Student Startup winner to develop gene therapy for Smith-Lemli-Opitz syndrome
Smith-Lemli-Opitz syndrome (SLOS) is a rare hereditary disorder caused by mutations in the DHCR7 gene, which encodes the enzyme 7-dehydrocholesterol reductase. This enzyme is involved in the final stage of cholesterol synthesis. Dysfunction of the enzyme leads to the accumulation of toxic precursors and a deficiency of cholesterol, which is vital for the normal development and function of cells, especially those of the nervous system. The incidence rate is estimated at 1 case per 20,000 to 60,000 newborns, making it an orphan (rare) disorder, explains the Student Startup grant winner, second-year master’s student of the Institute of Fundamental Medicine and Biology Danil Gallyamov.
Currently, patients only have access to symptomatic support aimed at compensating for cholesterol deficiency; however, this does not address the genetic defect itself. The student proposes an etiotropic approach to therapy, which addresses the underlying cause of the disease. The drug is designed to restore the function of the damaged gene, thereby normalizing cholesterol biosynthesis at the cellular level. “Currently, there is no etiotropic treatment. Therapy is limited to dietary measures and external cholesterol administration, which does not address the underlying cause of the disease. Therefore, the development of a gene therapy drug has high scientific and social significance, as it can provide real disease correction at the DNA level,” says the young scientist about the significance of his approach.
A single-dose gene therapy drug will be developed based on the adeno-associated viral vector 9 (AAV9), which, in turn, has a pronounced affinity for liver and central nervous system cells, the main target organs in HLHS. As a reminder, the competition rules allot one year for implementation.
“The construct we developed contains a functional copy of the DHCR7 gene under the control of tissue-specific regulatory elements, which ensures a physiological level of enzyme expression without the risk of overdose. Furthermore, the project incorporates solutions that enhance the stability and safety of the vector system, making the drug a promising candidate for preclinical and clinical trials,” Gallyamov continues.
The drug is designed for a single systemic administration, primarily intravenous. This allows the therapeutic gene to be delivered to key organs, including the liver and brain.
“The dosage is selected based on body weight and the expression level of the target gene, with the goal of achieving physiologically normal cholesterol levels without the risk of overexpression. The therapeutic effect is expected to manifest within a few weeks after administration and to persist for a long time, possibly throughout the patient’s life,” the grantee notes.
The mechanism of action involves several stages and is aimed at restoring the function of the defective enzyme, which not only halts disease progression but also addresses its underlying cause, ensuring sustained improvement in metabolic and neurological parameters. The first stage involves the delivery of the DHCR7 gene: after administration, the AAV9 viral vector selectively penetrates target cells. The delivered gene copy then begins to express, and the functional enzyme 7-dehydrocholesterol reductase is synthesized in the cell, the IPMBI master’s student explained. The enzyme’s activity normalizes cholesterol synthesis, reducing the level of toxic precursors. Finally, metabolic stabilization—restoring cholesterol metabolism—promotes improved membrane structure, neurogenesis, and organ development, leading to a lasting clinical effect, explains Gallyamov.
The drug will be developed at the Laboratory of Gene and Cell Technologies under the supervision of Albert Rizvanov, Head of the Laboratory, Professor of the Department of Genetics, Academician-Secretary of the Department of Medical and Biological Sciences at the Academy of Sciences of the Republic of Tatarstan; Yana Mukhamedshina, Chief Researcher, Professor at the Academy of Sciences of the Republic of Tatarstan; and Elvira Akhmetzyanova, Senior Researcher of the Laboratory.
“The project has very promising prospects. We are essentially creating the first-of-its-kind gene therapy capable of eliminating the cause of Smith-Lemli-Opitz syndrome, not just alleviating its symptoms. This technology can be used for other inherited metabolic diseases in the future. Furthermore, the project forms the basis for the development of domestic gene therapy platforms and elevating Russia to a global level in this field,” concludes the interviewee.
This time, 139 students from Kazan University were named winners of the sixth round of the Student Startup competition.