Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Attacking a rare disease at its source with gene therapy

27.08.2014

Penn proof-of-principle animal study reduces harmful accumulation of proteins in lysosomal storage disease

Treating the rare disease MPS I is a challenge. MPS I, caused by the deficiency of a key enzyme called IDUA, eventually leads to the abnormal accumulation of certain molecules and cell death.

The two main treatments for MPS I are bone marrow transplantation and intravenous enzyme replacement therapy, but these are only marginally effective or clinically impractical, especially when the disease strikes the central nervous system (CNS). Using an animal model, a team from the Perelman School of Medicine at the University of Pennsylvania has proven the efficacy of a more elegant way to restore IDUA levels in the body through direct gene transfer. Their work was published this week online in Molecular Therapy.

"The study provides a strong proof-of-principle for the efficacy and practicality of intrathecal delivery of gene therapy for MPS patients," said lead author James M. Wilson, MD, PhD, professor of Pathology and Laboratory Medicine and director of the Penn Gene Therapy Program. "This first demonstration will pave the way for gene therapies to be translated into the clinic for lysosomal storage diseases."

... more about:
»Attacking »CNS »CSF »Health »MPS »Medicine »Wilson »blood »diseases »enzyme »vector

This family of diseases comprises about 50 rare inherited disorders marked by defects in the lysosomes, compartments within cells filled with enzymes to digest large molecules. If one of these enzymes is mutated, molecules that would normally be degraded by the lysosome accumulate within the cell and their fragments are not recycled. Many of the MPS disorders can share symptoms, such as speech and hearing problems, hernias, and heart problems. Patient groups estimate that in the United States 1 in 25,000 births will result in some form of MPS. Life expectancy varies significantly for people with MPS I. Individuals with the most severe form rarely live more than 10 years.

The team used an adeno-associated viral (AAV) vector to introduce normal IDUA to glial and neuronal cells of the brain and spinal cord in a feline model. Their aim was to treat the CNS manifestations of MPS at the source. After a single injection of the AAV9 vector expressing a normal feline IDUA gene sequence and various promoters, the investigators collected blood serum and cerebrospinal fluid (CSF) samples from the test animals and from untreated controls

Some of the treated animals displayed a sharp decline in IDUA levels in the CSF after an initial elevation in the enzyme, which the researchers attribute to an antibody response against IDUA. However, IDUA still persisted at a level sufficient to elicit a positive therapeutic response.

The team also found that one CSF enzyme was elevated in the presence of MPS and propose it could be used as a biomarker for disease activity. All the treated animals displayed a marked decrease in this enzyme, confirming a definite biochemical response to the introduction of the gene vector.

Tissue samples from the brain and spinal cord showed widespread presence of the AAV9 vector throughout all regions of the CNS. IDUA deficiency in the CNS caused by MPS1 results in the accumulation of cholesterol and lipids called gangliosides in brain tissue and accumulation of the sugar glycosaminoglycan in connective tissue and cerebral blood vessels. The animals treated with the AAV9-IDUA vector displayed an almost complete reversal of these molecular markers of MPS.

"Signs of MPS were also virtually completely corrected in the liver and spleen," notes Wilson.

Even with a possible antibody response, conclude the researchers, a single injection nearly reversed all evidence of MPS pathology in the CNS of the treated animals. Next steps could include possible human trials and the expansion of this therapeutic approach to other lysosomal diseases that attack CNS cells.

###

Co-authors also included Mark E. Haskins from Penn School of Veterinary Medicine. This work was funded by NIH grants P40-OD010939 and DK25759 and ReGenX BioSciences, LLC, a Washington, D.C.-based biotech firm that holds licenses in technology used in this study.

Editor's Note:

J.M. Wilson is an advisor to ReGenX Biosciences and Dimension Therapeutics , and is a founder of, holds equity in, and receives grants from ReGenX Biosciences and Dimension Therapeutics; in addition, he is a founder, consultant and advisor to several other biopharmaceutical companies and is an inventor on patents licensed to various biopharmaceutical companies.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2013 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2013, Penn Medicine provided $814 million to benefit our community.

Karen Kreeger | Eurek Alert!
Further information:
http://www.uphs.upenn.edu

Further reports about: Attacking CNS CSF Health MPS Medicine Wilson blood diseases enzyme vector

More articles from Life Sciences:

nachricht About injured hearts that grow back - Heart regeneration mechanism in zebrafish revealed
10.02.2016 | Universität Ulm

nachricht Chemical cages: New technique advances synthetic biology
10.02.2016 | Arizona State University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: The most accurate optical single-ion clock worldwide

Atomic clock experts from the Physikalisch-Technische Bundesanstalt (PTB) are the first research group in the world to have built an optical single-ion clock which attains an accuracy which had only been predicted theoretically so far. Their optical ytterbium clock achieved a relative systematic measurement uncertainty of 3 E-18. The results have been published in the current issue of the scientific journal "Physical Review Letters".

Atomic clock experts from the Physikalisch-Technische Bundesanstalt (PTB) are the first research group in the world to have built an optical single-ion clock...

Im Focus: Goodbye ground control: autonomous nanosatellites

The University of Würzburg has two new space projects in the pipeline which are concerned with the observation of planets and autonomous fault correction aboard satellites. The German Federal Ministry of Economic Affairs and Energy funds the projects with around 1.6 million euros.

Detecting tornadoes that sweep across Mars. Discovering meteors that fall to Earth. Investigating strange lightning that flashes from Earth's atmosphere into...

Im Focus: Flow phenomena on solid surfaces: Physicists highlight key role played by boundary layer velocity

Physicists from Saarland University and the ESPCI in Paris have shown how liquids on solid surfaces can be made to slide over the surface a bit like a bobsleigh on ice. The key is to apply a coating at the boundary between the liquid and the surface that induces the liquid to slip. This results in an increase in the average flow velocity of the liquid and its throughput. This was demonstrated by studying the behaviour of droplets on surfaces with different coatings as they evolved into the equilibrium state. The results could prove useful in optimizing industrial processes, such as the extrusion of plastics.

The study has been published in the respected academic journal PNAS (Proceedings of the National Academy of Sciences of the United States of America).

Im Focus: New study: How stable is the West Antarctic Ice Sheet?

Exceeding critical temperature limits in the Southern Ocean may cause the collapse of ice sheets and a sharp rise in sea levels

A future warming of the Southern Ocean caused by rising greenhouse gas concentrations in the atmosphere may severely disrupt the stability of the West...

Im Focus: Superconductivity: footballs with no resistance

Indications of light-induced lossless electricity transmission in fullerenes contribute to the search for superconducting materials for practical applications.

Superconductors have long been confined to niche applications, due to the fact that the highest temperature at which even the best of these materials becomes...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Travel grants available: Meet the world’s most proficient mathematicians and computer scientists

09.02.2016 | Event News

AKL’16: Experience Laser Technology Live in Europe´s Largest Laser Application Center!

02.02.2016 | Event News

From intelligent knee braces to anti-theft backpacks

26.01.2016 | Event News

 
Latest News

About injured hearts that grow back - Heart regeneration mechanism in zebrafish revealed

10.02.2016 | Life Sciences

The most accurate optical single-ion clock worldwide

10.02.2016 | Earth Sciences

Absorbing acoustics with soundless spirals

10.02.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>