Severe Friedreich’s ataxia’s heart defects reversed with gene therapy

Scientists at Astellas Gene Therapies tested therapy in mouse model

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Gene therapy safely reversed heart problems, lowered blood markers for heart muscle damage, and extended survival in a mouse model of severe Friedreich’s ataxia (FA), a new study shows.

The findings further support the development of gene therapy for FA patients with severe heart complications, the researchers said.

Details of the gene therapy and its effectiveness in FA mice were published in Molecular Therapy – Methods & Clinical Development, in the study, “AAV8 Gene Therapy Reverses Cardiac Pathology and Prevents Early Mortality in a Mouse Model of Friedreich’s Ataxia.”

FA is caused by defects in the FXN gene, resulting in a frataxin protein deficiency and the progressive degeneration of nerve and muscle cells. FA symptoms include loss of muscle control, vision or hearing impairment, slurred speech, and heart problems.

Because mutations in a single gene cause FA, it can potentially be treated with gene therapy, where the faulty gene is replaced by a healthy copy.

Scientists at Astellas Gene Therapies tested one such gene therapy in an FA mouse model with severe heart complications. The company is also in the clinical stages of developing AT845, a gene therapy for a muscular condition called Pompe disease. Also, a Phase 1/2 clinical trial is evaluating Lexeo Therapeutics’ LX2006, an investigational gene therapy for heart disease in FA. Results are expected in the first half of this year.

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 treating FA mice with gene therapy

The FA mouse model in this study was designed to be without frataxin in heart and skeletal muscles, or those attached to bones. These mice showed progressive weight loss associated with heart problems, leading to death at about 10 weeks of age (2.5 months).

To avoid potential toxicity due to high frataxin production from the therapy, the researchers modified the DNA upstream of the full-length FXN gene to lower its activity, which was then packaged and delivered to cells using a harmless viral vector (AAV8). Initial experiments confirmed gene therapy increased frataxin production in mouse and human muscle cells.

Both human (AAV-hFXN) and mouse (AAV-mFXN) gene therapies were injected into mice intravenously (into the vein) at 6 weeks, so heart problems existed before treatment.

All FA mice treated with either AAV-hFXN or AAV-mFXN (at two different doses) were still alive at 10 weeks, while the untreated mice had all died. Treated FA mice showed a significant improvement in average body weight that was comparable to healthy mice.

Heart function was monitored by echocardiography (ultrasound), with untreated FA mice showing markedly reduced ejection fraction, which is the amount of blood the heart pumps with each beat.

Both doses of either AAV-hFXN or AAV-mFXN significantly increased the ejection fraction at 10 weeks, which was maintained until the final measurements at weeks 18-19. No notable differences were seen between treated FA mice and healthy mice.

The gene therapy also normalized other echocardiography measures, along with heart weight, which is typically higher in FA due to muscle thickening.

The higher dose of AAV-hFXN significantly reduced blood levels of the myosin light chain, a biomarker of heart muscle damage, from 1.5 to 0.1 nanograms/mL, similar to healthy mice. AAV-mFXN also reduced the myosin light chain.

Examination of tissue for therapeutic DNA found AAV-hFXN or AAV-mFXN modification was dose-dependent in FA mice. In heart tissue, the treatment-related production of frataxin was similar to or higher than that in healthy mice and broadly distributed across the heart. Frataxin was also increased in the brain and spinal cords of treated mice.

Iron accumulation in the heart muscle, associated with frataxin deficiency and seen in untreated FA mice, was eliminated with gene therapy. There were no signs of treatment-related toxicity to the heart muscle or other off-target tissues.

“These results support the potential of this well-tolerated and efficacious AAV8 gene therapy to treat patients with [FA] that develop severe, and often lethal, cardiovascular complications,” the researchers said.