Rare Daily Staff

Avrobio said the first patient has been dosed in the company’s phase 1/2 clinical trial of its experimental gene therapy program for cystinosis, a devastating lysosomal storage disease.

Cystinosis is a rare, inherited lysosomal storage disorder caused by a defect in the gene that encodes for cystinosin. The cystinosin protein enables transport of the amino acid cystine out of lysosomes. When it is absent, cystine accumulates and crystalizes, causing progressive damage to the kidneys, liver, muscles, eyes and other organs and tissues. Cystinosis affects both children and adults; they face shortened life spans and often painful symptoms, including muscle wasting, difficulty breathing, blindness and kidney failure. An estimated 1 in 170,000 people are diagnosed with cystinosis.

The gene therapy, AVR-RD-04, is derived from the patient’s own hematopoietic stem cells, which are genetically modified to produce functional cystinosin, a crucial protein that patients with cystinosis lack.

“The current standard of care does not avert deterioration; at best, it can attenuate symptoms. That’s why gene therapy is particularly exciting: It has the potential to change the course of disease—and the lives of patients—by addressing the underlying cause of cystinosis,” said Birgitte Volck, president of Research and Development at Avrobio. “We believe we can engineer patients’ own stem cells, so they sustainably produce the functional protein that is needed to prevent a toxic buildup of cystine and halt progression of the disease.

The clinical trial is being conducted in collaboration with Stephanie Cherqui at the University of California, San Diego.

AVR-RD-04 is a lentiviral-based gene therapy designed to potentially halt the progression of cystinosis with a single dose of the patient’s own hematopoietic stem cells. The stem cells are genetically modified so they can produce functional cystinosin with the aim of substantially reducing levels of cystine in cells throughout the patient’s body. Before the infusion of the cells, patients undergo personalized conditioning with busulfan to enable the cells to permanently engraft.

The single-arm trial will enroll four adults and a potential follow-on cohort of two adults or adolescents at least 14 years of age who are currently being treated with cysteamine, the standard of care for cystinosis. If started at an early age and taken on a strict dosing schedule, cysteamine can delay kidney failure. However, the treatment regimen is highly burdensome, with side effects that can be severe and unpleasant, and many patients find it difficult to adhere to this treatment regimen. Even if compliance is high, cysteamine therapy cannot prevent kidney failure or avert other complications.

The trial’s primary endpoints are safety and tolerability, assessed for up to two years after treatment, as well as efficacy, as assessed by cystine levels in white blood cells. Secondary endpoints to assess efficacy include changes in cystine levels in the blood, intestinal mucosa and skin and cystine crystal counts in the eye and skin. Efficacy will also be evaluated through clinical tests of kidney function, vision, muscle strength, pulmonary function and neurological and psychometric function, as well as through assessments of participants’ quality of life after treatment. The trial is funded by grants to UC San Diego from the California Institute for Regenerative Medicine as well as the Cystinosis Research Foundation.

“For people with cystinosis, there are no healthy days. They must take dozens of pills a day, around the clock, just to stay alive. It is a relentless disease and we urgently need new treatments,” said Nancy Stack, president of the Cystinosis Research Foundation, which supported development of the gene therapy with more than $5.4 million in grants to Cherqui’s lab at UC San Diego. “We believe that we are now an important step closer to the potential cure that our community has been working toward for many years.”

Photo: Birgitte Volck, president of Research and Development at Avrobio

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