Gene Therapy for Rare Diseases

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Source: AVROBIO

Sue Pearson Ph.D. Freelance Writer GEN

Are We There Yet?

“It’s time to look again at gene therapy for rare disorders,” states Anthony Chan, MBBS, professor at McMaster Children’s Hospital in Canada. “Because so many are monogenic diseases this makes them conducive to using gene therapy as a cure,” he adds.

Shari Fallet, M.D., Fabry clinical lead at Avrobio, agrees. “Our mission is to cure rare disease in a single dose. Just as enzyme replacement therapy has revolutionized treatment for Fabry disease in the past, we believe gene therapy can revolutionize it in the future.”

Although gene therapies to treat rare diseases have been in development since the 1990s, only a handful have been approved and few are being used routinely in the clinic. Speakers at the recent Rare 2018 Congress on treatments for rare diseases detailed some of the issues that are preventing approval and commercialization. They also discussed how far gene therapies to treat rare conditions, such as Fabry disease, hemophilia, and neuronopathic disorders, have advanced in the past 20 years.

“After the 1999 clinical trial of a gene therapy [using adenovirus to treat ornithine transcarbamylase deficiency] in which Jesse Gelsinger died, the FDA halted 257 gene therapy trials and it has taken years to develop good gene-delivery technology to overcome the risks of innate immune activation and insertional mutagenesis near oncogenes which can cause cancers,” says Dr. Chan.

Currently, lentiviruses and adeno-associated viruses (AAV) are the front runners for use in gene therapy delivery. Lentivirus can be used for ex vivo gene therapy involving the transplant of recombinant hematopoietic stem cells and AAV can be used for in vivo, direct, corrective gene therapy.


Ex Vivo Gene Therapy for Fabry Disease

According to Dr. Fallet, using lentiviral vectors for ex vivo gene therapy has several advantages. “These vectors have a large genetic capacity and can transduce both dividing and nondividing cells. Over 200 patients have been treated in clinical trials with lentiviral-based gene therapies, including Bluebird bio’s LentiGlobin® to treat beta thalassemia and GlaxoSmithKline's Strimvelis to treat adenosine deaminase severe combined immunodeficiency (ADA-SCID), so lentiviral gene delivery has a strong safety and efficacy record in rare diseases,” says Dr. Fallet.

Dr. Fallet also discussed how Avrobio is developing a lentiviral ex vivo gene therapy to treat Fabry disease, an X-linked lysosomal storage disorder caused by mutations in the gene that encodes alpha-galactosidase A (AGA). The resulting deficiency of the enzyme causes accumulation of glycosphingolipids in cells throughout the body and can lead to organ damage in the kidneys, heart, and brain.

“Currently, Fabry disease is treated with enzyme replacement therapy (ERT) or chaperone therapy but there are limitations associated with both; for example, ERT has to be given as biweekly infusions and the enzyme has a short half-life in plasma,” explains Dr. Fallet.

“To overcome some of these issues, we are developing an ex vivo, lentiviral vector-mediated gene therapy designated AVR-RD-01,” adds Dr. Fallet. To produce the therapy, patients’ stem cells are mobilized from the bone marrow to the blood stream and are removed. CD34+ stem cells are selected, genetically modified to express functional AGA, and the cells are frozen. The modified cells are then returned to the patient via IV infusion following a conditioning regimen, which is a mild form of myeloablation to remove some unmodified cells from the bone marrow to create space for the modified cells to engraft.

“Freezing cells has the advantage of allowing testing for safety and efficacy, as well as the convenience to schedule a time to return the modified cells to the patient in an outpatient setting anywhere in the world,” says Dr. Fallet.

Dr. Fallet presented preclinical data which showed that Fabry mice treated with AVR-RD-01 had reduced amounts of globotriaosylceramide (Gb3) in the heart, kidney, liver, lung, and spleen compared to untreated mice, indicating that AGA is being actively produced in the treated mice. Dr. Fallet also detailed that results from a Phase I safety study, where up to six male Fabry patients were treated with ERT, taken off ERT for one month, and then dosed with AVR-RD-01, showed increased plasma AGA to the normal AGA range that was sustained for 12 and 3 months, respectively, for the first two patients treated thus far.

“Since our gene therapy has been well-tolerated with promising results and only nonserious adverse events reported in the ongoing Phase I trial, a Phase II multinational clinical trial has been initiated in male patients with Fabry disease, who have not had enzyme replacement or chaperone therapy for their disease,” says Dr. Fallet. “We hope to treat 8­–12 patients and the first patient received AVR-RD-01 in June 2018.”


In Vivo Gene Therapy for Hemophilia

According to Dr. Chan, AAVs generate only mild immune responses and do not integrate genetic material into the host genome but deliver genetic material outside the genome. This means they are potentially safe to use and can have long-lasting effects. He cited that commercial rare disease treatments, such as Glybera to treat lipoprotein lipase deficiency and Luxturna to treat inherited retinal disease, use AAV to deliver their gene component.

“To treat hemophilia A or B requires transfection with the gene for Factor VIII or Factor XI respectively and expression of these proteins to prevent bleeding in joints, soft tissue, and the central nervous system,” says Dr. Chan. “However, these genes are huge, Factor VIII is 186,935 bp and Factor IX is over 32,739 bp, and in many of the gene therapy studies researchers are removing the B-domain of Factor VIII to enable successful cloning and packaging in the viral vector.”

Dr. Chan described three recent gene-therapy hemophilia clinical trials, one of which showed promising results with men suffering with severe hemophilia A. The men were dosed in low, intermediate, and high dose with the gene therapy and produced normalization of Factor VIII activity level over one year in six of seven participants who received a high dose. “All the hemophilia gene therapy trials are nonrandomized and unfortunately correcting Factor VIII or Factor XI gene, unlike some treatments for lysosomal storage disorders does not reverse joint damage,” says Dr. Chan.

“With gene therapy for rare diseases we’re almost there with the technology, but we’re still struggling to justify the cost,” Dr. Chan adds. He also detailed a 2018 study in which patients, clinicians, researchers, regulators, research agencies, health technology assessors, payers, and drug developers participated to produce a definitive set of core outcomes in hemophilia. These were identified as: frequency of bleeds, factor activity level, duration of expression, chronic pain, healthcare resource use, and mental health.

“Having a set of outcomes to measure will provide a guide to the value of a gene therapy, as we’re still not there yet with affordability, and this will give us a guide to the real cost-effectiveness of hemophilia gene therapies,” concludes Dr. Chan.


In Vivo Gene Therapy for Gaucher’s Disease

Currently, no therapeutics alter the disease progression of major neurodegenerative disorders seen in Parkinson’s and lysosomal storage diseases because of the difficulty in delivering small molecules and biologics to the brain through the blood–brain barrier. Gene therapy does, however, offer broad delivery across regions of the central nervous system and using AAV-based therapies could offer improved clinical approaches.

Prevail Therapeutics is developing AAV-based gene therapies to target Parkinson’s disease as well as lysosomal storage based rare diseases. Asa Abeliovich, M.D., Ph.D., founder and CEO of Prevail, presented data which showed that some of the underlying causes of Parkinson’s and Gaucher’s disease are similar.

“Gaucher’s disease is a lysosomal storage disorder in which the enzyme beta-glucocerebrosidase (GBA1) is deficient leading to glucocerebroside accumulation in cells and damaging organs including the liver, spleen, and brain. Around 10% of people with Parkinson’s have a mutation in the GBA1 gene, and in these patients there is mild reduction in GBA1 activity—around 20-30% of that compared with the reduction in Gaucher’s disease. One theory is that due to the aging neurons in Parkinson’s patients, this could result in similar lysosomal storage problems to those seen in Gaucher’s disease, so they may benefit from a similar treatment pathway,” says Dr. Abeliovich.

Prevail was awarded $75 million in Series A financing earlier in 2018 to develop its lead program, PR001 an AAV-based gene therapy for a genetic subset of Parkinson’s disease and related lysosomal storage disorders such as Gaucher’s disease.

“This is a very exciting time to be developing gene therapies because they present lots of opportunities to dramatically improve the lives of patients with genetically defined neurodegenerative and rare diseases,” concludes Dr. Abeliovich.







































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