HuidaGene’s gene-editing therapy named rare pediatric drug by FDA

HG302 uses enzyme expected to lead to better efficacy, safety

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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HuidaGene Therapeutics’ investigational gene-editing therapy, called HG302, for Duchenne muscular dystrophy (DMD) has been granted a rare pediatric drug designation by the U.S. Food and Drug Administration (FDA).

This status is intended to incentivize companies to develop treatments for rare and serious or life-threatening diseases affecting people under age 18. If a product with the designation is eventually approved, the company developing it may qualify for a voucher from the FDA that can be used to get a faster review of another therapy application later on. The voucher can also be sold to another company.

Compared with other gene-editing therapies in development, HG302 employs a special enzyme called hfCas12Max that’s expected to lead to better efficacy and safety.

The drug designation suggests “the recognition of the importance of DMD and the preclinical safety and efficacy of hfCas12Max gene-editing therapy by [the] FDA,” Alvin Luk, PhD, co-founder and CEO of HuidaGene, said in a company press release.

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DMD gene mutations result in lack of dystrophin

Mutations in the DMD gene, resulting in a lack of the dystrophin protein, are the cause of DMD. Dystrophin is important for protecting muscles from damage and therefore, its loss leads to symptoms of progressive muscle weakness and wasting.

“DMD patients are often wheelchair-bound before the age of 12 facing a significant unmet need,” Luk said.

Certain DMD-causing mutations disrupt the genetic transcript that’s used to produce proteins from DNA. In turn, cells’ protein-making machinery can’t read the transcript properly and therefore can’t make dystrophin.

In some cases, if problematic sections of the genetic code are cut out, it enables production of a shorter-than-normal transcript, but one that can still be turned into a working protein.

Time is muscle; we look forward to advancing HG302 into the clinic as soon as possible.

HG302 uses gene-editing approach to eliminate or skip over exon 51

HG302 employs a gene-editing approach to eliminate, or skip over, a protein coding portion of DMD called exon 51 in patients’ own cells when the transcript is being made. That allows production of a short but functional dystrophin protein, which is expected to improve muscle function.

About 13% of patients are believed to have mutations that would be responsive to exon 51 skipping. Approved therapy Exondys 51 works toward the same end, but does not do so via permanent gene editing but is given as a weekly infusion into the bloodstream (intravenous) to enable continued production of dystrophin.

HG302 is intended to be a one-time therapy, where the gene-editing materials are packaged into a viral carrier that helps it be taken up by muscle cells when delivered as a single intravenous infusion.

The gene-editing technology employed is called CRISPR/Cas. Simply, this treatment uses a guide molecule that indicates exactly where the DNA edit needs to be made, along with a Cas enzyme that actually cuts the DNA to initiate the edit.

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HG302’s enzyme expected to minimize unintended DNA editing

While an enzyme called Cas9 has historically been the most popular option for gene-editing therapies, HG302 instead uses a version of the Cas12i enzyme, called hfCas12Max. It was developed using HuidaGene’s proprietary HG-PRECISE platform.

According to the company, the enzyme is smaller than Cas9, making it easier to package into the viral carrier. It’s also expected to enable better gene-editing efficiency while minimizing unintended editing in other areas of DNA.

The company reports HG302 has been found to lead to stable genome editing with minimal off-target effects in both lab studies and animal models. Notably, the gene-editing therapy was found to improve muscle function in a mouse model of DMD.

“Time is muscle; we look forward to advancing HG302 into the clinic as soon as possible,” Luk said.