Tag: Medication

BOSTON – Timothy Yu, MD, PhD, a leading neurogeneticist at Boston Children’s Hospital and Harvard Medical School, was awarded one of the top honors by the American Society of Gene and Cell Therapy (ASGCT), the Jerry Mendell Award.

Yu was recognized for his trailblazing work over the past decade in devising bespoke oligonucleotide therapies for patients with ultra-rare genetic disorders. He entitled his talk: “The paradox of N-of-1: Scaling the logic of genetic intervention.” A suitable sub-title, Yu said, could be: “A neurogeneticist’s accidental injection into the field of gene therapy.”

Yu’s research has progressed from gene discovery to clinical applications of N-of-1 therapies. The long tail challenge of developing gene therapies for patients with rare diseases is actually immense. There are some 400 million individuals worldwide who suffer one of some 8,000 monogenic disorders. Three out of ten affected children do not see their fifth birthday, while most lack any kind of medical treatment.

But progress over the past 10-20 years has provided hope in the form of various molecular therapies—antisense, mRNA, gene therapy, siRNAs, CRISPR, and newer flavors of gene editing. The concept of “therapeutic programmability is very important,” Yu said.

Yu’s injection into the field began with a single patient, Mila Makovec, a young girl from Colorado, whom he met in 2018. This index patient was eventually diagnosed with a form of Batten disease, CLN7—a rare subtype that was progressive and fatal.

Mila’s gene mutation was private but correctable, an insertion sitting deep within an intron. This offered Yu’s team hope that they could block abnormal splicing. Clearly, no company could progress a therapy for a single patient, Yu recalled.

Allele-specific oligonucleotides are simple to manufacture and can boost gene expression, following the model of Spinraza for spinal muscular atrophy.

Yu’s team developed a customized ASO therapy in about a year, which was published in 2019. The therapy brought about a reduction in Mila’s seizures, but not in time to result in a cure. In May 2019, Yu’s team met with the FDA to establish a path forward. The first guidances were published in 2021.

Moving on

Yu recounted several other therapies designed for other patients with different genetic disorders. The second program, working with Jennifer Puck, MD, and colleagues, was for ataxia telangiectasia (A-T). One A-T mutation created a new splice site that appeared to be reversible with a custom ASO.

The pilot clinical study was initiated in 2018, when the child was two years old. It is, Yu said, the longest running N-of-1 trial. The child is now nine years old and shows no worsening of clinical symptoms. Various measurements and assays confirm there has been no clinical progression. “We have converted a classic case of A-T to a milder form,” Yu said. The trial is expanding in Europe, including ten additional children in Turkey.

A member of Yu’s lab, Claudia Lentucci, PhD, is among the team leading a third program treating infants with neonatal epilepsy (KCNT1-related epileptic encephalopathy). One patient had seizures halted but developed ventricular enlargement. The team has since modified the protocol to use intracerebroventricular injection, which reduces seizures by 60-70%.

A fourth example presented by Yu was a treatment for Grace, a 15-year-old girl with a rare form of retinitis pigmentosa. She presented seven years ago with vision loss and pain insensitivity. Launched in August 2023, the therapy corrects a deep intronic mutation. It has been well tolerated and resulted in a stabilization of her vision.

Yu summarized similar therapies developed for patients with Zellweger syndrome, Niemann Pick Type C, and Batten disease. In total, 35 N-of-1 oligonucleotides have been administered to more than 80 patients.

On hearing the news of Baby KJ last year, “we all stood up and took notice,” Yu said.

“Our motivations are to help patients without other options. We have expanded from a sick child in Colorado to generate pilot learnings for childhood neurologic diseases.” His team’s work is not only offering hope in a compassionate sense but is also leading the exploration of new delivery models for precision medicine.

Yu has built a large network of collaborators, including clinicians, regulators, and industry professionals. The N=1 Collaborative has grown to more than 2,000 members worldwide and will be holding its third conference this October in Denver.

A new approach

From what was once called “interventional genetics,” Yu said, “the data is inviting us to take a new approach” that he called “genetic surgery.”

N-of-1 therapies are “more akin to a complex surgery, [using] customized tools and procedures for therapeutic benefit akin to organ transplant or cardiac surgery,” he said.

Yu also highlighted the FDA’s Plausible Mechanism Pathway, announced last February, which offers opportunities to approve medicines on the basis of very small numbers of patients. But the guidance emphasized the importance of data sharing—an issue that required the community’s full attention.

“You can’t build a modular system in a silo,” Yu said. “If you want cures that are greater than the sum of their parts, you must share the data to see how the pieces fit together.”

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