The next generation of gene therapy for rare diseases forges ahead as developers weather hurdles

When gene therapy developer Generation Bio raised $110 million in venture funding in January and then followed up six months later with a $230 million initial public offering, it was as sure a sign as any that investors are stoked about the next generation of gene therapies to treat rare diseases.

Their enthusiasm hasn’t waned during the year, either, despite challenges ranging from the COVID-19 pandemic delaying clinical trials to regulators pushing back some development timelines so they can gather more data on emerging gene therapies.

And as two FDA-approved gene therapies for rare diseases gain ground in the market—Spark Therapeutics’s Luxturna for RPE65 mutation-associated retinal dystrophy and Novartis’ Zolgensma for spinal muscular atrophy (SMA)—the biopharma industry is hard at work on novel approaches to correcting rare disorders caused by errant genes. The advances range from new gene-insertion methods to innovations that allow the therapies to penetrate hard-to-reach tissues in the body.

Some, like Generation, are directly addressing one big concern that has plagued the first generation of gene therapies: Just how durable are they? It’s a question BioMarin faced in August when the FDA declined to approve its hemophilia A gene therapy valoctocogene roxaparvovec after data from a trial showed that levels of factor VIII fell 12 to 18 months after patients received the gene therapy, which is designed to restore the critical blood-clotting protein.

Generation’s lead gene therapy candidates are designed to treat rare blood disorders hemophilia A and phenylketonuria (PKU), and they’re still in preclinical development. What’s new about the company's approach is the delivery system: Rather than using a virus to insert a gene correction, Generation Bio uses an alternative technology that avoids touching off an immune response—a buildup of antibodies to the virus that would normally prevent a second round of treatment. 

Generation’s core technology, called non-viral closed-ended DNA (ceDNA), is carried into the body by a lipid nanoparticle. The potential for the technology to sidestep the immune response that’s typical with virus-based gene therapies could be important in diseases like PKU, where the gene correction needs to reach liver cells, or hepatocytes.

“The newborn liver divides incredibly quickly, and as it grows, the dose of gene therapy goes down,” said Geoff McDonough, M.D., CEO of Generation Bio, in an interview.  “We don’t view that as an existential problem. We’ll just re-dose.”

BioMarin, meanwhile, is working with the FDA to address its request for more data on valoctocogene roxaparvovec, which is an adeno-associated virus (AAV)-based gene therapy—but it’s also looking ahead to innovations that could improve future iterations of the technology. For one thing, it's investigating different capsids that that may reduce the immune response to the first dose, thus allowing re-dosing later.

But that may be only a small part of addressing a decline in response to gene therapy. “We also have to understand cellular determinants of expression, because maybe re-dosing isn’t actually the answer after all,” said Hank Fuchs, M.D., president of research and development at BioMarin, in an interview. To that end, BioMarin is studying liver biopsy tissue to try to understand how individual characteristics may affect the fate of the transgene.

And BioMarin is working with Swiss startup Dinaqor to develop gene therapies to treat heart diseases such as hypertrophic cardiomyopathy. To accomplish that, the companies are making capsids that travel not to the liver—the destination of many gene therapies—but to the heart. If they succeed, it could be “a significant platform play for us,” Fuchs said. “The morbidity for hypertrophic cardiomyopathy is terrible and 60% of cases are genetic. If we can do cardiac delivery, there are other genetic diseases that could be treated with gene therapy.”

Correcting genetic neurological diseases

In 2019, a group of executives who had pioneered SMA gene therapy Zolgensma launched Taysha Gene Therapies with an ambitious goal: They wanted to correct genetic nervous system disorders by delivering gene therapies directly to the spinal fluid. Now, backed by $125 million in private funding and a $157 million IPO, Taysha is in preclinical testing with three gene therapies for neurodegenerative diseases.

Taysha’s gene therapy for GM2 gangliosidosis, a disease that progressively destroys nerve cells, is distinctive for more than its intrathecal delivery, said CEO RA Session II in an interview.

The therapy uses a single viral vector to deliver not one, but two genes at the heart of the disorder—HEXA and HEXB. They’re linked by a self-cleaving peptide and a promoter, “which allows the two genes to be expressed at a one-to-one ratio, mimicking the endogenous system of a healthy cell,” Session explained in an interview.

Other gene therapy developers are targeting specific cells in the body with new technology. Encoded Therapeutics, for example, is developing a gene therapy to treat the seizure disorder Dravet syndrome. But rather than replacing the mutated SCN1A gene that causes the disorder, Encoded incorporates pieces of DNA into an AAV vector with the goal of dialing up production of the SCN1A protein that’s needed to correct the disorder.

RELATED: Encoded Therapeutics bags $135M to push 'precision gene therapy' into the clinic

Passage Bio is addressing GM1 gangliosidosis using a next-generation viral vector called AAVhu68, which in preclinical trials increased the expression of a needed protein not only in targeted cells, but also in the cerebral spinal fluid. The protein is then taken up by neighboring cells, creating an effect of “cross correction” that the company’s scientists hope will improve developmental milestones and survival in the children who have the disease, said CEO Bruce Goldsmith, Ph.D., in an interview.

In August, Passage Bio’s planned phase 1/2 trial was placed on a clinical hold by the FDA, which cited concerns about the delivery device planned for the trial. The company is conducting risk assessments and testing the device so it can address the agency’s questions, and Goldsmith expects to maintain a close dialogue with the FDA going forward.

“Infantile GM1 can occur quite early, so we want to make sure the FDA is a collaborator on defining what developmental scales will be appropriate for measuring outcomes. That means not only primary outcomes but also durability—what they’re looking for in terms of meaningful outcomes,” he said. U.K. regulators gave their go-ahead for a clinical trial of the therapy in December.

Navigating a more vigilant FDA

Improving cross-correction in gene therapy is also a priority for Avrobio, which is developing gene therapies for several rare diseases, including Hunter syndrome and Fabry disease. Its technology platform, called plato, consists of a lentiviral vector and “tags” that help the therapeutic proteins reach the target cells’ lysosomes—the organelles inside of cells that orchestrate vital processes in the body.  

“In diseases like Fabry, all that’s needed is cross-correction, where the enzyme in circulation is taken up by the cells and creates a profound effect,” correcting a deficiency that causes organ damage, said CEO Geoff MacKay in an interview. “The tags aid the uptake of a therapeutic protein. It’s like a first-class ticket to the target tissues, like muscles and the central nervous system."

In November, Avrobio announced that in phase 1 and 2 trials of its Fabry gene therapy, the response lasted up to 3.5 years.

RELATED: Avrobio tracks improvements in first patient treated with Gaucher gene therapy

LogicBio Therapeutics’ approach to moving gene therapy into the future is to harness the power of genome editing.

The company’s technology, GeneRide, uses strands of DNA to deliver a functioning copy of a faulty gene into cells’ nuclei, prompting natural DNA repair mechanisms to insert the good gene exactly where it belongs in the chromosome. The therapeutic gene becomes part of that cell—and of its daughter cells when it divides—potentially preventing a dilution of effect over time that can occur with other gene therapies.

LogicBio’s lead program, LB-001 to treat the liver disorder methylmalonic acidemia in children age 3 and older, was hit with a delay in February, when the FDA put a hold on the planned clinical trial so the company could address safety-monitoring concerns.

So LogicBio built in a protocol for caregivers to monitor post-treatment safety at home, and it added survival as a secondary endpoint, said LogicBio’s chief operating officer Kyle Chiang, Ph.D., in an interview. The company hopes to dose the first patient in the trial in early 2021.

BioMarin’s Fuchs predicts that each new development in gene therapy will raise more questions for the FDA—but that the delays won’t prevent the advances from benefiting patients.

“As regulators, it’s not in their DNA to take risks,” Fuchs said. But the quest for gene therapy approvals, he added, “will continue to go well, as regulators get more familiar with the technology and developers generate more and more data.”