Gene therapy/gene editing combo could offer hope for some genetic disorders

February 12, 2020

WASHINGTON-(Feb. 12, 2020)-A hybrid approach that combines elements of gene therapy with gene editing converted an experimental model of a rare genetic disease into a milder form, significantly enhancing survival, shows a multi-institutional study led by the University of Pennsylvania and Children's National Hospital in Washington, D.C. The findings, published online Feb. 12, 2020, in Science Advances, could offer hope for children and adults with a variety of inborn errors of metabolism.

The study focused on a condition called ornithine transcarbamylase deficiency (OTCD), the most common disease in a family of conditions called urea cycle disorders, explains Mark L. Batshaw, M.D., Children's National executive vice president, physician-in-chief and chief academic officer. Dr. Batshaw, the study's co-senior author, sees patients with these disorders in his clinic.

These diseases affect about 1 in 30,000 people and impair how the body breaks down dietary proteins. Typically, proteins are digested into individual amino acids, which are then reused to create new proteins for the body's use. However, excess proteins are broken down for energy, which necessitates removing chemical groups called amines from these molecules. These amines are converted into ammonia, which is toxic to cells. But urea cycle enzymes produced by the liver convert ammonia into harmless urea that is excreted through the urinary system.

This process can go awry for patients with a deficiency in one of the urea cycle enzymes, Dr. Batshaw explains, leading to a toxic buildup of ammonia that causes episodes of vomiting and lethargy, and eventually can lead to coma and death if untreated. While the mother can provide protection to affected fetuses during pregnancy, babies born with this condition often deteriorate in the first week of life and may die before the problem is even diagnosed.

For children and older patients, treatment options are not optimal. They include:"Through these therapies, we've turned this fatal disease into a chronic one for most patients," Dr. Batshaw says. "But there's still no curative approach other than liver transplantation."

Because these conditions are caused by genetic mutations, Dr. James M. Wilson at the University of Pennsylvania and Dr. Batshaw have tried different gene therapy approaches to treat OTCD using an experimental model of this condition that carries a mutation that replicates a moderate form of this disease in humans. This approach involves infecting the preclinical models with a virus that carries a properly functioning form of the OTC gene, which provides the instructions to make the missing essential enzyme, ornithine transcarbamylase. While this method worked well in older animals, it didn't have long-lasting effects in newborn animals due to their rapid liver growth.

A different approach, known as gene editing, can effectively correct mutations in the genome, Dr. Batshaw explains. Drs. Wilson and Batshaw's labs successfully treated OTCD in an experimental model with gene editing, reporting this advance in 2017. However, because this approach requires a tailored vector to correct a specific mutation, it's not universally applicable for the more than 400 different mutations that can cause OTCD.

Seeking a long-lasting way to help patients with this condition regardless of their mutation type, Drs. Wilson, Batshaw and colleagues tested a new approach that combined elements of gene therapy with CRISPR/Cas9-mediated gene editing. The researchers created a viral vector that carried an enzyme necessary to create a targeted break in DNA, a step used in gene editing. However, rather than simply correct a mistake, a second vector carried a copy of the correct OTC gene sequence.The two vectors were given at the same time.

Their results show that for newborn experimental models given this treatment, the new gene successfully integrated in cells and expanded in patches in their livers as they grew, producing successively more of the necessary detoxifying enzyme. These effects were in contrast to animals given a vector that wasn't targeted to the affected gene or those that went completely untreated.

When the animals were challenged with a nitrogen load, those who'd been effectively treated by the combined strategy had about 60% lower ammonia levels in their bloodstreams compared with untreated animals. While all the treated animals survived the seven-day test, only about one-quarter of the untreated ones did.

While this approach has multiple hurdles to cross before it could become available in the clinic - including safety studies in other preclinical models and safety and efficacy studies in people - it could hold promise for OTCD as well as a variety of other genetic disorders.

"Theoretically, this could be a curative approach for OTCD," Dr. Batshaw says. "And if it worked for that, we could create similar templates to treat other related disorders."
In addition to Dr. Batshaw, other Children's National co-authors include Chenyu Xu and Hiroki Morizono, Ph.D., director of biomedical informatics. Other study co-authors include Lili Wang, Yang Yang, Camilo Ayala Breton, Peter Bell, Mingyao Li, Jia Zhang, Yan Che, Alexei Saveliev, Zhenning He, John White, Caitlin Latshaw, Deirdre McMenamin, Hongwei Yu and James M. Wilson, co-senior study author, all of University of Pennsylvania.

Financial support for research described in this post was provided by the National Institute of Child Health and Human Development under award number P01-639 HD057247; the Kettering Family Foundation; The State Key Laboratory of Biotherapy and Cancer Center; West China Hospital; Sichuan University and the Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China.

Children's National Hospital

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