Poliovirus replicons encoding therapeutic agents and uses...

Details Poliovirus replicons encoding therapeutic agents and uses... Poliovirus replicons encoding therapeutic agents and uses...

2001-04-16

2004-01-20

Ketter, James (Department: 1636)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving virus or bacteriophage

C424S093210, C514S04400A

Reexamination Certificate

active

06680169

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to methods and compositions for delivering a polypeptide to a cell using poliovirus-based replicons. The invention relates to delivery of polypeptides that elicit an immune response in a subject. The invention relates to delivery of polypeptides that are capable of treating a disease condition in a subject. The invention further pertains to methods for generating cells that produce a non-poliovirus protein or fragment thereof.
BACKGROUND OF THE INVENTION
Recent epidemiological data suggest that worldwide more than seventy percent of infections with human immunodeficiency virus (HIV) are acquired by heterosexual intercourse through mucosal surfaces of the genital tract and rectum. Most HIV vaccines developed to date have been designed to preferentially stimulate the systemic humoral immune system and have relied on immunization with purified, whole human immunodeficiency virus type 1 (HIV-1) and HIV-1 proteins (Haynes B F, 1993
, Science
260:1279-1286), or infection with a recombinant virus or microbe which expresses HIV-1 proteins (McGhee J R et al., 1992
, AIDS Res. Rev.
2:289-312). A general concern with these studies is that the method of presentation of the HIV-1 antigen to the immune system will not stimulate systemic and mucosal tissues to generate effective immunity at mucosal surfaces. Given the fact that the virus most often encounters a mucosal surface during sexual (vaginal or anal) transmission, a vaccine designed to stimulate both the systemic and mucosal immune systems is essential (McGhee J R et al., 1992
, AIDS Res. Rev.
2:289-312; Forrest B D, 1992
, AIDS Research and Human Retroviruses
8:1523-1525).
Worldwide,
Helicobactor pylori
is the most common cause of gastroduodenal ulcer and is an important risk factor for gastric cancer and gastric lymphoma (Novak M J et al., 1999
, Vaccine
17(19):2384-2391).
H. pylori
infections can generally be treated with antibiotics.
However, drug-resistant variants exist and frequent use of antibiotics will exacerbate this problem by increasing the number of such variants. Thus, a vaccine for
H. pylori
would be of great benefit in developed and developing countries where
H. pylori
is endemic and gastric cancer is the second leading cause of cancer-related deaths. Eradication of
H. pylori
worldwide will likely require an effective therapeutic and prophylactic vaccine.
The use of neurotrophic viruses as vectors for targeted gene delivery to the central nervous system (CNS) has many applications for the development of new therapies for neurological diseases and spinal cord trauma.
Traumatic brain injury (TBI) affects nearly 200,000 people each year, most of them young men. Aggressive medical management has reduced the death rate, and currently, 75% of people survive a brain injury, but many are left with lasting cognitive and memory impairments that prevent their return to work or resumption of normal activities. Alterations in cognitive function remain a significant cause of long term morbidity after trauma to the central nervous system. Mild traumatic brain injury can result in cognitive deficits that are observed clinically and following experimental brain injury models (Dacey et al., 1993, in Cooper P R (ed):
Head Injury
. Baltimore. Williams and Wilkins pp. 159-182; Hicks, 1993
, J. Neurotrauma
10: 405-414).
Most current therapies in clinical trials target prevention of neuronal injury and are aimed at early administration. This approach has not yet proven effective and must compete with intensive medical management of these very sick patients. Nerve growth factor belongs to the family of neurotrophic factors that regulate the survival and differentiation of nerve cells.
Thus, the unmet need for therapies for this population remains high.
One of the factors determining the degree to which elements of the central nervous system can recover from injury may be the availability of neurotrophic substances. Administration of various neuronal growth factors has been demonstrated to support neuronal cells in a variety of different models of central nervous system injury (Korsching S., 1993
, J. Neurosci.
13:2739-2748; Maness et al., 1994
, Neurosci. Biobehav. Rev.
18:143-159). Nerve growth factor remains the most extensively studied neurotrophic factor, and treatment with NGF has been shown to reduce cell death after neuronal injury (Kerr, JFR et al., 1991, in Tomei D L, Cope/FO (eds):
Apoptosis The Molecular Basis of Cell Death
, Cold Spring Harbor, N.Y.: Cold Spring Harbor Press pp. 5-29; Frim D. M. et al., 1993
, J. Neurosurg.
78: 267-273; Hagg T. et al., 1988
, Exp. Neurol.
101: 303-312; Schumacher J. M. et al., 1991
, Neuroscience
45: 561-570; Shigeno T. et al., 1991
, J. Neurosci.
11: 2914-2919).
DeKosky S. T. et al., (1994
, Exp. Neurol.
130:173-177), have demonstrated the presence of NGF in the cerebrospinal fluid of brain-injured human patients and NGF infusion can significantly improve the cognitive deficits normally associated with fluid-percussion brain trauma (Sinson G. et al., 1995
, J. Neurochem.
65:2209-2216). Recent data indicates that NGF administration, in the acute, posttraumatic period following fluid-percussion brain injury, may have potential in improving post-traumatic cognitive deficits (Sinson et al., 1995
, J. Neurochem.
65:2209-2216).
Nerve growth factor has been demonstrated to be a neurotrophic factor for forebrain cholinergic nerve cells that die during Alzheimer's disease and with increasing age (PCT Publication WO 90/07341). Additionally, NGF can prevent the death of forebrain cholinergic nerve cells after traumatic injury and NGF has been reported to reverse the cognitive losses that occur with aging.
Intravenous application of certain nerve growth factors for the treatment of neuronal damage associated with ischemia, hypoxia or neurodegeneration has been described, however, the usefulness of such therapies is questionable given the presence of the blood brain barrier which prevents exposure of the damaged neuronal tissue to the intravenously administered NGF (PCT Publication Number WO 90/0882). Nerve growth factor can also be infused into the brain for treating neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease or Amyotrophic Lateral Sclerosis (ALS) by means of an implantable pump as described in PCT Publication Number WO 98/48723. In addition, NGF microencapsulation compositions having controlled release characteristics for use in promoting nerve cell growth, repair, survival, differentiation, maturation or function are described (PCT Publication Number WO 98/56426).
Poliovirus, a small RNA-virus of the family Picornaviridae, is an attractive candidate system for delivery of nucleic acids and proteins that may be useful in treating each of the foregoing maladies. Poliovirus-based replicons offer an attactive means to deliver antigens to the mucosal immune system and possibly treat or immunize against HIV or
H. pylori
infection. Additionally, poliovirus-based replicons offer an attractive means of delivering proteins, such as NGF, to neurons for alleviation or treatment of neurological disorders.
First, the live attenuated strains of poliovirus are safe for humans and are routinely administered to the general population in the form of the Sabin oral vaccine. Live or attenuated viruses have long been used to stimulate the immune system in a subject. A viral genome adapted for use in antigen delivery, therefore, should pose no greater health risk than that associated with administration of the attenuated vaccines alone.
Second, the pathogenesis of poliovirus is well-studied and the important features identified. The poliovirus is naturally transmitted by an oral-fecal route and is stable in the harsh conditions of the intestinal tract. Primary replication occurs in the oropharynx and gastrointestinal tract, with subsequent spread to the lymph nodes (Horstmann, D M et al., 1959
, JAMA
170:1-8).
Upon entry into host cells, the RNA genome undergoes a rapid amplification cycle follo

Affiliated with

Also associated with

Rating

Poliovirus replicons encoding therapeutic agents and uses... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Poliovirus replicons encoding therapeutic agents and uses..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Poliovirus replicons encoding therapeutic agents and uses... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3233766