Abstract
According to AAVLife, FA is an excellent candidate for gene therapy because it is caused by a mutation in a single gene. That mutation is not in a coding region of the frataxin gene that codes for the frataxin protein. In individuals with FA, the frataxin protein is in short supply, yet perfectly formed and functional. These individuals do not have to battle an abnormal protein.
And if gene therapy can supplement the native gene with a new, correct gene that produces additional frataxin, the company reasons further, the body should recognize the needed frataxin, should not mount an immune response to the supplemental frataxin protein, and should benefit significantly from a more normal supply of this important protein.
AAVLife intends to build on the work of Hélène Puccio, PhD, a research director at the
The results—published April 6 in Nature Medicine—showed that a single intravenous injection of AAVrh10 expressing frataxin was not only capable of preventing the development of heart disease in the mouse, but also, fully and rapidly treated the mice with advanced stages of heart disease, returning the heart to normal function. The study established the preclinical proof of concept for the potential of gene therapy in treating FA cardiomyopathy.
“Our preclinical study paves the way for a cardiac gene therapy–based clinical trial in patients with FA with severe cardiomyopathy, once the dose-response efficacy of the vector as well as the delivery method and possible toxicity are tested in large animals. As suggested by the successful heart transplantation cases reported for FA, leading to an improved clinical picture, we hope that this cardiac gene therapy approach may improve the survival and quality of life in individuals with FA,” Dr. Puccio and colleagues concluded in the study (Perdomini et. al., 2014).
Battling the cardiomyopathy also attacks one of the most heartbreaking aspects of FA—its ability to take an individual's life at an early age. “While we also want to have therapies that treat the neurological aspects of the disease, the significance of the cardiac disease is often underappreciated,” Jennifer Farmer, executive director of the
Two colleagues of Dr. Puccio from the study have joined her in founding AAVLife—Patrick Aubourg, MD, PhD, head of neuropediatrics at Hôpital Bicêtre Paris Sud and Ronald Crystal, MD, chairman of genetic medicine and professor of internal medicine at Weill Cornell Medical College. Another colleague on the study, Amber Salzman, PhD (Weill Cornell Medical College, 2014), is AAVLife's president and CEO.
Baxter said the acquisition, announced April 2, will enable it to gain broad access to Chatham's gene therapy platform—including a previously partnered hemophilia B (FIX) program, a preclinical hemophilia A (FVIII) program, and the potential future application to additional hemophilia treatments.
“Chatham's gene therapy platform technology offers the potential to redefine treatment of both hemophilia A and B,” Ludwig Hantson, PhD, president of Baxter BioScience, said in a statement. “This technology will be highly complementary to our expanding pipeline of bleeding disorder treatments as we continue our pursuit of a bleed-free world” (Baxter International and Chatham Therapeutics, 2014).
On March 27, Baxter indicated that it will split into two separate companies—a medical products concern that will retain the Baxter name and a new biopharma that will focus on diagnosis and treatment of blood-related conditions and chronic diseases. Baxter said the new biopharma will build a product pipeline focused on treating unmet medical needs. The spinout is expected to be completed by midyear 2015.
Baxter will spend $70 million upfront to acquire Chatham, adding that it may make additional payments in the future based on specified developmental, regulatory, and commercial milestones—none of them disclosed.
The deal also caps a two-year partnership between the companies that started in May 2012, when Baxter and Chatham launched a collaboration to evaluate Chatham's Biological Nano Particle (BNP™) platform. Baxter uses BNP in a phase I/II open-label study of its experimental treatment BAX 335—an advanced recombinant adeno-associated virus (rAAV)–based gene therapy technology designed to fight hemophilia B.
Baxter said it will continue the clinical trial, which aims to enroll up to 16 hemophilia B patients. The trial is intended to assess the safety and optimal dosing schedule of BAX 335. The BNP technology enables the patient's own liver to begin producing FIX following a single dose of the genetically engineered treatment. The vector is designed to allow more targeted delivery of the FIX therapeutic “cargo” into the natural site of FIX synthesis. Baxter reasons that this may permit effective therapy with low quantities of the vector.
Chatham said it will maintain its licensing and development relationship with Asklepios for hemophilia therapeutic gene therapy candidates using BNP. AskBio is involved with the development of the platform for therapeutics targeting diseases in the heart, central nervous system, muscle, and ocular and liver tissues.
Under their collaboration agreement, Genable will license adeno-associated virus (AAV) vector manufacturing patents from Spark. In return, Spark will serve as exclusive manufacturer of GT038 and provide development advice and expertise to Genable to help in ongoing development of the gene therapy.
GT038 uses AAV vectors with an established safety and efficacy profile to deliver RNA interference (RNAi) molecules to suppress the expression of faulty and normal copies of RHO and restore normal gene expression. GT038 has been granted orphan drug designation in both the United States and Europe.
“The collaboration with Spark provides an exciting opportunity to greatly expedite development of Genable's novel therapy targeted towards RHO-adRP,” Professor Jane Farrar, founder and director of Genable Technologies and a professor at Trinity College (Dublin), said in a statement (Spark Therapeutics and Genable, 2014).
RHO adRP is a debilitating form of inherited blindness resulting from any one of approximately 150 different mutations in the RHO gene. While developing individual therapies for so many mutations is practically impossible, Genable says its “suppression and replacement” therapeutic approach allows a single therapy to treat all of the mutations in a gene while still correcting the primary genetic defect. The suppression component eliminates the target mRNA independent of the particular mutation present in the affected individual, while the replacement component supplies an mRNA encoding the wild type or normal protein.
According to Genable, RHO adRP affects approximately 1 in 30,000 people and represents an already identified and potentially treatable population of around 30,000 patients in the United States and Europe. Genable estimates the market opportunity for GT038 in the RHO adRP subtype to be over $500 million. Genable says its plans to develop other gene therapies for a number of other adRP subtypes.
With $50 million committed by CHOP, Spark has set out to develop and deliver multiple one-time gene therapy products for debilitating diseases. Spark says it intends to build on a legacy established in 2004 when the company's founding team launched the company as a center of gene therapy innovation in research, translation, and manufacturing at the Center for Cellular and Molecular Therapeutics (CCMT) at CHOP.
ReGenX granted AveXis an exclusive, worldwide license with sublicensing rights to ReGenX's NAV rAAV9 vector for treatment of SMA disease in humans. In return, ReGenX received an undisclosed upfront payment, certain milestone fees, and royalties on net sales of products incorporating NAV rAAV9.
ReGenX's NAV vector technology includes novel AAV vectors such as rAAV7, rAAV8, rAAV9, and rAAVrh10. The company says its NAV technology provides further advantages over traditional AAV vectors, including greater efficiency for delivering genes in vivo, faster onset of gene expression, high tissue selectivity, and high-titer manufacture. The treatments being developed by ReGenX include programs for hypercholesterolemia, mucopolysaccharidoses, and retinitis pigmentosa.
SMA is the first focus for AveXis, a private clinic-ready synthetic biology platform company based in Dallas. SMA is the most common genetic cause of death in children under age two. There is no approved medical treatment for SMA, which the FDA has classified as an orphan disease. “We feel rAAV9 is the most promising vector to achieve this goal,” AveXis CEO John A. Carbona said. “We've named the product ChariSMA™ from Greek origin meaning ‘a gift of grace.’ ”
ChariSMA is the basis of a single-dose gene therapy in which a viral vector carries a survival motor neuron (SMN) gene into the cells of the body. The viral vector is named scAAV9.CB.SMN and consists of four parts: • Self-complementary (sc) modification, a patented process owned and developed at the University of North Carolina that allows chariSMA™ to work faster when in the cells; • rAAV9, which is capable of crossing the blood–brain barrier; • cytomegalovirus (CMV)-enhanced beta-actin promoter or CB, an always-on “promoter” that tells the cell's machinery when to start making copies of the gene; and • SMN, which is mutated in patients with spinal muscular atrophy. ChariSMA is designed to add more copies of a functional SMN gene.
“We are pleased to be formally collaborating with AveXis, which has assembled a world-class team of scientific and clinical experts in SMA, led by Brian K. Kaspar, PhD, and his colleagues at Nationwide Children's Hospital and The Ohio State University,” Ken Mills, president and CEO of ReGenX, said in a statement (ReGenX Biosciences and AveXis, 2014). Dr. Kaspar is a principal investigator at the Center for Gene Therapy within The Research Institute at Nationwide Children's Hospital (
“The new investor support gives us the necessary resources to expand Periphagen as a clinical stage biopharmaceutical company, and we deeply appreciate their confidence in our ability to efficiently develop new treatments to the benefit of patients with significant unmet medical needs,” Darren Wolfe, CEO and cofounder of Periphagen, said in the announcement (Diamyd Medical, 2014).
Wolfe told the Pittsburgh Business Times that proceeds from the capital raise will be used for product development and hiring. PeriphaGen currently employs seven and plans to add three near-term employees, chiefly technicians, to help run clinical trials, he said (Tascarella, 2014).
PeriphaGen develops gene therapy products for hard-to-treat neurologic disorders with unmet medical needs. The products—based on PeriphaGen's Neuronal Therapeutic (NET) platform—are designed to direct therapeutic gene expression in neurons for unparalleled treatment specificity without the side effects of standard systemic pharmaceuticals. The company's lead pipeline product is NET-ENK, a phase II candidate NET drug that expresses enkephalin and is being studied for intractable cancer pain.
PeriphaGen was founded as Nurel, a University of Pittsburgh spinout acquired in 2006 by Diamyd Medical. In October 2012, a management group that included Wolfe, PeriphaGen's CMO David Krisky and the company's CSO James Wechuck bought the business from Diamyd Medical. The purchase by PeriphaGen Holdings included rights to the gene therapy platform, which is based on a highly engineered herpes simplex virus type 1 (HSV) vector, taking full advantage of its natural affinity to delivery DNA directly to sensory neurons.
PeriphaGen Holdings paid $1 and issued shares in the acquiring company, giving Diamyd Medical a 10% ownership stake in PeriphaGen Holdings. The management group also gave Diamyd Medical a claim of $1 million with a 15-year duration, and the potential for up to an additional $9 million in payments tied to development milestones, plus 10% of upfront payments and other payments that Periphagen Holdings may receive from future partners, as well as royalties on future sales of drugs based on the gene therapy technology.
Shares for the $9.5 million yet to be raised are “purchasable upon achievement of milestones,” PeriphaGen stated in the filing. (PeriphaGen Holdings, 2014).