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Posts from the ‘Gene Therapy’ category

Imagine that you are born deaf and live in a world of silence – what price would you pay for a new treatment that might restore your hearing?

That is the market opportunity that may be available for biotechnology and pharmaceutical companies as the basic science around congenital hearing loss starts to yield insights that could translate into new products.

Research published in the July 26, 2012 issue of the journal “Neuron” by Omar Akil from UCSF and colleagues at the University of Pittsburgh and Ohio State University, showed the ability to reverse hearing loss in mice through the use of gene therapy (viral-mediated insertion) to replace the absent vesicular glutamate transporter-3 gene (VGLUT3).

VGLUT3 is a gene involved with the transport of the neurotransmitter glutamate that is required by inner hair cells in order to generate neural responses to sound. Mice lacking VGLUT3 can’t hear.

Insertion of the VGLUT3 gene into mice cochlear cells resulted in restoration of hearing that lasted for 9 months (that’s a long time for mice). The authors noted that:

“These findings represent a successful restoration of hearing by gene replacement in mice, which is a significant advance toward gene therapy of human deafness.”

Over 50% of all human hearing loss is genetically based, and as tools to understand the human genome develop, scientists have been able to identify a number of genes associated with hearing loss.

Research in animal models is ongoing, with the potential in the future that we may be able to replace, repair or correct a defect a genetic mutation.

Could this lead to the restoration of human hearing? The answer is “yes”.

An accompanying editorial in Neuron by Donna Martin and Yehoash Raphael from The University of Michigan describes the work by Akil and colleagues as a major breakthrough:

“Results presented in their paper are a true breakthrough because they show that gene therapy can lead to functional recovery from sensorineural deafness. Even more exciting is the direct relevance of this work to a large population of humans who have mutations in the VGLUT3 gene.”

There remain a number of challenges before gene therapy to correct human deafness becomes a reality, but biopharmaceutical companies such as GenVec (NASDAQ: GNVC) already see the market opportunity and potential for gene therapy to correct hearing loss. Novartis have a collaboration agreement with GenVec that is worth up to $213.6M in milestone payments.

The potential of gene therapy to restore hearing loss will offer hope to many with deafness. It is an exciting area to watch as innovative science translates into personalized medicine.

References

ResearchBlogging.orgOmar Akil, Rebecca P. Seal, Kevin Burke, Chuansong Wang, Aurash Alemi, Matthew During, Robert H. Edwards, & Lawrence R. Lustig (2012). Restoration of Hearing in the VGLUT3 Knockout Mouse Using Virally Mediated Gene Therapy Neuron, 283-293 DOI: 10.1016/j.neuron.2012.05.019

Donna M. Martin, & Yehoash Raphael (2012). Have You Heard? Viral-Mediated Gene Therapy Restores Hearing Neuron, 75, 188-190 DOI: 10.1016/j.neuron.2012.06.008

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In a letter to the science journal Nature, published online on August 21, 2011, scientists from Northwestern University in Chicago report findings that could help develop drugs for patients with Amyotrophic Lateral Sclerosis (ALS), more commonly known as Lou Gehrig’s disease.

ALS is a progressive, fatal, degenerative motor neurone disease, which results in the inability to walk, get out of bed, move arms, hands, swallow or chew. Unlike Alzheimer’s disease, cognitive functions are not usually impaired, making it a particularly nasty disease when faced with awareness of disease progression.

According to Wikipedia, ALS is one of the most common neuromuscular diseases worldwide, with 1 or 2 people in every 100,000 developing ALS each year.

One of the characteristics of ALS and other neurodegenerative disease is the accumulation of protein aggregates or inclusions. Amyloid-ß plaques and intracellular tau neurofibrillary tangles are common in Alzheimer’s disease, for example.

By contrast, in ALS, a hallmark of the disease pathology is the presence of ubiquitin-positive, protein aggregates in spinal motor neurons.

The new research from Northwestern University shows how a mutation in UBQLN2, the gene that encodes ubiquilin 2, may be the cause of ALS in some patients.

The UBQLN2 mutation results in a failure to properly encode the protein, ubiquilin 2, a member of the ubiquitin-like protein family known as ubiquilins. The result is that normal protein degradation through the ubiquilin pathway is impaired, leading to cellular deposits and abnormal protein aggregation.

How did the team at Northwestern discover this insight?

Using DNA sequencing they looked at a five-generation family with 19 affected by ALS and sought to identify the causative gene in the transmission of this disease.  They found that a mutation in UBQLN2, the gene that encodes ubiquilin 2 was the key difference in those family members with or without ALS.

They subsequently tested the hypothesis that UBQLN2 mutations were causative of ALS using clinical data from 40 individuals in 5 families with UBQLN2 mutations. Interestingly in eight patients with the UBQLN2 mutation and ALS, dementia was also present suggesting a possible link between ubquilin 2 inclusions and dementia.

The team explored this correlation by examining brain autopsy samples of 15 cases without UBQLN2 mutations, of which 5 had experienced dementia as well as ALS. They found no ubiquilin 2 pathology in the hippocampus of the 10 ALS patients without dementia, but did find it in the 5 that had experienced both ALS and dementia. They noted:

The correlation of hippocampal ubiquilin 2 pathology to dementia in ALS cases with or without UBQLN2 mutations indicates that ubiquilin 2 is widely involved in ALS-related dementia, even without UBQLN2 mutations.

They also observed that:

We did not observe obvious differences in the distributions of wild-type and mutant ubiquilin2.

The authors concluded:

These data provide robust evidence for an impairment of protein turnover in the pathogenesis of ALS and ALS/dementia, and possibly in other neurodegenerative disorders as well.

These interesting findings by the Northwestern group were reported in Nature, and while promising, must be treated with caution for several reasons:

  1. It is still early-stage preliminary research on a small group of subjects.
  2. The exact function of ubiquilin 2 is not well understood.
  3. Not all ALS patients have the UBQLN2 mutation
  4. If the UBQLN2 mutation is not present in all ALS patients, then this mutation is not the sole means by which ALS develops.
  5. UBQLN2 may not be the only mutation involved in the pathophysiology of ALS.

The data from Northwestern does, however, offer hope that in the future, gene therapy or new treatments could be developed that stop or slow disease progression. Targeting the ubquilin pathway and the UBQLN2 mutation may, for example, prevent the abnormal protein turnover and aggregation that leads to impaired signaling and loss of function seen in ALS.

Further research into pathogenic pathways could lead to new targets for drug development, not only for the treatment of ALS but also dementia, and other neurodegenerative disorders.

ResearchBlogging.orgDeng, H., Chen, W., Hong, S., Boycott, K., Gorrie, G., Siddique, N., Yang, Y., Fecto, F., Shi, Y., Zhai, H., Jiang, H., Hirano, M., Rampersaud, E., Jansen, G., Donkervoort, S., Bigio, E., Brooks, B., Ajroud, K., Sufit, R., Haines, J., Mugnaini, E., Pericak-Vance, M., & Siddique, T. (2011). Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia Nature DOI: 10.1038/nature10353

Story source:  LA Times & Fierce Biotech

Today, my attention was caught by The New York Academy of Sciences forthcoming seminar on “Angiogenesis: Breakthroughs in Basic Science and Therapeutic Applications.”

Sponsored by Johnson & Johnson and the Dr Paul Janssen Award for Biomedical Research, the seminar (free registration) features some distinguished speakers including Napoleone Ferrara, MD who is giving a presentation on the “Discovery of Anti-Angiogenesis Therapies for Cancer and Ocular Disease.

I’m particularly interested in hearing the panel discussion in the afternoon on the “future of angiogenic medicine,” and the potential of gene transfer therapy as a treatment option.

Those following this area will already know that ocular gene therapy was a topic of discussion at the FDA Cellular, Tissue and Gene Therapies Advisory Committee meeting in June this year.

The briefing document for the meeting discusses how a number of inherited retinal diseases such as Leber Congenital Amaurosis, Stargardt Disease and Retinitis Pigmentosa might benefit from gene therapy.  Given the standard of care is largely supportive in many of these disorders, the potential benefits are huge.

Gene therapy may also offer benefits in the treatment of acquired retinal disorders such as age-related macular degeneration (AMD), the leading cause of blindness in people aged 50 years of older in the developed world.

In a presentation to the meeting by Professor Peter Campochiaro of the Wimer Eye Institute at Johns Hopkins, he noted the burden of regular introcular injections.

Potential gene therapy products for retinal disease, such as those using viral vectors and plasmid DNA vectors into which a transgene can be inserted, will be an interesting area to watch.

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