{"id":4478,"date":"2024-07-10T13:19:39","date_gmt":"2024-07-10T13:19:39","guid":{"rendered":"https:\/\/www.col4a1.net\/?p=4478"},"modified":"2024-07-10T13:22:13","modified_gmt":"2024-07-10T13:22:13","slug":"gene-therapy-for-rare-genetic-vascular-disorders-a-patient-driven-journey-in-drug-development","status":"publish","type":"post","link":"https:\/\/www.col4a1.net\/en\/gene-therapy-for-rare-genetic-vascular-disorders-a-patient-driven-journey-in-drug-development\/","title":{"rendered":"Gene therapy for rare genetic vascular disorders: a patient-driven journey in drug development"},"content":{"rendered":"

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Gene therapy for rare genetic vascular disorders: a patient-driven journey in drug development<\/h1><\/div>

Dr. Patricia Musolino, in her presentation titled \u201cGene therapy for rare genetic vascular disorders: a patient-driven journey in drug development,\u201d discusses the current state of gene therapy for rare genetic diseases. Diagnosing a genetic disease is the first step, although it can be complicated. For example, using imaging (such as MRI) to diagnose a disease can be very challenging. However, in our case, a common denominator is small vessel disease, which is common to all COL4A1 phenotypes in the eye, brain, posterior circulation, and anterior circulation.<\/p>\n

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Many genes govern the wall of a blood vessel, and COL4A1 is one of them. Its mutation leads to vascular wall alteration, hindering proper neuronal function and causing issues with cognitive processing and innovation. Gene therapy should aim to modify the function of the mutated gene (through RNA modification or small molecules on the protein itself) or to modify the gene (genetic editing) by directly acting on the mutated gene. Generally, gene therapy can be done inside the body, called in vivo, or cells can be taken from the body, modified in the lab, and reinserted into the patient from whom they were taken, called ex vivo.<\/p>\n

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Two types of viruses are involved in gene therapy for central nervous system diseases: adenoviruses and lentiviruses. These two types of viruses, known as viral vectors, are used in gene therapies where approximately 2,000 patients have already been treated. These viruses do not cause any disease (like a cold) but are used as gene carriers. When considering a possible gene therapy for COL4A1, fundamental questions must be answered for the authorities to approve the therapy: where to treat, when to treat, and who to treat? Dr. Musolino hypothesizes that COL4A1 patients could be treated in the eye, as this organ is frequently and severely affected.<\/p>\n

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Dr. Musolino\u2019s first example of gene therapy in white matter-associated diseases is an FDA-approved gene therapy. The disease is X-linked adrenoleukodystrophy, where cerebral disorder causes rapid degeneration of white matter, leading patients to become severely disabled in a short time. The presented case was of a six-year-old boy who had significant brain inflammation and degeneration just 12 months after diagnosis. The mutated gene is ABCD1. They hypothesized that a bone marrow transplant with modified cells could produce normal immune cells capable of blocking degeneration. Unfortunately, this engineered transplant failed, but 25 years of research revealed that a bone marrow transplant could help these children, but only after an early diagnosis. However, a bone marrow transplant with modified cells caused myelodysplasia (a group of diseases affecting the hematopoietic system), although it had a significant impact on brain degeneration, rapidly halting it.<\/p>\n

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The standard therapy, therefore, is a bone marrow transplant from a compatible donor, but when this is not possible, gene therapy is used, monitoring the patient for 15 years post-infusion. Among the three children in gene therapy, shown in Dr. Musolino\u2019s presentation, the first developed myelodysplastic syndrome after seven years\u2014a time frame sufficient to find a compatible donor for a transplant, which the disease would not otherwise allow.<\/p>\n

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Another example of gene therapy for a vascular disorder is using targeted gene correction with enzymes. These enzymes, derived from bacteria, are called CRISPR-Cas9 and act by cutting the DNA or inserting themselves between the two DNA strands. Another attached enzyme changes the mutated letter without cutting the DNA. According to Dr. Musolino, this technique could be used for COL4A1 to learn to regulate COL4A1. However, treatments should be very early, targeting the endothelium or smooth muscle. Basic research results, not yet published, show that gene therapy on smooth muscle cells of arteries could offer hope, but scientific progress takes time. Only in 2005 was COL4A1 first associated with perinatal hemorrhage.<\/p>\n

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The dream would be to achieve gene therapy not with viruses but with nanoparticles, offering greater flexibility in the mode of administration. Another condition with an ocular phenotype, like COL4A1, being studied for gene therapy is ACTA2 smooth muscle vasculopathy. If children with ACTA2 could be treated early, as they are currently doing, there could be windows for treatment, at least preventive treatments for stroke. They suffer from vessel narrowing, leading mainly to ischemic strokes rather than hemorrhages. It is a very multisystemic disease of smooth muscle, so everything involving smooth muscle is dysfunctional. Studies have created a mouse model with an arginine 179 mutation, also present in a patient, exhibiting the exact phenotype with brain vasculature narrowing, gastroparesis, and small pupils. These mouse models, treated very early with a viral vector carrying the non-mutated gene, showed improved mobility, with a prolonged effect over time. Thus, smooth muscle cells can be a target for gene therapy.<\/p>\n

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From this model, Dr. Musolino is trying to move to other models, like sheep and pigs, to scale up and ensure safety before reaching humans. They are also trying to determine the dosage.<\/p>\n

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Given these results on other diseases and understanding that the disease associated with the COL4A1 mutation is complex and multisystemic, Dr. Musolino, in collaboration with Dr. Gould, is trying to create a mouse model with the most common human mutation and a cellular model with different iterations for various mutations to study and understand the disease better, and then proceed with gene therapy development.<\/p>\n<\/div>

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