Ensayo clínico para Enfermedad de Huntington

Landmark Huntington's trial starts.

The first drug that can potentially correct the underlying defect that causes Huntington's disease has been taken by patients in a clinical trial.

BBC.
Via: Bionews.

Genética en el Congreso 2010 de la MDS

14avo Congreso Internacional de Enfermedad de Parkinson y Movimientos Anormales, realizado en Buenos Aires, en junio del 2010.

1. En diversas conferencias y seminarios se revisaron aspectos de genética y movimientos anormales. En base esto se tuvo una buena actualización de los aspectos de Genética de la enfermedad de Parkinson y de Genética de la enfermedad de Huntington (fundamentalmente nuevos intentos de tratamiento y neuroprotección).
Lo más relevante es el reporte de algunos genes “nuevos” causantes o favorecedores de EP, con lo que cada día se conocen mejor las causas de esta afección.

2. Una importante sesión fue dedicada a la Terapia Génica para EP.
Se describieron en detalle las posibles “vías” por las que una terapia génica (usar ADN como “medicamento”) podría ser útil en la terapia de la EP. Probablemente por este medio no se logre una cura, pero si mejorar (enlentecer) la progresión de la enfermedad.
Se han realizado diversos estudios en animales de experimentación con modelos de EP, en los que se han obtenido muy buenos resultados. Actualmente se está pasando a la etapa (más lenta, costosa y complicada) de ensayos clínicos, es decir, analizar en pacientes humanos su efectividad y que no tengan efectos adversos severos.
En los próximos años veremos resultados de estos estudios.

3. Otro de los temas relevantes fue el correcto uso de los “test genéticos” en EP (así como en
otras afecciones neurogenéticas) y la importancia del Asesoramiento Genético para las familias afectadas por las mismas.
Es muy importante usar estas herramientas de la forma adecuada, para obtener, cuando es posible, un beneficio clínico de las mismas y no generar stress adicional a los pacientes o familias.

4. Posteriormente al congreso se realizó la reunión de LARGE-PD, la red Latinoamericana para el estudio de la Genética de la EP, que en parte ya viene funcionando y de la que somos participantes. Otros aspectos de esta red se están consolidando en estos momentos y se planean actividades a futuro.
Es en el marco de este grupo de investigación que se están realizando los análisis genéticos para pacientes uruguayos.
Se destaca el valor de la participación voluntaria de los pacientes en este tipo de programa de investigación.
El trabajo a futuro inmediato estará orientado a incorporar más pacientes y paulatinamente analizar otros genes vinculados (o posiblemente vinculados) a la EP en este grupo. Se continuará con el desarrollo del banco de datos clínicos, de historia familiar y de ADN, que permitan investigaciones sobre la genética de la EP en poblaciones latinoamericanas.

Ensayos de Terapia Génica en Enfermedad de Parkinson

Estos son los ensayos publicados recientemente sobre Terapia Génica en EP.
Han sido realizados en modelos animales, células en cultivo y en seres humanos (Fase I).


Neurology. 2008 May 20;70(21):1980-3. Epub 2008 Apr 9.
Results from a phase I safety trial of hAADC gene therapy for Parkinson disease.
Eberling JL, Jagust WJ, Christine CW, Starr P, Larson P, Bankiewicz KS, Aminoff MJ.
Department of Molecular Imaging and Neuroscience, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. jleberling@lbl.gov
BACKGROUND: In a primate model of Parkinson disease (PD), intrastriatal infusion of an adeno-associated viral (AAV) vector containing the human aromatic l-amino acid decarboxylase (hAADC) gene results in robust gene expression. After gene transfer, low doses of systemically administered l-dopa are converted to dopamine in the transduced striatal neurons, resulting in behavioral improvement without the side effects typically associated with higher doses of l-dopa. These studies led to the initiation of a phase I safety trial. Here we report the findings for the first cohort of five patients. METHODS: Patients with moderate to advanced PD received bilateral infusion of a low dose of the AAV-hAADC vector into the putamen. PET scans using the AADC tracer, 6-[18F]fluoro-l-m-tyrosine (FMT), were performed at baseline and at 1 and 6 months after infusion as an in vivo measure of gene expression. RESULTS: PET results showed an average 30% increase in FMT uptake (K(i)(c)) in the putamen after gene transfer. Preliminary analysis of clinical data indicates a modest improvement, but absence of a control and the nonblinded analyses make interpretation difficult. CONCLUSIONS: Thus far, this gene therapy approach has been well tolerated and shows PET evidence of sustained gene expression. These initial findings demonstrate the safety of the therapy; higher doses of adeno-associated viral vector containing the human aromatic l-amino acid decarboxylase gene in the next cohort of patients may further increase dopamine production in the putamen and provide more profound clinical benefit.

Lancet. 2007 Jun 23;369(9579):2097-105.
Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial.
Kaplitt MG, Feigin A, Tang C, Fitzsimons HL, Mattis P, Lawlor PA, Bland RJ, Young D, Strybing K, Eidelberg D, During MJ.
Department of Neurological Surgery, Weill Medical College of Cornell University, New York, NY, USA.
BACKGROUND: Dopaminergic neuronal loss in Parkinson's disease leads to changes in the circuitry of the basal ganglia, such as decreased inhibitory GABAergic input to the subthalamic nucleus. We aimed to measure the safety, tolerability, and potential efficacy of transfer of glutamic acid decarboxylase (GAD) gene with adeno-associated virus (AAV) into the subthalamic nucleus of patients with Parkinson's disease. METHODS: We did an open label, safety and tolerability trial of unilateral subthalamic viral vector (AAV-GAD) injection in 11 men and 1 woman with Parkinson's disease (mean age 58.2, SD=5.7 years). Four patients received low-dose, four medium-dose, and four high-dose AAV-GAD at New York Presbyterian Hospital. Inclusion criteria consisted of Hoehn and Yahr stage 3 or greater, motor fluctuations with substantial off time, and age 70 years or less. Patients were assessed clinically both off and on medication at baseline and after 1, 3, 6, and 12 months at North Shore Hospital. Efficacy measures included the Unified Parkinson's Disease Rating Scale (UPDRS), scales of activities of daily living (ADL), neuropsychological testing, and PET imaging with 18F-fluorodeoxyglucose. The trial is registered with the ClinicalTrials.gov registry, number NCT00195143. FINDINGS: All patients who enrolled had surgery, and there were no dropouts or patients lost to follow-up. There were no adverse events related to gene therapy. Significant improvements in motor UPDRS scores (p=0.0015), predominantly on the side of the body that was contralateral to surgery, were seen 3 months after gene therapy and persisted up to 12 months. PET scans revealed a substantial reduction in thalamic metabolism that was restricted to the treated hemisphere, and a correlation between clinical motor scores and brain metabolism in the supplementary motor area. INTERPRETATION: AAV-GAD gene therapy of the subthalamic nucleus is safe and well tolerated by patients with advanced Parkinson's disease, suggesting that in-vivo gene therapy in the adult brain might be safe for various neurodegenerative diseases.

J Gene Med. 2007 Jul;9(7):605-12.
Comparison of cDNA and genomic forms of tyrosine hydroxylase gene therapy of the brain with Trojan horse liposomes.
Xia CF, Chu C, Li J, Wang Y, Zhang Y, Boado RJ, Pardridge WM.
Department of Medicine, UCLA, Los Angeles, CA 90024, USA.
BACKGROUND: The present study examines whether chromosomal derived forms of therapeutic genes can be delivered to brain following intravenous administration. The brain expression of a rat tyrosine hydroxylase (TH) cDNA is compared to the brain expression of a plasmid DNA encoding the 18 kb rat TH gene. METHODS: TH gene expression is measured in cell culture and in vivo in brain in experimental Parkinson's disease (PD). A total of four eukaryotic expression plasmids encoding rat TH were engineered wherein the size of the TH expression cassette ranged from 1.5 kb, in the case of the cDNA form of the gene, to 17.5 kb, in the case of the largest size genomic construct. The TH expression plasmids were delivered to either cultured cells or to rat brain in vivo with Trojan horse liposomes (THLs), which target the non-viral plasmid DNA to cells via cell membrane receptors. RESULTS: The pattern of TH gene expression in cell culture and in vivo was similar: the cDNA form of the TH gene was fast-acting with short duration of action, and the genomic form of the TH gene was slow-acting with longer duration of action. The most sustained replacement of striatal TH enzyme activity in experimental PD was produced by combination gene therapy where both the cDNA and the genomic forms of the TH gene were administered simultaneously. CONCLUSIONS: Eukaryotic expression plasmids encoding genomic forms of therapeutic genes, as large as 18 kb, can be successfully incorporated in THLs and delivered to brain following intravenous administration.

Gene Ther. 2006 Dec;13(23):1639-44.
Koike H, Ishida A, Shimamura M, Mizuno S, Nakamura T, Ogihara T et al, Prevention of onset of Parkinson's disease by in vivo gene transfer of human hepatocyte growth factor in rodent model: a model of gene therapy for Parkinson's disease.
Division of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SNi). As neurotrophic factors support the survival and enhance the function of dopaminergic neurons, gene therapy using neurotrophic factors has become the center of interest. Thus, we focused on hepatocyte growth factor (HGF) as a neurotrophic and angiogenic growth factor. At 7 days before injection of 6-hydroxydopamine into the SNi, stereotaxic transfection of human HGF or lacZ plasmid was performed into the unilateral striatum of rats. Expression of human HGF in the injected sites could be detected in rats transfected with HGF plasmid DNA, using immunohistochemical staining. Consistently, human immunoreactive HGF protein could be detected at least up to 12 days after transfection. Interestingly, PD rats transfected with lacZ demonstrated amphetamine-induced rotational asymmetry. However, transfection of HGF plasmid DNA resulted in significant inhibition of abnormal rotation up to 24 weeks in a dose-dependent manner. Over 90% of dopaminergic neurons were lost in PD rats transfected with lacZ, whereas over 70% survived in rats transfected with HGF, as assessed by immunohistochemical staining. Overall, the present study demonstrated that overexpression of HGF prevented neuronal death in a PD rat model, providing a potential novel therapy for PD.