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HomeWORLD NEWSCustom gene therapy suggests a new route for treating rare diseases.

Custom gene therapy suggests a new route for treating rare diseases.

Timothy Yu started the area of personalized medicine when he created the medication milasen specifically for a young girl named Mila who had Batten disease. The first medication made just for one person was called Milasen, and it took just about a year to produce.

Nonprofit groups have developed in reaction to milasen pushing for the creation of tailored medicines for the 400 million patients with rare diseases who are thought to exist globally.

These drugs, often known as “n of 1” therapies, are frequently developed to treat crippling genetic disorders that are too uncommon to pique the interest of pharmaceutical firms.

Yu, an attending physician in the division of genetic and genomics at Boston Children’s Hospital, and his colleagues have now created atipeksen, another personalized medication, for a young child with the genetic condition known as A-T, or ataxia-telangiectasia.

A-T is brought on by a genetic coding change in a crucial enzyme involved in DNA damage repair. The mutation renders the enzyme inactive by preventing normal processing. In the end, this inactivity results in severe neurodegeneration and a life expectancy of 25 years on average.

A dedicated father of two sons with A-T inspired the creation of atipeksen, just like milasen.

I was presenting our plan to try to create a medicine for [Mila] at that time at a local conference, Yu recalled. There was a man in the back of the room who kept on asking these nagging pointed questions, especially directed at the pharmaceutical industry, about why they weren’t moving faster for specific orphan or rare diseases. This audience included scientists, doctors, and pharmaceutical executives.

The “gentleman” was Brad Margus, president and creator of the A-T Children’s Project (ATCP), a group dedicated to raising money, enlisting scientists and medical professionals, and compiling patient data in order to develop a treatment for A-T.

Margus was adamant about discovering cures despite the fact that his own two sons had missed the window to get A-T therapy. He remarked, “I just thought it was outrageous that top-notch research wasn’t being done on [A-T] just because it was rare.

Through ATCP, Margus had gained a lot of control over the situation. He had already assembled a database with the sequenced genomes of 235 A-T children by the time he met Yu. This information was precisely what Yu needed to address his next important query regarding the more general applications of customized antisense oligonucleotide (ASO) therapies.

Yu stated that “we knew that this field deserved a more systematic assessment of what the true opportunity was” for antisense oligonucleotides and “that A-T provided that opportunity to actually address it in a non-anecdotal way.”

ASOs are specialized synthetic DNA fragments that bind to a specific region of a person’s defective genetic code, essentially patching it so the cell can no longer detect the defective mutation. They may be employed to correct a mutation in the A-T-causing DNA damage repair enzyme, regaining appropriate processing and function.

Yu and his associates were able to carry out systematic studies using the patient data to not only pinpoint all the genetic variants that caused A-T in this group, but also to determine which mutations might be receptive to ASO treatment.

They came to the conclusion that 15% of the youngsters in this group had advantageous mutations. Yu and his team decided to create a therapy for a young girl after choosing one mutation from this 15% that had a high potential of responding favorably to ASOs.

Margus explained that she had to coordinate the [A-T] community’s families and explain how they would choose the first child. “We made it really clear that it would be based on whichever kid had a mutation that was very tractable with an ASO approach,” he remarked. “It would be huge if we could just treat one kid successfully.”

In an effort to determine whether ASOs could correct the DNA damage repair enzyme’s malfunction, Yu’s team started testing them on the girl’s cells.

They created a therapy that was prepared for use within a year. Since beginning treatment at age 2, the youngster has been receiving her customized drug for more than three years.

We saw that this instance was Mila’s kissing cousin because it involved a very similar circumstance and an ASO-amenable mutation, said Yu. In contrast to Mila, “this case was one that we had identified… at a very, very young age.”

Though Milasen had first demonstrated encouraging results, Mila passed away at age 10 three years after beginning her therapy since the disease had already progressed that far. Yu believes that by beginning therapeutic intervention on the girl with A-T at such an early age, the disease’s progression may be more effectively halted.

The ability to treat these disorders early was considered crucial by our clinical team, according to Yu. Mila is a prime illustration of that.

The clinical result of the little child with A-T is still uncertain because the study only reports the tolerability of the medication. However, Yu stated that he has “been really pleased that the treatment’s been very well tolerated, and she seems to be doing very well.”

Toshifumi Yokota, a professor of medical genetics at the University of Alberta who was not involved in the study, believes that Yu’s findings give reason for optimism for the increased usefulness of ASO treatments because “the framework is possibly applicable to many other genetic diseases.”

Yokota specifically thinks that genetic disorders caused by brief mutations can benefit from this strategy. But they assert that genetic changes that result in reduced proteins or changes in the genetic code that give rise to entirely new protein sequences will probably be more resistant to ASOs.

Amondys 45, which treats Duchenne muscular dystrophy, and Spinraza, which treats spinal muscular atrophy, are two examples of ASOs for hereditary illnesses that have achieved commercial success. Since only a small number of genetic mutations result in various genetic disorders, the medications can effectively cure a significant proportion of patients. In comparison, 235 children with A-T had 469 mutations that could have caused the condition, according to Yu and his team.

Margus stressed how crucial it is to keep in mind that the great majority of children with A-T are not feasible candidates for ASO therapy, despite Yu’s encouraging improvement. Margus and Yu both anticipate that some of the remaining population will be susceptible to nucleotide base editors and siRNAs, among other genetic technologies.

But, according to Yu, “we’ll actually learn to use them much more nimbly than we are currently, if we’re going to use these [genetic] tools to their ultimate potential.” According to Yu, this will necessitate major “attitude shifts” on the part of academics, the pharmaceutical sector, and regulatory bodies.

The N=1 Collaborative co-founder and Mila’s mother, Julia Vitarello, concurred that the regulatory framework for individualized medications needs to be altered. “They cannot conceivably acquire an IND for every single child under the [FDA’s] existing methodology. That isn’t realistic, she said.

To begin any human clinical studies, an investigational new drug application, or IND, must be submitted to the Food and Drug Administration.

Margus noted that, encouragingly, the FDA has thus far shown a willingness to eventually relax these rules. They only need to see the data, and that is reasonable, he added. “Maybe they’ll start to lower the bar, which makes it faster and cheaper for us,” the researcher said. “If they see that we’ve done, say, 12 ASOs while altering the sequence.

Through her company, EveryONE Medicines, Vitarello said she is actively looking at reimbursement plans for companies who provide customized medications. Still other businesses, like Quantile Health, are attempting to pay insurers, which might aid in democratizing access to personalized drugs. Financing, however, continues to be a significant barrier to scale.

The absence of infrastructure to enable scaling, in Vitarello’s opinion, is a further problem. The N=1 Collaborative is trying to help academia and business create a successful model.

Finally, she continued, businesses are joining in. Vitarello thinks a workable business model is coming into view as the industry begins to enter the picture.

Vitarello, Yu, and Margus all made remarks about the fact that the idea of individualized medicine is not new. “The good news is that there are precedents,” Yu added in reference to CAR-T therapies, which are specially designed for people with particular forms of cancer.

He argues why society has “decided it’s worth taking a risk and spending a lot of money… when it comes to end-stage cancer,” but not for uncommon genetic disorders, and claims that the resistance to “n-of -1” treatments is a matter of perception.

Margus concurred that misinformation about individualized medicine exists. He remarked, “I think it’s the way it’s framed. “It sounds terrible if we say we’re going to develop drugs for each kid.”

Margus, however, anticipates a “plug and play” framework for customized medicines with sufficient case studies, in which children are guided through sequencing screens for ASO qualification and into a regular pipeline for ASO creation.

The name “n of 1” itself, according to Vitarello, may be the largest distortion of all. It suggests that these are one-time events. And it conveys the impression that there aren’t many of them, she continued.

Vitarello is optimistic that a similar number will hold true for other uncommon genetic illnesses in light of Yu’s finding that up to 15% of youngsters with A-T stand to benefit from ASO treatments.

It is irrelevant to Vitarello what the figure is, he says. It’s important to focus on the underlying genetic causes, she said. “Even if there is just one or there are 15 more, you’re still treating each patient genetically as one,” the speaker said.



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