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SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Maze Therapeutics, a company translating genetic insights into new precision medicines, today revealed its first three lead therapeutic candidates in the companys wholly owned pipeline. The candidates include:

Each of the three lead candidates was enabled by Mazes COMPASS platform, which uncovered important new findings for the genetic target, discerning which specific signals may be critical for the treatment of patients, and which are likely non-actionable. The Maze pipeline will have the potential to serve as precision medicines for rare diseases and mechanistically defined subsets of common diseases based on certain genetic drivers.

In addition, Maze is concurrently leveraging COMPASS to advance additional discovery-stage research programs across three main therapeutic areas of focus: metabolic, cardio/renal and neurological diseases. These programs will constitute a broad, diverse pipeline for Maze and will be a combination of wholly owned and partnership-led collaborations.

Maze was built by co-founders, including Charles Homcy and other preeminent thinkers in the field of genetics, on a bold vision to leverage growing knowledge of genetic drivers of disease in order to create precision medicines for the treatment of both rare and more common diseases, said Jason Coloma, Ph.D., president and chief executive officer of Maze. Since our founding, we have been leveraging insights from leading geneticists, combined with the growing availability of paired human genetic and clinical data, the evolution of functional genomic technologies and advances in computational power, to build our COMPASS platform in order to bring unique insights into efficient, genetics-based drug development. We are excited by the significant progress we have made with our platform and pipeline, bringing us an important step closer to our goal of delivering the right drug to the right patient at the right time.

Mazes therapeutic candidates are designed to: 1) target genes whose activity affects the phenotype associated with another, often distant, gene, referred to as genetic modifiers; 2) mimic the activity of protective genetic variants; 3) correct the effects of toxic genetic variants; or 4) leverage new genetic insights to address otherwise challenging drug targets.

COMPASS is a proprietary, purpose-built platform that combines human genetic data, functional genomic tools and data science technology to map novel connections between known genes and their influence on susceptibility, timing of onset and rate of disease progression. In addition, Maze is exploring applications of COMPASS in diseases of haploinsufficiency by identifying genetic mechanisms that increase levels of a deficient protein and translating them into therapeutics.

New findings using COMPASS helped fill in fundamental data gaps, turning known but challenging targets into exciting, differentiated approaches to the genetic drivers of disease for our first three programs, said Sarah Noonberg, M.D., Ph.D., chief medical officer of Maze. While it has been shown that targets with human genetic evidence are more likely to yield efficacious treatments, very few groups have had the capabilities to then turn genetic insights into viable drug programs. We believe our COMPASS platform, integrated with our extensive drug discovery capabilities, will allow us to accelerate the pace of therapeutic development, as well as increase the likelihood of producing therapies that provide meaningful clinical benefit for patients. We are excited to advance these initial programs and look forward to continued progress toward the clinic as efficiently as possible.

About Mazes Wholly Owned Programs

GYS1 Program for Pompe DiseasePompe disease is a rare, inherited autosomal recessive disorder with an incidence of approximately 1 in 40,000 live births in the U.S., and is estimated to affect 5,000 to 10,000 patients worldwide. It is caused by mutations in the GAA gene, which codes for an enzyme responsible for breaking down lysosomal glycogen into glucose. As a result of this mutation, glycogen accumulates in various tissues, particularly skeletal and cardiac muscle tissues, causing progressive weakness and respiratory insufficiency.

Maze is developing a novel, oral approach to treating Pompe disease by inhibiting the protein muscle glycogen synthase, which is encoded by the gene GYS1. Targeting this protein leads to reduction in the synthesis of glycogen, which is expected to restore glycogen balance through a mechanism called substrate reduction. While GYS1 has been a therapeutic target of interest, its attractiveness as a therapeutic target has been limited due to its structural complexity and uncertainties related to the tolerability of a long-term reduction in muscle glycogen levels. Critical insights derived from COMPASS have enabled Maze to overcome these challenges. Maze has interrogated the structurally complex protein to develop an oral inhibitor of muscle glycogen synthase, a target not previously addressable by small molecule therapies. Maze is rapidly progressing its GYS1 program toward an Investigational New Drug application and expects to initiate clinical trials in the first half of 2022.

APOL1 Program for Chronic Kidney DiseaseCKD affects approximately 37 million people in the U.S., including more than 700,000 patients who suffer from end-stage renal disease (ESRD), many of whom require chronic dialysis. Individuals of African ancestry are at an approximately 3.5-fold greater risk of developing ESRD than individuals of European ancestry. Previous studies have shown that two coding variants of the apolipoprotein L1 (APOL1) encoded by the gene APOL1 cause toxic gain-of-function variants and are important genetic drivers of kidney disease that are responsible for much of the increased risk for CKD and ESRD in individuals of African ancestry. There are currently no approved therapies that address the underlying causes of APOL1-associated CKD, and efficacious treatment options for individuals with APOL1 risk variants and CKD represent a significant unmet medical need.

Maze employed COMPASS to functionalize human genetic variants to uncover the underlying biology of the target and has designed a small molecule that corrects the effects of toxic gain-of-function variants to potentially enable a therapeutic solution. Maze plans to name the development candidate in early 2022.

ATXN2 Program for Amyotrophic Lateral SclerosisALS is a progressive and fatal neurodegenerative disease with a prevalence of approximately 16,000 patients in the U.S. Current available treatments for ALS primarily focus on providing symptomatic relief and have limited impact on disease progression. A high variability in disease phenotype and life expectancy is observed and believed to be related to the presence of genetic modifiers.

One of Mazes founders, Aaron Gitler, identified a potent genetic modifier, ATXN2, whose inhibition has been shown to limit the toxicity of a certain protein, TDP-43, which is involved in pathologic aggregates seen in up to 97% of all ALS cases. Maze is translating these important insights by developing a novel microRNA gene therapy that targets ATXN2 and has used the proprietary application of its functional genomics tools to optimize its properties. Maze plans to name the development candidate in early 2022.

About Maze TherapeuticsMaze Therapeutics is focused on translating genetic insights into new precision medicines for rare diseases and mechanistically defined subsets of common diseases. Maze has developed the COMPASS platform, a proprietary, purpose-built platform that combines human genetic data, functional genomic tools and data science technology to map novel connections between known genes and their influence on susceptibility, timing of onset and rate of disease progression. Using COMPASS, Maze is building a broad portfolio, including wholly owned programs targeting Pompe disease, chronic kidney disease and amyotrophic lateral sclerosis, as well as partnered programs in cardiovascular and ophthalmic diseases. Maze is based in South San Francisco. For more information, please visit mazetx.com, or follow us on LinkedIn.

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Maze Therapeutics Reveals Its Initial Three Lead Programs Targeting Underlying Genetic Drivers of Life-Threatening Diseases - Business Wire

The history of genetics dates from the classical era with contributions by Pythagoras, Hippocrates, Aristotle, Epicurus, and others. Modern genetics began with the work of the Augustinian friar Gregor Johann Mendel. His work on pea plants, published in 1866, established the theory of Mendelian inheritance.

The year 1900 marked the "rediscovery of Mendel" by Hugo de Vries, Carl Correns and Erich von Tschermak, and by 1915 the basic principles of Mendelian genetics had been studied in a wide variety of organisms most notably the fruit fly Drosophila melanogaster. Led by Thomas Hunt Morgan and his fellow "drosophilists", geneticists developed the Mendelian model, which was widely accepted by 1925. Alongside experimental work, mathematicians developed the statistical framework of population genetics, bringing genetic explanations into the study of evolution.

With the basic patterns of genetic inheritance established, many biologists turned to investigations of the physical nature of the gene. In the 1940s and early 1950s, experiments pointed to DNA as the portion of chromosomes (and perhaps other nucleoproteins) that held genes. A focus on new model organisms such as viruses and bacteria, along with the discovery of the double helical structure of DNA in 1953, marked the transition to the era of molecular genetics.

In the following years, chemists developed techniques for sequencing both nucleic acids and proteins, while many others worked out the relationship between these two forms of biological molecules and discovered the genetic code. The regulation of gene expression became a central issue in the 1960s; by the 1970s gene expression could be controlled and manipulated through genetic engineering. In the last decades of the 20th century, many biologists focused on large-scale genetics projects, such as sequencing entire genomes.

The most influential early theories of heredity were that of Hippocrates and Aristotle. Hippocrates' theory (possibly based on the teachings of Anaxagoras) was similar to Darwin's later ideas on pangenesis, involving heredity material that collects from throughout the body. Aristotle suggested instead that the (nonphysical) form-giving principle of an organism was transmitted through semen (which he considered to be a purified form of blood) and the mother's menstrual blood, which interacted in the womb to direct an organism's early development.[1] For both Hippocrates and Aristotleand nearly all Western scholars through to the late 19th centurythe inheritance of acquired characters was a supposedly well-established fact that any adequate theory of heredity had to explain. At the same time, individual species were taken to have a fixed essence; such inherited changes were merely superficial.[2] The Athenian philosopher Epicurus observed families and proposed the contribution of both males and females of hereditary characters ("sperm atoms"), noticed dominant and recessive types of inheritance and described segregation and independent assortment of "sperm atoms".[3]

In the Charaka Samhita of 300CE, ancient Indian medical writers saw the characteristics of the child as determined by four factors: 1) those from the mother's reproductive material, (2) those from the father's sperm, (3) those from the diet of the pregnant mother and (4) those accompanying the soul which enters into the fetus. Each of these four factors had four parts creating sixteen factors of which the karma of the parents and the soul determined which attributes predominated and thereby gave the child its characteristics.[4]

In the 9th century CE, the Afro-Arab writer Al-Jahiz considered the effects of the environment on the likelihood of an animal to survive.[5] In 1000 CE, the Arab physician, Abu al-Qasim al-Zahrawi (known as Albucasis in the West) was the first physician to describe clearly the hereditary nature of haemophilia in his Al-Tasrif.[6] In 1140 CE, Judah HaLevi described dominant and recessive genetic traits in The Kuzari.[7]

The preformation theory is a developmental biological theory, which was represented in antiquity by the Greek philosopher Anaxagoras. It reappeared in modern times in the 17th century and then prevailed until the 19th century. Another common term at that time was the theory of evolution, although "evolution" (in the sense of development as a pure growth process) had a completely different meaning than today. The preformists assumed that the entire organism was preformed in the sperm (animalkulism) or in the egg (ovism or ovulism) and only had to unfold and grow. This was contrasted by the theory of epigenesis, according to which the structures and organs of an organism only develop in the course of individual development (Ontogeny). Epigenesis had been the dominant opinion since antiquity and into the 17th century, but was then replaced by preformist ideas. Since the 19th century epigenesis was again able to establish itself as a view valid to this day.[8][9]

In the 18th century, with increased knowledge of plant and animal diversity and the accompanying increased focus on taxonomy, new ideas about heredity began to appear. Linnaeus and others (among them Joseph Gottlieb Klreuter, Carl Friedrich von Grtner, and Charles Naudin) conducted extensive experiments with hybridisation, especially hybrids between species. Species hybridizers described a wide variety of inheritance phenomena, include hybrid sterility and the high variability of back-crosses.[10]

Plant breeders were also developing an array of stable varieties in many important plant species. In the early 19th century, Augustin Sageret established the concept of dominance, recognizing that when some plant varieties are crossed, certain characteristics (present in one parent) usually appear in the offspring; he also found that some ancestral characteristics found in neither parent may appear in offspring. However, plant breeders made little attempt to establish a theoretical foundation for their work or to share their knowledge with current work of physiology,[11] although Gartons Agricultural Plant Breeders in England explained their system.[12]

Between 1856 and 1865, Gregor Mendel conducted breeding experiments using the pea plant Pisum sativum and traced the inheritance patterns of certain traits. Through these experiments, Mendel saw that the genotypes and phenotypes of the progeny were predictable and that some traits were dominant over others.[13] These patterns of Mendelian inheritance demonstrated the usefulness of applying statistics to inheritance. They also contradicted 19th-century theories of blending inheritance, showing, rather, that genes remain discrete through multiple generations of hybridization.[14]

From his statistical analysis, Mendel defined a concept that he described as a character (which in his mind holds also for "determinant of that character"). In only one sentence of his historical paper, he used the term "factors" to designate the "material creating" the character: " So far as experience goes, we find it in every case confirmed that constant progeny can only be formed when the egg cells and the fertilizing pollen are off like the character so that both are provided with the material for creating quite similar individuals, as is the case with the normal fertilization of pure species. We must, therefore, regard it as certain that exactly similar factors must be at work also in the production of the constant forms in the hybrid plants."(Mendel, 1866).

Mendel's work was published in 1866 as "Versuche ber Pflanzen-Hybriden" (Experiments on Plant Hybridization) in the Verhandlungen des Naturforschenden Vereins zu Brnn (Proceedings of the Natural History Society of Brnn), following two lectures he gave on the work in early 1865.[15]

Mendel's work was published in a relatively obscure scientific journal, and it was not given any attention in the scientific community. Instead, discussions about modes of heredity were galvanized by Darwin's theory of evolution by natural selection, in which mechanisms of non-Lamarckian heredity seemed to be required. Darwin's own theory of heredity, pangenesis, did not meet with any large degree of acceptance.[16][17] A more mathematical version of pangenesis, one which dropped much of Darwin's Lamarckian holdovers, was developed as the "biometrical" school of heredity by Darwin's cousin, Francis Galton.[18]

In 1883 August Weismann conducted experiments involving breeding mice whose tails had been surgically removed. His results that surgically removing a mouse's tail had no effect on the tail of its offspring challenged the theories of pangenesis and Lamarckism, which held that changes to an organism during its lifetime could be inherited by its descendants. Weismann proposed the germ plasm theory of inheritance, which held that hereditary information was carried only in sperm and egg cells.[19]

Hugo de Vries wondered what the nature of germ plasm might be, and in particular he wondered whether or not germ plasm was mixed like paint or whether the information was carried in discrete packets that remained unbroken. In the 1890s he was conducting breeding experiments with a variety of plant species and in 1897 he published a paper on his results that stated that each inherited trait was governed by two discrete particles of information, one from each parent, and that these particles were passed along intact to the next generation. In 1900 he was preparing another paper on his further results when he was shown a copy of Mendel's 1866 paper by a friend who thought it might be relevant to de Vries's work. He went ahead and published his 1900 paper without mentioning Mendel's priority. Later that same year another botanist, Carl Correns, who had been conducting hybridization experiments with maize and peas, was searching the literature for related experiments prior to publishing his own results when he came across Mendel's paper, which had results similar to his own. Correns accused de Vries of appropriating terminology from Mendel's paper without crediting him or recognizing his priority. At the same time another botanist, Erich von Tschermak was experimenting with pea breeding and producing results like Mendel's. He too discovered Mendel's paper while searching the literature for relevant work. In a subsequent paper de Vries praised Mendel and acknowledged that he had only extended his earlier work.[19]

After the rediscovery of Mendel's work there was a feud between William Bateson and Pearson over the hereditary mechanism, solved by Ronald Fisher in his work "The Correlation Between Relatives on the Supposition of Mendelian Inheritance".

In 1910, Thomas Hunt Morgan showed that genes reside on specific chromosomes. He later showed that genes occupy specific locations on the chromosome. With this knowledge, Alfred Sturtevant, a member of Morgan's famous fly room, using Drosophila melanogaster, provided the first chromosomal map of any biological organism. In 1928, Frederick Griffith showed that genes could be transferred. In what is now known as Griffith's experiment, injections into a mouse of a deadly strain of bacteria that had been heat-killed transferred genetic information to a safe strain of the same bacteria, killing the mouse.

A series of subsequent discoveries led to the realization decades later that the genetic material is made of DNA (deoxyribonucleic acid) and not, as was widely believed until then, of proteins. In 1941, George Wells Beadle and Edward Lawrie Tatum showed that mutations in genes caused errors in specific steps of metabolic pathways. This showed that specific genes code for specific proteins, leading to the "one gene, one enzyme" hypothesis.[20] Oswald Avery, Colin Munro MacLeod, and Maclyn McCarty showed in 1944 that DNA holds the gene's information.[21] In 1952, Rosalind Franklin and Raymond Gosling produced a strikingly clear x-ray diffraction pattern indicating a helical form. Using these x-rays and information already known about the chemistry of DNA, James D. Watson and Francis Crick demonstrated the molecular structure of DNA in 1953.[22] Together, these discoveries established the central dogma of molecular biology, which states that proteins are translated from RNA which is transcribed by DNA. This dogma has since been shown to have exceptions, such as reverse transcription in retroviruses.

In 1972, Walter Fiers and his team at the University of Ghent were the first to determine the sequence of a gene: the gene for bacteriophage MS2 coat protein.[23] Richard J. Roberts and Phillip Sharp discovered in 1977 that genes can be split into segments. This led to the idea that one gene can make several proteins. The successful sequencing of many organisms' genomes has complicated the molecular definition of the gene. In particular, genes do not always sit side by side on DNA like discrete beads. Instead, regions of the DNA producing distinct proteins may overlap, so that the idea emerges that "genes are one long continuum".[24][25] It was first hypothesized in 1986 by Walter Gilbert that neither DNA nor protein would be required in such a primitive system as that of a very early stage of the earth if RNA could serve both as a catalyst and as genetic information storage processor.

The modern study of genetics at the level of DNA is known as molecular genetics and the synthesis of molecular genetics with traditional Darwinian evolution is known as the modern evolutionary synthesis.

See the article here:
History of genetics - Wikipedia

Background: An identical homozygous missense variant in EIF3F, identified through a large-scale genome-wide sequencing approach, was reported as causative in nine individuals with a neurodevelopmental disorder, characterized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phenotypic and molecular spectrum of EIF3F-related neurodevelopmental disorder, we examined independent patients.

Results: 21 patients were homozygous and one compound heterozygous for c.694T>G/p.(Phe232Val) in EIF3F. Haplotype analyses in 15 families suggested that c.694T>G/p.(Phe232Val) was a founder variant. All affected individuals had developmental delays including delayed speech development. About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature. Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum. Minor dysmorphic features were observed, although neither the individuals' facial nor general appearance were obviously distinctive. Symptoms in the compound heterozygous individual with an additional truncating variant were at the severe end of the spectrum in regard to motor milestones, speech delay, organic problems and pre- and postnatal growth of body and head, suggesting some genotype-phenotype correlation.

Conclusions: Our study refines the phenotypic and expands the molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.

Keywords: Altered muscular tone; Behavioral difficulties; Deafness; EIF3F gene; Neurodevelopmental disorder; Short stature.

Link:
EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum - NCBI