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Progress and a Setback in Treating Rare Genetic Diseases: Hemophilia A, CLN1, SMA, and DMD

In these strange days of the pandemic, it’s easy to forget that people are still sick with the illnesses that we’ve always faced – and not just the common ones like cardiovascular disease and cancer. Times are particularly tough for the millions of people who have rare diseases.

Research continues into developing new treatments for rare diseases, despite the current difficulties, with some recent good news. But first, a setback.

Hemophilia A: Two More Years of Data Needed

On August 18, FDA ruled that a submission for approval of a gene therapy to treat severe hemophilia needs another two years of evidence to demonstrate that the treatment is really a “one-and-done.” The agency is seeking data demonstrating “a durable effect using Annualized Bleeding Rate,” a metric that the developer, Biomarin, claims had not been brought up prior to submission of the phase 3 findings.

Perhaps the extra scrutiny reflects the fact that treatment has been available since 1992 –recombinant clotting factor VIII. And gene therapy has been in the works for awhile. In fact, I interviewed the very first patient to receive gene therapy for hemophilia A, back in 1999. That trial used the same dangerous vector, a retrovirus, to deliver the gene that would kill Jesse Gelsinger later that year and derail the entire field.

Still, the delay that FDA announced August 18 was unexpected. I wrote at Genetic Literacy Project on January 8, “The clotting disorder hemophilia A may become the third gene therapy that the US Food and Drug Administration approves, joining treatments for a form of retinal blindness in 2017, and spinal muscular atrophy in 2019.”

The announcement sent Biomarin’s stock tumbling, but let’s take a breath. The delay affects only one of several gene therapy approaches underway to treat this one condition. Plus, more than one biotechnology can be deployed against a particular single-gene disease. So here’s some good news for three other rare genetic diseases.

CLN1 Batten Disease Gene Therapy Trial Back on Track

Taylor King, in the opening image, would have turned 22 on August 19, but she died of infantile neuronal ceroid lipofuscinosis 1 (CLN1) almost two years ago. She was diagnosed at age 7. Her family formed Taylor’s Tale to raise funds to develop gene therapy, and with a few other organizations have supported the research leading to the trial about to begin.

The eight forms of Batten disease are ultrarare – together they account for only 1 in 100,000 individuals. A different gene is mutant in each, but all cause neurodegeneration.

CLN1 typically becomes noticeable before the first birthday, but caused Taylor’s first symptoms later – difficulty doing math problems and visual impairment. Gradually, motor skills lapse and cognition declines. Seizures follow, and finally early death. I used to send Taylor fragrant things for her birthday, because her sense of smell remained her strongest.

Gene therapy for CLN1 is a one-time infusion of working copies of the implicated gene (encoding palmitoyl-protein thioesterase) aboard a virus (AAV9). Steven Gray, Ph.D., now at UT Southwestern Medical Center, developed the gene therapy at the University of North Carolina in Chapel Hill. It’s similar to the gene therapy he developed for another rare neurological disease, giant axonal neuropathy.

The phase 1/2 clinical trial for CLN1 gene therapy, from Abeona Therapeutics, got the go-ahead May 30, 2019. Three weeks later, FDA granted fast-track designation. But by May 2020, Sharon King, Taylor’s mom, wondered why the trial hadn’t yet treated patients. Clues may lie in the company’s news releases.

On March 17, Abeona announced treating the first patient in a phase 3 trial for recessive dystrophic epidermolysis bullosa, a horrific skin disease that I wrote about here. Gene therapy protocols are also forging ahead at the company for two mucopolysaccharidoses (MPS IIIA and IIIB). Perhaps priorities have shifted to indications farther along in the pipeline, or not directly involving the central nervous system (CNS).

Meanwhile, Taysha Gene Therapies, in collaboration with Dr. Gray and Berge Minassian, MD, also of UT Southwestern, has picked up the CLN1 gene therapy trial, through license and inventory purchase agreements with Abeona. Taysha’s focus is single-gene conditions that affect the CNS. The gene therapy may enter the market in 2021 for this disease that currently has no treatment.

SMA Treatments Reawaken a Silenced Gene Copy

Spinal muscular atrophy (SMA) isn’t nearly as rare as CLN1 – 1 in 50 people in the US is a carrier. The disease begins in infancy, impairing the lower motor neurons, causing progressive muscle weakness and wasting. It is typically lethal in early childhood.

The disease is unusual in that the mutant gene, “survival motor neuron 1” (SMN1), has an echo, a second gene (SMN2) near it on chromosome 5 in reverse orientation with a glitch that normally disables it. Comparing the DNA sequences of SMN1 and SMN2 is like comparing “monkey” to “yeknam” within a very long sentence where all else is spelled correctly.

Treatments tweak the normally silent second copy of the gene into action.

The first drug to treat SMA, Spinraza, approved at the end of 2016, is injected into the spinal cord. It is a DNA-like snippet that has an “antisense” function, binding to the echo gene and enabling it to instruct the cell to produce the missing protein.

The second SMA drug, Zolgensma, is a gene therapy, approved May 24, 2019. And the third, the first oral drug, is Evrysdi, was approved August 7. It’s a “splicing modifier,” altering how parts of SMN2 are cut and pasted so that the encoded protein that’s normally suppressed is instead produced.

Children in the clinical trial began taking Evrysdi at 2 to 7 months old. Their responses might not seem spectacular, but any treatment that delays or keeps kids off ventilators is a success:
• 7 of 17 children sat unassisted for 5 seconds or longer a year after treatment with Evrysdi
• 19 of 21 children were alive at 21 months and didn’t need ventilation after 12 months
• 17 of 21 children were alive without needing a ventilator by 28 months or longer after 23 months of treatment

Efficacy of SMA treatments has been amazing. In 2017 Jocelyn Kaiser reported in Science about three-year-old Evelyn, treated with the first approved drug. The child who danced around her living room to the song “Happy” when Kaiser visited would not have survived without the treatment – her older sister died of SMA at 15 months.

DMD Drugs Patch an Errant Gene

Like SMA, Duchenne muscular dystrophy (DMD) has entered the realm of the treatable. DMD affects one in 3,600 boys worldwide.

Three drugs enable patients to make increased levels of shortened, but functional, versions of the giant protein dystrophin. All are given as intravenous infusions.

Unlike CLN1 and SMA, which target neurons, DMD affects the muscles directly. Because so much of a human body is muscle, reaching enough cells to make a noticeable difference has been challenging.

FDA approved the first drug, Exondys 51, in 2016 for the 13% of boys with DMD who have a specific mutation. The approach, called exon-skipping, is a version of “antisense” technology that is based on the complementary base-pairing that underlies the choreography of DNA and RNA as they coax cells to produce proteins. Exondys 51 covers a key part of the gene that controls how gene parts are spliced. The result is enough of a partial normal gene sequence to enable cells to produce some dystrophin – hopefully enough to fuel improvement in mobility as well as extend life.

At the end of 2019, FDA approved a second exon-skipper, Vyondys 53, for another 8 percent of boys, and August 12, 2020 a third treatment, Viltepso.

The approvals were controversial, because the studies demonstrated increased dystrophin in muscle samples and improvement in the standard 6-minute walk test, but clinical efficacy and prolongation of life won’t be apparent for years. Still, FDA green-lighted the drugs based on the life-threatening and debilitating nature of the disease.

The new treatments for SMA and DMD – three each! – indicate what is possible. I hope that CLN1 joins them, and that gene therapy for hemophilia A reaches that newly-extended finish line with flying colors.


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