Gene Therapy Briefs

Gene therapy developer bluebird bio (www.bluebirdbio.com) completed a $60 million Series D financing round. According to bluebird, Shire joined as a strategic investor during the round, in which new investors Deerfield Partners, RA Capital, Ramius Capital Group, and two undisclosed “blue chip” public investment funds joined existing investors ARCH Venture Partners, Third Rock Ventures, TVM Capital, and Forbion Capital Partners.

Proceeds will be used to advance bluebird bio's clinical programs in severe genetic disorders, including childhood cerebral adrenoleukodystrophy (CCALD), β-thalassemia, and sickle cell disease. Using proceeds from this financing, and based on promising early clinical proof of concept results, the company plans to initiate a phase 2/3 clinical study in CCALD in both the United States and Europe in 2013, as well as a second U.S.-based phase 1/2 study in β-thalassemia in 2013.

bluebird bio also said it expects to initiate a more extensive sickle cell disease development program and invest in manufacturing, clinical, and commercial infrastructure to support its upcoming clinical trials and precommercial launch activities.

“The strong support from our existing and new investors is incredible and will fuel our efforts for some time,” Nick Leschly, CEO of bluebird bio, said in a statement.

The Cowen Group served as a strategic advisor on the financing.

uniQure (www.uniqure.com) is just one step removed from having its Glybera (alipogene tiparvovec) gene therapy for lipoprotein lipase deficiency (LPLD) become the first gene therapy sanctioned in Europe or the United States following a recommendation of approval for its use, although only under exceptional circumstances, by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA; www.ema.europa.eu/ema). If the European Commission decides to go with the recommendation and sanction Glybera, a registry will have to be set up to monitor patient outcomes, and results reported back to the EMA.

CHMP's recommendation reverses more than a year of negative opinions issued by the committee. “The use of Glybera in a more restricted indication than initially applied for, which targets the patient population with greatest need for treatment, and additional analyses by the Committee for Advanced Therapies (CAT), have added to the robustness of the data provided and allowed the CHMP to conclude that the benefits of Glybera are greater than its known risks,” Tomas Salmonson, M.D., acting chair of the CHMP, said in a statement.

The pursuit of approvals for Glybera resulted in the demise of Amsterdam Molecular Therapeutics (AMT), which originally developed the gene therapy. In early April AMT's assets were passed on to uniQure, a firm established to take on the AMT gene therapy technologies and pipeline. CHMP repeatedly recommended against approving Glybera on risk/benefit grounds despite a positive recommendation by the expert Scientific Advisory Group for the product, and CAT, which concluded that any concerns could be addressed by postmarketing studies. CHMP's last nonapproval recommendation came in April despite a 16 to 15 vote in favor of recommending Glybera; 17 positive votes were required.

Although the EC could still refuse to approve the drug, uniQure expressed optimism that regulatory clearance will occur soon, allowing Glybera to become the first in a class of gene therapy products approved in Europe to treat orphan diseases. “We expect final approval from the EC within three months after the CHMP decision,” Jörn Aldag, uniQure CEO, said in a statement.

The FDA (www.fda.gov) may regulate stem cell therapy in the United States if the stem cell products in question can be classified as “drugs” because they undergo more than “minimal manipulation,” a federal judge has ruled.

U.S. District Court Judge Rosemary Collyer ruled that the Regenexx-C stem-cell therapy offered by Regenerative Sciences (www.regenexx.com) at its Broomfield, Colorado, clinic was an unapproved treatment because it entailed more-than-“minimal” manipulation and was thus a drug requiring agency approval. Judge Collyer also cited the therapy's use of cultured cell products—mesenchymal stem cells—that had not been shown to be effective in clinical studies, and noted Regenerative's labs failed to meet FDA standards.

In granting the FDA's request for a permanent injunction against Regenerative Sciences, Judge Collyer also ruled that that the agency has jurisdiction to regulate the company's treatment. She rejected a contrary argument by the company that the agency's scrutiny was unwarranted because its procedure used patients' own human stem cells without significant modification.

Those cells, Regenerative Sciences argued, were harvested, manipulated, and injected back into the same patient without significant modification, and thus the procedure should be categorized as a routine treatment.

The FDA has approved for first-in-human use in clinical trials an investigational new drug that uses stem cells to repair damage caused by heart attacks.

The therapy, which will be advanced by Capricor (www.capricor.com), uses cardiosphere-derived cells (CDCs) to reduce scarring and to repair the damage caused to heart muscle by a heart attack. The cells—found in heart tissue—have the potential to change into a variety of different heart cell types. Researchers believe these cells will help support the heart's own healing mechanisms.

In preliminary studies with a related product derived from the patient's own cells, giving patients these modified CDCs was shown by an imaging study to reduce the amount of scarring left by the heart attack.

Research that contributed to the potential therapy was funded by the California Institute for Regenerative Medicine (CIRM; www.cirm.ca.gov), the state's stem-cell agency, through a $5.5 million Disease Team grant to Cedars-Sinai Heart Institute in Los Angeles, and led by the institute's director, Eduardo Marbán, M.D., Ph.D.

“In the next phase of clinical testing we hope to achieve the shared goal of making regenerative medicine a reality for the millions of patients afflicted by ‘irreversible’ heart disease,” Dr. Marbán said in a statement.

Eager to promote more translation of stem cell research into new drugs, CIRM on July 26 approved a $150 million second round of Disease Team awards. Disease Team II awards consist of eight grants of up to $20 million per academic–industry research team working on projects deemed to hold the best promise of producing therapies. Winning teams were selected from 21 applications reviewed by an independent group of scientists.

The teams are expected to file a request to begin clinical trials or to complete phase 1 or phase 2 clinical trials within 4 years. Five of the teams propose to finish a clinical trial within the period of the award.

A preclinical study published in the July 26 issue of the journal Neuron concluded that a new gene therapy approach can reverse hearing loss caused by a genetic defect in a mouse model of congenital deafness—findings that present a promising avenue for new therapies to treat individuals who are born deaf.

Current treatment options such as hearing amplification devices and cochlear implants do not restore hearing to normal levels. Correcting the underlying genetic defects—which account for about half of the cases of congenital hearing loss—still holds the promise of someday fully restoring hearing in people.

Previous attempts to reverse hearing loss caused by genetic mutations have not been successful. Looking to address that challenge, the research team used mice with hereditary deafness caused by a mutation in a gene encoding a protein called vesicular glutamate transporter-3 (VGLUT3). The protein is crucial for inner hair cells to send signals that enable hearing.

Two weeks after the researchers delivered the VGLUT3-encoding gene into the inner ear via an injection, hearing was restored in all of the mice. Improvement lasted between 7 weeks and 1.5 years for adult mice that were treated, and at least 9 months for newborn mice receiving the treatment. In addition, the therapy did not damage the inner ear, and even corrected some structural defects in the inner hair cells.

“This is the first time that an inherited, genetic hearing loss has been successfully treated in laboratory mice, and as such represents an important milestone for treating genetic deafness in humans,” says senior study author Lawrence R. Lustig, M.D., director of the University of California, San Francisco's Cochlear Implant Center, in a statement.

In addition to UCSF, researchers from the University of Pittsburgh and Ohio State University's Comprehensive Cancer Center joined in the study.

Because the specific gene delivery method used is safe and effective in animals, Dr. Lustig said, the findings hold promise for future human studies: “For years, scientists have been hinting at the possibility of gene therapy as a potential cure for deafness. In this study, we now provide a very real and big step towards that goal.”

However, several additional steps will be needed before the therapy can be practiced in humans, two University of Michigan researchers not connected with the study wrote in a commentary in the journal Neuron. Donna M. Martin, M.D., Ph.D., and Yehoash Raphael, Ph.D., wrote that first, proof that this method works in mature ears needs to be provided; the study used mouse pups that were 1–3 or 10–12 days old, both ages in which the mouse auditory system is still immature.

Also, they said, most if not all of the relevant underlying pathologies causing the deafness may need to be corrected: “Ongoing neuronal degeneration would probably degrade long-term correction of inner ear defects and would need to be addressed for optimal treatment of patients with VGLUT3 mutations.

“Despite these limitations, the possibilities raised by this study warrant high enthusiasm,” Drs. Martin and Raphael concluded. “For individuals with hereditary hearing loss who are currently treated with cochlear implants, there is reason to believe that approaches like this could lead to the development of significantly better, more specifically targeted therapies to correct their hearing.”