In 2018, an American film titled "Midnight Sun" was released, which tells the story of Katie Price, a protagonist suffering from Xeroderma Pigmentosum (XP), a rare genetic disorder that makes her extremely sensitive to ultraviolet (UV) light. The film follows her love story with Charlie Reed, who she meets and falls in love with over their shared passion for music. However, Katie has to lead an inverted schedule, dating Charlie only at night because she cannot be exposed to sunlight. Tragically, during one of their dates, they lose track of time and Katie is exposed to daylight, leading to a rapid deterioration of her condition and ultimately her death due to the lack of curative treatment. The lovers, brought together by their love for music, are tragically separated by the progression of XP. Patients like Katie, who cannot live life under the sun, suffer immensely from the disease and face significant challenges in seeking medical care. They experience intense conflicts between the need for self-protection and the desire for social interaction, highlighting the need for greater humanistic care for individuals with XP.
In 2018, an American film titled "Midnight Sun" was released. The film tells the story of Katie Price, a young girl who suffers from Xeroderma Pigmentosum (XP), a rare genetic disorder that makes her extremely sensitive to ultraviolet (UV) light. The film follows her love story with Charlie Reed, whom she meets and falls in love with over their shared passion for music. However, Katie has to lead an inverted schedule, dating Charlie only at night because she cannot be exposed to sunlight. Tragically, during one of their dates, they lost track of time and Katie is exposed to daylight, leading to a rapid deterioration of her condition and ultimately her death due to the lack of curative treatment. The lovers, brought together by their love for music, are tragically separated by the progression of XP. Patients like Katie, who cannot live under the sun, suffer immensely from the disease and face significant challenges in seeking medical care. They experience intense conflicts between the need for self-protection and the desire for social interaction, highlighting the demand for greater humanistic care for individuals with XP.
</p>
<p>
Xeroderma pigmentosum (XP) is an autosomal recessive genetic disorder that is found in all races across continents (DiGiovanna et al., 2012). Based on the different gene mutations, XP is classified into several subtypes (e.g., XPA, XPB, XPC, etc.), each with its specific genetic defects (Sancar et al., 1994). XP-C, which accounts for 25% of all cases, is one of the most common types. The condition arises from mutations in the XPC gene, leading to a deficiency in the XPC DNA repair protein. This deficiency prevents the repair of DNA damage caused by ultraviolet (UV) radiation, resulting in a blockage of global genome nucleotide excision repair (NER) (Marteijn et al.,2014).
Xeroderma pigmentosum (XP) is an autosomal recessive genetic disorder that is found in all races across continents (DiGiovanna et al., 2012). Based on the different gene mutations, XP is classified into several subtypes (e.g., XPA, XPB, XPC, etc.), each with its specific genetic defects (Sancar et al., 1994). XP-C, which accounts for 25% of all cases, is one of the most common subtypes. The condition arises from mutations in the XPC gene, which causes a dificiency in the XPC DNA repair protein. This deficiency hinders the repair of DNA damage caused by ultraviolet (UV) radiation, resulting in a blockage of global genome nucleotide excision repair (NER) (Marteijn et al.,2014).
</p>
<p>
Patients with XP are highly sensitive to UV light, typically showing symptoms between 6 months and 3 years of age. Sun-exposed areas may develop blisters, freckles, epidermal hyperplasia, scar formation, and tumors. Two-thirds of patients die before the age of 20 due to multiple tumors (Leung et al.,2022). Traditional treatment methods mainly rely on prevention and management, without directly addressing the genetic defects in XP patients. Strategies for patient care primarily include sun protection, regular skin examinations, and surgical removal of cancerous tissues (Kraemer et al., 2007). However, while these methods can alleviate symptoms, they do not reverse or halt the progression of the disease. The core goal of gene therapy is to restore normal function by correcting or replacing the defective genes in XP patients. Currently, gene therapy for XP is mainly focused on preclinical research stages. Studies have shown that post-gene editing, cells exhibit significantly enhanced tolerance to UV light, resulting in a marked reduction in cancer risk (Rass et al., 2007;Dupuy et al., 2013).
Patients with XP are highly sensitive to UV light, typically showing symptoms between 6 months and 3 years of age. Sun-exposed areas may develop blisters, freckles, epidermal hyperplasia, scar formation, and tumors. Two-thirds of the patients die before the age of 20 due to multiple tumors (Leung et al.,2022). Traditional treatment methods rely mainly on prevention and management, without directly addressing the genetic defects in XP patients. Strategies for patient care primarily include sun protection, regular skin examinations, and surgical removal of cancerous tissues (Kraemer et al., 2007). However, while these methods can alleviate symptoms, they do not reverse or halt the progression of the disease. The core goal of gene therapy is to restore the normal function of human body by correcting or replacing the defective genes in XP patients. Currently, gene therapy for XP is mainly focused on preclinical research stages. Studies have shown that after gene editing, cells exhibit significantly enhanced tolerance to UV light, resulting in a marked reduction in cancer risk (Rass et al., 2007;Dupuy et al., 2013).
<figcaption> Fig.1 Symptom map of XP patients</figcaption>
...
...
@@ -64,7 +64,7 @@
</div>
<divclass="block"style="font-family: Arial">
<p>
Our project aims to develop a gene switch that responds to ultraviolet light and use this gene switch for the treatment of Xeroderma Pigmentosum Type C. Our project is mainly divided into three modules: First, we have verified the interaction of UVR8, COP1, and RUP2 in mammalian cells and their response to ultraviolet light; Second, we have successfully constructed a UV-responsive gene switch that activates the expression of target genes upon UV irradiation and demonstrated that RUP2 can dissociate the interaction between UVR8 and COP1, thereby stabilizing the expression level of the target gene to a certain extent; Third, through modeling, we have obtained results predicting the expression of the target protein after sequence optimization of RUP2, and successfully constructed plasmids with different numbers of rare codons added to the RUP2 gene, which will be validated through wet lab experiments.
Our project aims to develop a gene switch that responds to ultraviolet light and use this gene switch for the treatment of Xeroderma Pigmentosum Type C. Our project is mainly divided into three modules: First, we have verified the interaction of UVR8, COP1, and RUP2 in mammalian cells and their response to ultraviolet light. Second, we have successfully constructed a UV-responsive gene switch that activates the expression of target genes upon UV irradiation and demonstrated that RUP2 can dissociate the interaction between UVR8 and COP1, thereby stabilizing the expression level of the target gene to a certain extent. Third, through modeling, we have obtained results predicting the expression of the target protein after sequence optimization of RUP2 and successfully constructed plasmids with different numbers of rare codons added to the RUP2 gene, which will be validated through wet lab experiments.
</p>
<p>
XPCures now takes the stage! We innovatively introduce the plant UV receptor system into the gene therapy of Xeroderma Pigmentosum Type C, using UV-B as an external regulatory factor to induce the expression of the XPC gene, and develop a new type of therapy that uses optogenetic technology as the control end and gene therapy as the foundation. According to the pathogenesis of XPC patients, we have created a gene expression system regulated by UV-B, achieving controllable expression of the XPC gene in patients, turning the pathogenic UV into therapeutic UV.
