacy: In preclinical studies, it was found a high level of vector DNA sequences in intraocular fluids as anterior chamber fluid or vitreous. Lower levels were detected in optic nerves, optic chiasm, spleen and liver. There was a very small amount found in lymph nodes. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Voretigene neparvovec is an important consideration for its dosing schedule: Based on the pharmacokinetic preclinical studies performed with VN-rzyl and previous studies with different AAVV, it is possible to determine that the half-life of VN-rzyl is approximately 1.7 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Route of Elimination:

The elimination of Voretigene neparvovec from the body primarily occurs through: VN-rzyl is eliminated transiently and at low levels in tears of both, the injected (45%) and non-injected eye (7%) until day 3 post-injection. Most of the drug elimination by the tears happend during day 1 post-injection. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Voretigene neparvovec is distributed throughout the body with a volume of distribution of: VN-rzyl was shown to be distributed in serum. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Voretigene neparvovec is a critical factor in determining its safe and effective dosage: According to the kinetics of AAVV obtained in preclinical trials, VN-rzyl will present a rapid clearance with less than 3% of the administered dose left after 4 hours. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Voretigene neparvovec exerts its therapeutic effects through: Subretinal injection generates the transduction of retinal pigment epithelial cells, restoring the visual cycle. In clinical trials, there was a significant increase in the mean bilateral multi-luminance mobility testing scores with a shown maximum possible improvement. The eyes receiving the treatment presented also a more effective drive in pupillary response even 3 times greater than the baseline. There was also a significant reduction of nystagmus. The improved vision was determined by the ability of the treated patients to cross an obstacle course at various light levels which showed a significant amelioration. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Voretigene neparvovec functions by: VN-rzyl is designed for the delivery, in the cells of the retina, of a normal copy of the gene encoding for the human retinal pigment epithelial protein whose molecular weight is 65 kDa. The delivery of this gene will allow the production of the RPE65 protein re-establishing the visual cycle and restoring the visual function. The adeno-associated viral vectors (AAVV) presents two open reading frames encoding for its replication (*rep*) and capsid (*cap*). It contains as well a zone with inverted terminal repeats which are required for the replication and packing of the viral genome. The replication of the AAVV requires the presence of a co-infector such as adenovirus or herpesvirus. Thus, without this co-infector, AAVV stays latent with its viral genome in the infected cell. The AAVV construct will contain the transgene in the inverted terminal repeats and it will replace the *rep* and *cap* sequences. The final AAVV will enter the cell nucleus and persist in different states. The first one involves the conversion of the AAVV genome into double-stranded circular episome which will later become a concatamer and provide a long-term transgene expression, particularly in non-dividing cells. The second option, presented in 0.1% of AAVV, is the integration at non-homologous sites of the host genome as single-copy proviruses or concatamers. In both options, there will be the presence of transgene expression. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Voretigene neparvovec is categorized under the following therapeutic classes: Adeno-associated Viral Vector Therapies, Ophthalmologicals, Sensory Organs. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Voretigene neparvovec include:

• Water Solubility: Soluble
• Melting Point: 72-90ºC
• Molecular Weight: 1330000.0