Advanced Molecular Diagnostic Test for Neurofibromatosis

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$1,150,044.00
Award Year:
2007
Program:
SBIR
Phase:
Phase II
Contract:
2R44NS053110-02
Award Id:
76423
Agency Tracking Number:
NS053110
Solicitation Year:
n/a
Solicitation Topic Code:
n/a
Solicitation Number:
n/a
Small Business Information
313 Pleasant Street, Watertown, MA, 02472
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
878574755
Principal Investigator:
MARK LIM
(617) 923-9930
MLIM@AMBERGEN.COM
Business Contact:
SHELLA BATELMAN
() -
shella@ambergen.com
Research Institution:
n/a
Abstract
DESCRIPTION (provided by applicant): Advanced Molecular Diagnostic Test for Neurofibromatosis ABSTRACT Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by mutations in the NF1 gene. In children, NF1 causes learning disabilities, coor dination problems and benign tumors later in life that grow on nerve tissue. Currently more than 100,000 Americans suffer from NF1 with the disease having one of the highest prevalence rates for a genetic disorder (~1 out of 4,000 births). Progress has rec ently been made in identifying possible drugs for this disease including the proposed use of statins to alleviate learning disabilities in children with NF1. There is a critical need for a cost-effective test to screen for mutations in the NF1 gene. Howeve r, a significant problem is the wide variety of NF1 mutations which have been found to occur. Most inactivating mutations (gt80%) are chain truncating and distributed throughout the gene. The preferred method to detect such mutations is the protein truncat ion test (PTT). However, because of the many limitations of conventional PTT, it is not practical for routine clinical use. Instead, current diagnosis is normally based on established non-genetic clinical criteria. Significant progress was made during Phas e I in overcoming these limitations by developing a cost- effective alternative to conventional PTT. One approach utilizes an ELISA-based protein truncation test (ELISA-PTT) to detect chain-truncations. In contrast to conventional PTT, ELISA-PTT eliminates the need for electrophoresis and radioactivity. A second and complementary approach, based on mass spectrometric analysis of in vitro expressed proteins (MASSIVE-PRO), is able to additionally scan for missense mutations by precisely measuring the mass shi ft from single amino acid substitutions. Studies performed using these improved assays on normal and mutant cDNAs as well a limited number of NF1 patient samples revealed that these tests are highly effective with sensitivities comparable to and in some ca ses superior to standard DNA sequencing. During Phase II, we will further develop and extensively evaluate these novel NF1 diagnostic assays. The ELISA-PTT will be improved to allow scanning of the entire NF1 coding region using mRNA isolated from patient blood and a single-step PCR protocol. The MASSIVE-PRO assay will also be improved so that it can provide specific sequence information about mutations in the NF1 gene. Advanced technologies based on several innovations which can significantly reduce the nu mber of PCR and cell-free translation reactions will also be evaluated. These assays, once optimized, will be extensively evaluated in collaboration with Dr. Ludwine Messiaen, Director of Genomics at the University of Alabama and a world leader in NF1 test ing using a repository of validated genomic DNA and mRNA samples from NF1 patients. Clinical beta-testing will be performed during the third year in Dr. Messiaen's laboratory. In addition, Quest Diagnostics will work closely with AmberGen in order to assur e these NF1 tests are properly designed for the requirements of the clinical laboratory environment. Advanced Molecular Diagnostic Test for Neurofibromatosis NARRATIVE Currently more than 100,000 Americans suffer from neurofibromatosis type 1 (NF1) which i s among the most prevalent genetic disorders (~1 out of 4,000 births). An important goal is to develop a cost- effective test to screen for mutations in the NF1 gene. Significant progress was made during Phase I in developing a cost-effective alternative t o conventional genetic tests. During Phase II, we propose to further develop and extensively evaluate these novel NF1 mutation assays in collaboration with Dr. Ludwine Messiaen, Director of Genomics at the University of Alabama and a world leader in NF1 te sting using a repository of validated genomic DNA and mRNA samples. If successful, the test will enable more extensive screening and consequently increased s

* information listed above is at the time of submission.

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