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New Method Used To Develop RNA Therapy For The Treatment Of Rare Diseases

Having a rare genetic disease is actually pretty common. Rare diseases affect approximately 1 in 10 individuals, and more than 30 million people in the U.S. Have a rare disease diagnosis. What makes them rare is that these 1 in 10 people affected have an estimated 7,000 different conditions, with treatments available for only about 5% of them.

Rare disease research led by the Korea Advanced Institute of Science and Technology (KAIST), Republic of Korea, has accelerated the treatment potential for one such disease, ataxia-telangiectasia, with antisense oligonucleotides.

In a paper, "A framework for individualized splice-switching oligonucleotide therapy," published in Nature, the team details their methods to identify treatment potential for one rare disease and illustrate how the process could tackle other untreatable conditions. A Clinical Briefing published in the same journal issue summarizes the work done by the team.

The research is based on splice-switching antisense oligonucleotides (ASOs). ASOs are short sequences of synthetic nucleic acids, a chain of nucleotides adenine (A), cytosine (C), guanine (G) and thymine (T), connected in a specific sequence. The specific sequence is called "antisense" because it complements an RNA target sequence, binding with it to alter its function.

The alteration can induce degradation, modulation of splicing, prevention of translation, or in this case, paste a correction over a mis-splicing event. By correcting mis-spliced RNA, the normal production of downstream proteins can resume the role they would carry out in a healthy individual.

Ataxia-telangiectasia (A-T) is caused by a loss of function of ATM, a gene involved in the cellular response to DNA double-strand breaks. A-T is characterized by progressive cerebellar degeneration, immunodeficiency and high cancer susceptibility. Early manifestations include ataxia, involuntary movements, neuropathy, oculomotor apraxia, dysphagia, slurred speech and ocular and skin telangiectasias.

The disease has a poorly understood prevalence, with estimates as high as 1 in 40,000 or as low as 1 in 100,000 live births worldwide. Average life expectancy is low at just 25 years, and death is most frequently due to lung disease or cancer.

The researchers performed whole-genome sequencing on 235 individuals with A-T to develop a predictive taxonomy assessment of variants targetable by ASO intervention. ASOs were then designed and tested successfully in patient tissue samples, rescuing the mis-spliced mRNA and restoring ATM cell signaling.

In a pilot clinical study, one of the ASOs created was administered to a child with A-T and showed good tolerability for three years. The study provides a framework for prospectively identifying individuals who may benefit from splice-switching ASO therapy.

Rare diseases like A-T often lack effective therapies because they require an intensive understanding of a single patient's genetic variants and custom-made therapeutics. Health care systems are designed around more universally understood treatments and pathologies, leaving 10% of the population with rare disease diagnoses untreated.

Over a hundred ASOs are in various stages of clinical trials, and hundreds more are being developed. The treatment potentials range from rare diseases not covered in medical school to more well-studied afflictions like Alzheimer's disease, Parkinson's disease, and rheumatoid arthritis. ASOs also have tremendous potential in most forms of cancer.

The current study presents a framework for identifying individuals with genetic variants treatable by an ASO therapeutic approach, accelerating the development of custom-made ASOs for a wide range of neglected diseases.

One of the obstacles ASOs face is the current cost of treatment. FDA-approved ASO treatments can cost hundreds of thousands of dollars a year for a single individual, and many national health care systems and insurers are declining patient access to treatment.

This is likely a temporary situation that could get much worse before it improves. It could worsen in that more ASO treatments will become approved and available to the public only to be denied access for cost reasons. As with any drug platform in the past, this should improve as demand rises and ASOs become a streamlined part of therapeutic manufacturing processes.

If governments and health care systems are not prepared to incur the current costs of treatments, investment in research and manufacturing technology that will optimize production and lower costs in the future should be a top priority.

ASOs are poised to improve the lives of hundreds of millions of people across multiple diseases and disorders, reducing mortality and eliminating the negative effects of a wide range of neurodegenerative diseases. Not being prepared to deliver these treatments would be a major global health crisis.

More information: Jinkuk Kim et al, A framework for individualized splice-switching oligonucleotide therapy, Nature (2023). DOI: 10.1038/s41586-023-06277-0

Clinical Briefing: A framework for identifying targets for individualized therapy in genetic disease, Nature (2023). DOI: 10.1038/d41586-023-01994-y

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Saint Louis University And Industry Partners Discover Treatment For Rare, Genetic Liver Disease

ST. LOUIS — Researchers at Saint Louis University's School of Medicine, in collaboration with Arrowhead Pharmaceuticals and Takeda Pharmaceuticals, report the first effective drug to treat a rare, genetic liver disease that formerly could only be treated with a liver transplant.

The study, "Fazirsiran for Liver Disease Associated with Alpha1-Antitrypsin Deficiency," was published online in the New England Journal of Medicine, one of the world's leading medical journals. 

The multicenter, phase 2, open-label trial investigated the safety and efficacy of fazirsiran, an RNA interference drug, in patients 18 to 75 years of age with liver disease associated with alpha-1 antitrypsin (AAT) deficiency. AAT is a protein made in the liver and released into the blood in large quantities to help protect the body when warding off infections.

Jeffrey Teckman, M.D., professor of pediatrics and biochemistry and molecular biology, is the paper's senior author.

"This is the culmination of over a decade of work to cure this disease, and a significant part of the work was done here," said Teckman, who also is director of pediatric gastroenterology and hepatology at SLU. "We have patients come around the country to see SLU's expert faculty members at SSM Health Cardinal Glennon Children's Hospital with this disease for care and to participate in our studies."

Teckman is a leading authority on AAT deficiency, which affects 1 in 3,500 births and causes severe lung disease in adults or liver disease in adults and children. Symptoms may include shortness of breath and wheezing, repeated infections of the lungs, yellow skin, fatigue, cirrhosis of the liver, liver failure and even death.

Teckman says those impacted by the disease are often undiagnosed or misdiagnosed as fatty liver disease, asthma, or smoking-related lung disease. The diagnosis may be suspected by finding low levels of AAT in the blood and confirmed by genetic testing.

"When I was in medical school, I learned that reduction in liver fibrosis, or scar tissue in the liver, with AAT deficiency was impossible, but now we see that we can reverse this process in humans with minimal side effects," Teckman said.

Longtime collaborator Arrowhead Pharmaceuticals utilized technology during the trial, allowing physicians to shut down one gene in the human liver with almost no side effects.

"In this case, we chose to shut down the abnormal alpha-1 antitrypsin gene in the liver, and the new drug can do that effectively, stopping the disease and allowing the liver to heal," Teckman said.

Next, the team will expand the international study to additional adult patients and children in collaboration with Takeda Pharmaceuticals.

Arrowhead Pharmaceuticals supported this work. Strnad is supported by the German Research Foundation (DFG) (grant STR1095/6-1) and by the DFG consortium CRC/SFB 1382 "Gut–liver axis" (ID 403224013).  Teckman is supported for this work by Arrowhead Pharmaceuticals, Takeda, and The Alpha-1 Foundation.

Additional authors include Pavel Strnad, M.D., Department of Internal Medicine III, University Hospital; Christian Trautwein, M.D., Department of Internal Medicine III, University Hospital; Mattias Mandorfer, M.D., Ph.D., the Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna; Gourab Choudhury, M.D., the Department of Respiratory Medicine, Royal Infirmary of Edinburgh University Hospital, University of Edinburgh, Edinburgh; William Griffiths, M.D., the Department of Hepatology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge; Rohit Loomba, M.D., the Division of Gastroenterology, University of California San Diego School of Medicine; Thomas Schluep, Sc.D., Ting Chang, Ph.D., Min Yi, Ph.D., Bruce D. Given, M.D., James C. Hamilton, M.D., and Javier San Martin, M.D., Arrowhead Pharmaceuticals.

Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious diseases.

Enzyme Engineering For Rare Genetic Diseases And Cancer

Amino acids (AAs) are fundamental building blocks of life, making up proteins, cycling nitrogen, providing energy and transmitting signals. Nine of the 21 AAs found in proteins are 'essential', meaning they must come from dietary sources. Four other AAs, including arginine and cysteine, are 'semi-essential', meaning there are biosynthetic pathways to produce them in humans, but a dietary source is required in some circumstances. Although adequate supplies of these AAs are clearly necessary for health, an oversupply of some AAs can, perhaps surprisingly, be devastating and even fatal.

Aeglea BioTherapeutics is a leader in the creation and development of novel human enzymes that act in the circulation to degrade specific AAs. Aeglea's engineered proteins are designed as enzyme-replacement therapies for the treatment of rare genetic diseases, removing excess AAs that would otherwise accumulate to toxic levels. These enzymes also hold promise as therapies for certain cancers that have become dependent on AAs to fuel their growth. The depletion of key AAs in blood may selectively starve tumor cells, targeting a tumor growth pathway that otherwise can't be blocked by antibodies or small-molecule therapeutics.

Aeglea is focused on discovering and developing treatments for abnormalities in AA metabolism for which the biology is well understood and there is a compelling unmet medical need. Rare genetic diseases are a large collection of over 700 disorders, including in AA metabolism. These rare metabolic diseases currently have limited treatment options, and no single therapy is appropriate to treat the full range of diseases. Aeglea concentrates its efforts on treatments that are amenable to a blood-based mechanism of action. According to Aeglea's CEO, David G. Lowe, this focus offers a high probability of success in creating effective treatments that will have a substantial impact on the course of disease. Serum AA levels are an accessible and clinically meaningful pharmacodynamic measure that provides proof of mechanism and serves as a potential surrogate marker for clinical benefit. Clinical and preclinical testing of several engineered human enzymes has shown reduced AA levels in blood after treatment.

All cells require a balance of AAs for normal function, but tumor cells can become particularly dependent on specific AAs. The energetic cost of AA production is high. In some cases, tumor cells can gain a growth advantage during oncogenesis by suppressing certain biosynthetic pathways, such as synthesis of the semi-essential AA arginine. While it creates a growth advantage for the tumor, the loss of this pathway also provides Aeglea with a potential biomarker or companion-diagnostic strategy to identify arginine-dependent tumors that are vulnerable to a reduction in arginine. Two US Food and Drug Administration– approved microbial enzymes that target asparagine conceptually validate AA targeting in cancer treatment, although immunogenicity appears to be a limiting factor for this approach. Although it is generally thought that the human genome cannot provide direct product candidates enabling broader exploitation of tumor dependence on AAs, Aeglea believes that its product candidate AEB1102, an engineered human arginase enzyme, has the potential to reduce blood arginine levels and to be less immunogenic than microbe-derived enzymes.

AEB1102, Aeglea's first product candidate to enter the clinic, has been shown to reduce blood arginine levels in clinical studies, thus providing proof of mechanism. Aeglea has an open phase 1/2 trial in the United States for patients with impaired arginine degradation caused by a mutation in the arginase 1 gene (ARG1) (Fig. 1). ARG1 deficiency is a devastating, life-threatening urea-cycle disorder that presents in early childhood. Affected children develop neurologic symptoms, such as spasticity, seizures and neurocognitive deficits that may ultimately lead to severe intellectual disability. To date, no therapy has been approved that addresses the fundamental defect underlying the disease. To Aeglea's knowledge, AEB1102 is the first attempt to create a potential enzyme-replacement therapy for ARG1 deficiency. The hope is that it may dramatically alter patients' lives if treatment is begun early in life, thereby delaying or even preventing progressive neurological and neurocognitive impairment.

Figure 1: Aeglea's product pipeline.

AEB1102 is also currently in phase 1 trials in cancer patients with advanced solid tumors and with hematological malignancies. Biomarkers of tumor dependence on arginine have shown value as predictors of sensitivity to arginine depletion—for example, in patient-derived xenograft models with a direct cell-killing effect—and will help guide the selection of future cancer indications to pursue in later clinical trials with AEB1102.

This work has focused Aeglea's attention on a select number of tumors predicted to be arginine-dependent, such as small-cell lung cancer, cutaneous melanoma, uveal melanoma, Merkel cell carcinoma, acute myeloid leukemia and myelodysplastic syndromes. Furthermore, contrary to expectation, arginine depletion is not broadly immunosuppressive. In preclinical studies, Aeglea has found additive or synergistic activity of arginine depletion with AEB1102 in combination with immune-checkpoint inhibitors, opening the possibility of combination trials.

In addition to the ongoing trials with AEB1102, Aeglea has a robust pipeline of engineered human enzymes that target other key AAs (Fig. 1). These product candidates degrade cysteine and its oxidized form, cystine, to target tumor dependence on glutathione for protection against oxidative stress, as well as methionine, an essential AA for which some cancers have an increased appetite. A third enzyme, AEB4104, degrades homocystine, which accumulates in people with the rare genetic disease classical homocystinuria as a result of a deficiency of the enzyme cystathionine β-synthase. Aeglea is committed to creating value by pursuing multiple clinical pathways in parallel, each focused on diseases with the potential to be markedly affected by a single enzyme.

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