Advertisement

Topics

SOD1 Inhibition by Pyrimethamine in Familial Amyotrophic Lateral Sclerosis (ALS)

2014-08-27 03:15:22 | BioPortfolio

Summary

The objective of this study will be to evaluate the safety, tolerability and effect on SOD1 levels by pyrimethamine in patients with familial amyotrophic lateral sclerosis.

Description

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing relentlessly progressive weakness of the arms, legs and respiratory muscles that is uniformly fatal. There are approximately 30,000 patients living with ALS in the United States. There is no treatment. The cause is uncertain in most patients. However, 3% of patients (< 1000 in number) have a familial form of ALS (FALS), phenotypically identical to the sporadic illness, that is caused by a mutation in the gene coding for the free radical scavenging enzyme copper/zinc superoxide dismutase (SOD1). Inserting the SOD1 mutant gene into mice causes them to develop a disease closely resembling ALS.

Inhibiting expression of the SOD1 gene prevents animals from developing the disease. Increasing or decreasing the number of mutated genes proportionately speeds or slows the progression of the disease. Therefore, reducing SOD1 levels in patients with SOD1 associated FALS may be a promising therapeutic approach. Through an extensive in vitro screening program for medications having the ability to reduce SOD1 levels, several molecules that reduce SOD1 protein levels are known. One of the most potent molecules is pyrimethamine, an FDA approved medication used for the treatment of malaria and toxoplasmosis. Pyrimethamine dramatically reduces SOD1 levels in mice and our preliminary studies show similar findings in humans. Our study's primary objective is to determine if familial ALS patients taking pyrimethamine will show a decline in SOD1 levels in the CSF by 15% or more. We will also determine if SOD1 and pyrimethamine are present in the blood and if the SOD-1 levels decline over the course of the study. We will also evaluate the safety and tolerability of pyrimethamine in patients with FALS. Secondary objectives will be to determine dose optimization for maximal SOD1 level reduction. We will also assess the feasibility of proceeding to phase II/III studies using pyrimethamine. Using futility methodology in which patients treated with pyrimethamine will be compared to historical controls, 40 patients with mild to moderate FALS and SOD1 mutations will receive up to 75 mg of pyrimethamine for 36 weeks. A change of 15% in the slope of decline will be deemed significant with a power of 80.7 percent. Change in ALS-FRS and quality of life will also be measured. A clinical effect realized in patients with FALS associated with an SOD1 mutation may serve as an important foundation toward finding a treatment for sporadic ALS.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Conditions

Familial Amyotrophic Lateral Sclerosis

Intervention

Pyrimethamine

Location

Weill Cornell Medical Center/New York Presbyterian Hospital
New York
New York
United States
10021

Status

Recruiting

Source

Weill Medical College of Cornell University

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:15:22-0400

Clinical Trials [1351 Associated Clinical Trials listed on BioPortfolio]

Therapeutic Treatment of Amyotrophic Lateral Sclerosis

The goal of this study is to investigate the safety and tolerability of allogeneic Wharton's jelly-derived mesenchymal stem cells administration in the individuals with diagnosed amyotroph...

Safety, Tolerability, and Activity Study of ISIS SOD1Rx to Treat Familial Amyotrophic Lateral Sclerosis (ALS) Caused by SOD1 Gene Mutations

This study will test the safety, tolerability and pharmacokinetics of single doses of ISIS 333611 administered into the spinal canal as 12 hour infusions.

The Pre-Familial Amyotrophic Lateral Sclerosis (Pre-fALS) Study

We aim to recruit unaffected (healthy) people from families with a known genetic mutation in which at least two relatives have been affected with ALS. Our goal is to identify factors, both...

F 18 T807 Tau PET Imaging in Familial Amyotrophic Lateral Sclerosis

The purpose of this research study is to evaluate tau distribution in the brain of subjects with: ALS caused by different genetic mutations, any mutation carriers (with or without symptoms...

Determinants of Disease Severity in Amyotrophic Lateral Sclerosis

OBJECTIVES: I. Determine specific clinical features, molecular abnormalities, and laboratory-based biological markers of free radical stress that are associated with amyotrophic lateral...

PubMed Articles [3021 Associated PubMed Articles listed on BioPortfolio]

An assessment of treatment guidelines, clinical practices, demographics, and progression of disease among patients with amyotrophic lateral sclerosis in Japan, the United States, and Europe.

There is an increasing clinical research focus on neuroprotective agents in amyotrophic lateral sclerosis (ALS). However, it is unclear how generalisable clinical study trial results are between diffe...

Association of Serum Retinol-Binding Protein 4 Concentration With Risk for and Prognosis of Amyotrophic Lateral Sclerosis.

Knowledge about the metabolic states of patients with amyotrophic lateral sclerosis (ALS) may provide a therapeutic approach.

Pharmacokinetic profile of edaravone: a comparison between Japanese and Caucasian populations.

Amyotrophic lateral sclerosis (ALS) affects persons of all races, and there continues to be a need for effective therapies to treat the disease.

A safety analysis of edaravone (MCI-186) during the first six cycles (24 weeks) of amyotrophic lateral sclerosis (ALS) therapy from the double-blind period in three randomized, placebo-controlled studies.

There continues to be a need for new therapies to treat ALS.

Correlating serum microRNAs and clinical parameters in Amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a debilitating neurologic disorder with poor survival rates and no clear biomarkers for disease diagnosis and prognosis.

Medical and Biotech [MESH] Definitions

A glutamate antagonist (RECEPTORS, GLUTAMATE) used as an anticonvulsant (ANTICONVULSANTS) and to prolong the survival of patients with AMYOTROPHIC LATERAL SCLEROSIS.

A superoxide dismutase (SOD1) that requires copper and zinc ions for its activity to destroy SUPEROXIDE FREE RADICALS within the CYTOPLASM. Mutations in the SOD1 gene are associated with AMYOTROPHIC LATERAL SCLEROSIS-1.

Diseases characterized by a selective degeneration of the motor neurons of the spinal cord, brainstem, or motor cortex. Clinical subtypes are distinguished by the major site of degeneration. In AMYOTROPHIC LATERAL SCLEROSIS there is involvement of upper, lower, and brainstem motor neurons. In progressive muscular atrophy and related syndromes (see MUSCULAR ATROPHY, SPINAL) the motor neurons in the spinal cord are primarily affected. With progressive bulbar palsy (BULBAR PALSY, PROGRESSIVE), the initial degeneration occurs in the brainstem. In primary lateral sclerosis, the cortical neurons are affected in isolation. (Adams et al., Principles of Neurology, 6th ed, p1089)

A Poly(A) RNA-binding protein that negatively regulates EGFR ENDOCYTOSIS. An increased risk for developing AMYOTROPHIC LATERAL SCLEROSIS 13 is observed in patients who have more than 23 CAG repeats in the ATXN2 gene coding sequence. Larger CAG expansions in the ATXN2 gene occur in SPINOCEREBELLAR ATAXIA 2 patients.

Diseases characterized by the presence of abnormally phosphorylated, ubiquitinated, and cleaved DNA-binding protein TDP-43 in affected brain and spinal cord. Inclusions of the pathologic protein in neurons and glia, without the presence of AMYLOID, is the major feature of these conditions, thus making these proteinopathies distinct from most other neurogenerative disorders in which protein misfolding leads to brain amyloidosis. Both frontotemporal lobar degeneration and AMYOTROPHIC LATERAL SCLEROSIS exhibit this common method of pathogenesis and thus they may represent two extremes of a continuous clinicopathological spectrum of one disease.

More From BioPortfolio on "SOD1 Inhibition by Pyrimethamine in Familial Amyotrophic Lateral Sclerosis (ALS)"

Advertisement
Quick Search
Advertisement
Advertisement

 

Relevant Topics

Alzheimer's Disease
Of all the types of Dementia, Alzheimer's disease is the most common, affecting around 465,000 people in the UK. Neurons in the brain die, becuase  'plaques' and 'tangles' (mis-folded proteins) form in the brain. People with Al...

Respiratory
Asthma COPD Cystic Fibrosis Pneumonia Pulmonary Medicine Respiratory Respiratory tract infections (RTIs) are any infection of the sinuses, throat, airways or lungs.  They're usually caused by viruses, but they can also ...


Searches Linking to this Trial