RECENT ADVANCES IN GENE THERAPY

- Purvi Shah

Gene therapy is an experimental technique that uses genes to treat or

prevent disease. In the future, this technique may allow doctors to treat a

disorder by inserting a gene into a patients cells instead of using drugs or

surgery.

Gene therapy was first conceptualized in 1972

Researchers are testing several approaches to gene therapy, including:

Replacing a mutated gene that causes disease with a healthy copy of the

gene.

Inactivating, or “knocking out,” a mutated gene that is functioning

improperly.

Introducing a new gene into the body to help fight a disease.

What Is Gene Therapy

Although early clinical failures led many to dismiss gene therapy as

over-hyped, clinical successes since 2006 have bolstered new optimism

in the promise of gene therapy.

These include successful treatment of patients with the retinal

disease, X-linked SCID, adrenoleukodystrophy, chronic lymphocytic

leukemia(CLL), acute lymphocytic leukemia(ALL), multiple

myeloma and Parkinson's disease.

These recent clinical successes have led to a renewed interest in gene

therapy, with several articles in scientific and popular publications

calling for continued investment in the field.

Types Of Gene Therapy

Gene therapy may be classified into two types:

1. Somatic gene therapy - the therapeutic genes are

transferred into the somatic cells, or body, of a patient. Any

modifications and effects will be restricted to the individual

patient only, and will not be inherited by the patient's

offspring or later generations

2. Germ line gene therapy - sperm or eggs, are modified by

the introduction of functional genes, which are integrated

into their genomes. This would allow the therapy to be

heritable and passed on to later generations

Gene Therapy Depends on Delivery of Corrective Genes

Viral vectors are a tool commonly used by molecular

biologists to deliver genetic material into cells.

This process can be performed inside a living

organism (in vivo) or in cell culture (in vitro).

Viruses have evolved specialized molecular

mechanisms to efficiently transport their genomes

inside the cells they infect

Viruses are used as Delivery Tolls

Viruses are used as vectors to introduce the genetic

material inside the bodies.

These viruses are inactivated, they are not able to

reproduce

1. Adenoviruses

2. Herpes viruses - DNA tumor viruses

3. Retroviruses - RNA tumor viruses

First Approved Gene Therapy

On September 14, 1990 at the U.S. National Institutes of Health, W. French

Anderson M.D. and his colleagues R. Michael Blaese, M.D., C. Bouzaid, M.D., and

Kenneth Culver, M.D., performed the first approved gene therapy procedure on

four-year old Ashanthi DeSilva, Born with a rare genetic disease called severe

combined immunodeficiency (SCID)

What did they do In Ashanthi's gene therapy procedure, doctors removed white blood cells from the

child's body, let the cells grow in the laboratory, inserted the missing gene into the

cells, and then infused the genetically modified blood cells back into the patient's

bloodstream.

A success story

As of early 2007, she was still in good health, and

she was attending college. Some would state that the

study is of great importance despite its indefinite

results, if only because it demonstrated that gene

therapy could be practically attempted without

adverse consequences

'mending broken hearts' by using gene therapy

Novel techniques to “mend broken hearts” using gene therapy and stem cells

represent a major new frontier in the treatment of heart disease

It was achieved by the researchers at Gladstone Institute of Cardiovascular Disease in

California

They were able to re-programme scar-forming cells into heart muscle cells, some of

which were capable of transmitting the kind of electrical signals that make the heart beat

They performed on a live mice, transforming scar-forming cells, called fibroblasts,

into beating heart muscle cells

They injected three genes (cocktail of genes) into the heart of live mice that had been

damaged by heart attack, fibroblasts could be turned into working heart cells.

Researchers said that the “cocktail of genes” used to regenerate cells could one day be

replaced with “small drug-like molecules” that would offer safer and easier delivery

First Real-Time MRI-Guided Gene Therapy for Brain Cancer

Neurosurgeons at the University of California, San Diego School of Medicine and UC San Diego Moores Cancer Center are among the first in the world to utilize real-time magnetic resonance imaging (MRI) guidance for delivery of gene therapy as a potential treatment for brain tumorsUsing MRI navigational technology, neurosurgeons can inject Toca 511 (vocimagene amiretrorepvec), a novel investigational gene therapy, directly into a brain malignancyThe new approach offers a precise way to deliver a therapeutic virus designed to make the tumor susceptible to cancer-killing drugs

Toca 511 is a retrovirus engineered to

selectively replicate in cancer cells, such as

glioblastomas.

Toca 511 produces an enzyme that converts

an anti-fungal drug, flucytosine (5-FC), into

the anti-cancer drug 5-fluorouracil (5-FU). 

After the injection of Toca 511, the patients

are treated with an investigational extended-

release oral formulation of 5-FC called Toca

FC.

Cancer cell killing takes place when 5-FC

comes into contact with cells infected with

Toca 511.

UCLA researchers combine cellular and gene therapies to develop

treatment for breast cancerCarol Kruse, a professor of neurosurgery and member of the Jonsson Cancer Center

and the UCLA Brain Research Institute led the research on breast cancer

Breast cancer is the most common form of cancer in women, and metastasis is a

major cause of health deterioration and death from the disease

Cellular therapy and gene therapy were used together to treat breast cancer

Cellular therapy is a type of immunotherapy that uses T cells, the foot soldiers of

the immune system, that have been sensitized in the laboratory to kill breast cancer

cells.

These sensitized T cells are injected into the parts of the brain to which cancer has

spread.

The research shows that the T cells can move through tissue and recognize and

directly kill the tumor cells

stem cell gene therapy gives hope to prevent inherited neurological

diseaseScientists from The University of Manchester have used stem cell gene

therapy to treat a fatal genetic brain disease

It was used to treat Sanfilippo – a fatal inherited condition which causes

progressive dementia in children

Sanfilippo, is currently untreatable mucopolysaccharide (MPS) disease

It is caused by the lack of SGSH enzyme in the body which helps to breakdown

and recycle long chain sugars, such as heparan sulphate (HS)

Children with the condition build up and store excess HS throughout their body

from birth which affects their brain and results in progressive dementia and

hyperactivity, followed by losing the ability to walk and swallow

Researchers have developed a stem cell gene therapy which overproduces

the SGSH enzyme specifically in bone marrow white blood cells to increase

SGSH enzyme from bone marrow transplants, and to target it to the cells that

traffic into the brain

It was seen that mice treated by this method produce five times the normal

SGSH enzyme levels in the bone marrow and and 11 per cent of normal

levels in the brain

The enzyme is taken up by affected brain cells and is enough to correct

brain HS storage and neuro inflammation to near normal levels and

completely corrects the hyperactive behaviour in mice with Sanfilippo

Mucopolysaccharidosis Type IIIA potential gene therapy

Mucopolysaccharidosis Type IIIA (MPSIIIA) is a metabolic disorder in which the body

is missing an enzyme that is required to break down long chains of sugars known as

glycosaminoglycans

The glycosaminoglycans collect in the body and cause damage, particularly in the

brain if not broken

Fàtima Bosch and colleagues at Universitat Autònoma de Barcelona in Spain

developed a form of gene therapy to replace the enzyme that is missing in MPSIIIA

They injected the replacement gene into the cerebrospinal fluid that surrounds the

brain and spinal cord

This study demonstrates that gene therapy can be delivered to the brain through the

cerebrospinal fluid and suggests that this approach could potentially be used as a therapy

for MPSIIIA

IS GENE THERAPY TOTALLY SAFE ??

Although gene therapy is a promising treatment

option for a number of diseases (including inherited

disorders, some types of cancer, and certain viral

infections), the technique remains risky and is still

under study to make sure that it will be safe and

effective.

Gene therapy is currently only being tested for the

treatment of diseases that have no other cures

Technical Difficulties in Gene Therapy

Gene delivery: Successful gene delivery is not easy or

predictable, even in single-gene disorders.

For example, although the genetic basis of cystic fibrosis is well

known, the presence of mucus in the lungs makes it physically

difficult to deliver genes to the target lung cells.

Delivery of genes for cancer therapy may also be complicated

by the disease being present at several sites.

Gene-therapy trials for X-linked severe combined

immunodeficiency (X-SCID), however, have been more

successful

Problems with Gene Therapy

Short Lived

Hard to rapidly integrate therapeutic DNA into genome and rapidly dividing nature

of cells prevent gene therapy from long time

Would have to have multiple rounds of therapy

Immune Response

new things introduced leads to immune response

increased response when a repeat offender enters

the gene might be over-expressed (toxicity)

Viral Vectors

patient could have toxic, immune, inflammatory response

also may cause disease once inside

Multigene Disorders

Heart disease, high blood pressure, Alzheimer’s, arthritis and diabetes are hard to

treat because you need to introduce more than one gene

Do not forget Genes can be Unpredictable ?